Tumour Cell Size Control and Its Impact on Tumour Cell Function

Abstract

Cell size is an important component of cell morphological characteristics. It reflects the characteristics of the cell type, nutritional status, growth stage and physiological function. The cell size of cells of the same type tends to be homogeneous and stable. However, in tumour cells, mutations in cell cycle genes and cytoskeletal genes and overexpression of the corresponding signalling pathways often lead to large variations in tumour cell size. Tumour cells regulate cell size and growth and proliferation through multiple signalling pathways, such as PI3K/Akt/mTOR, Myc and Hippo pathways, which work together to regulate cell size and proliferation. This allows tumour cells to adapt to different survival environments. Alterations in cell size also cause tumours to perform different functions, leading to alterations in tumour stemness, invasive migration and anti-tumour immunity by affecting immune cells in the tumour immune microenvironment. In this review, we describe the endogenous and exogenous factors affecting tumour cell size, analyse the mechanisms by which tumour cells regulate cell size and the effects of cell size on tumour malignancy and tumour immunity, summarise the potential therapeutic targets for cell size, and look forward to possible future research directions and clinical applications.

Keywords

anti-cancer immunity / cancer cell size / cancer metastasis / cancer stem cells / cell cycle / cell size / EMT / mTOR / tumour microenvironment

References

[1] N. Rind, “Cell-Size Control,” Current Biology 31, no. 21 (2021): R1414–R1420.

[2] M. C. Lanz, E. Zatulovskiy, M. P. Swaffer, et al., “Increasing Cell Size Remodels the Proteome and Promotes Senescence,” Molecular Cell 82, no. 17 (2022): 3255–3269.e8.

[3] I. A. Hatton, E. D. Galbraith, N. S. C. Merleau, T. P. Miettinen, B. M. Smith, and J. A. Shander, “The Human Cell Count and Size Distribution,” Proceedings of the National Academy of Sciences of the United States of America 120, no. 39 (2023): e2303077120.

[4] L. Kim, S. J. Choi, I. S. Park, J. Y. Han, J. M. Kim, and Y. C. Chu, “Cytomorphologic Features of Small Cell Carcinoma of Lung in Effusion Fluid Using a Liquid-Based Cytology Technique,” Diagnostic Cytopathology 48, no. 3 (2020): 203–210.

[5] J. A. Ferry, “Burkitt's Lymphoma: Clinicopathologic Features and Differential Diagnosis,” Oncologist 11, no. 4 (2006): 375–383.

[6] D. Arciuolo, A. Travaglino, A. Raffone, et al., “Endometrial Giant Cell Carcinoma: New Insights From a Morphological, Immunohistochemical, and Molecular Analysis of Three Cases,” Virchows Archiv 481, no. 2 (2022): 321–326.

[7] F. Portugal-Gaspar, A. Lopez-Beltran, G. P. Paner, et al., “Giant Cell Carcinoma of the Urinary Bladder: Clinicopathologic Analysis and Oncological Outcomes,” Virchows Archiv 485, no. 3 (2024): 535–546.

[8] A. Agaimy, “Pleomorphic (Giant Cell) Carcinoma Revisited: A Historical Perspective and Conceptual Reappraisal,” Seminars in Diagnostic Pathology 38, no. 6 (2021): 187–192.

[9] A. Michelucci, L. Sforna, A. Di Battista, F. Franciolini, and L. Catacuzzeno, “Ca2+ −Activated K+ Channels Regulate Cell Volume in Human Glioblastoma Cells,” Journal of Cellular Physiology 238, no. 9 (2023): 2120–2134, https://doi.org/10.1002/jcp.31072.

[10] S. Son, J. H. Kang, S. Oh, M. W. Kirschner, T. J. Mitchison, and S. Manalis, “Resonant Microchannel Volume and Mass Measurements Show That Suspended Cells Swell During Mitosis,” Journal of Cell Biology 211, no. 4 (2015): 757–763.

[11] E. Zlotek-Zlotkiewicz, S. Monnier, G. Cappello, M. Le Berre, and M. Piel, “Optical Volume and Mass Measurements Show That Mammalian Cells Swell During Mitosis,” Journal of Cell Biology 211, no. 4 (2015): 765–774.

[12] G. Salbreux, G. Charras, and E. Paluch, “Actin Cortex Mechanics and Cellular Morphogenesis,” Trends in Cell Biology 22, no. 10 (2012): 536–545.

[13] C. M. Bielski, A. Zehir, A. V. Penson, et al., “Genome Doubling Shapes the Evolution and Prognosis of Advanced Cancers,” Nature Genetics 50, no. 8 (2018): 1189–1195.

[14] X. Li, Y. Zhong, X. Zhang, A. K. Sood, and J. Liu, “Spatiotemporal View of Malignant Histogenesis and Macroevolution via Formation of Polyploid Giant Cancer Cells,” Oncogene 42, no. 9 (2023): 665–678.

[15] G. E. Neurohr, R. L. Terry, J. Lengefeld, et al., “Excessive Cell Growth Causes Cytoplasm Dilution and Contributes to Senescence,” Cell 176, no. 5 (2019): 1083–1097.e18.

[16] S. Manohar, M. E. Estrada, F. Uliana, et al., “Genome Homeostasis Defects Drive Enlarged Cells Into Senescence,” Molecular Cell 83, no. 22 (2023): 4032–4046.e6.

[17] H. S. Choi and K. H. Baek, “Pro-Apoptotic and Anti-Apoptotic Regulation Mediated by Deubiquitinating Enzymes,” Cellular and Molecular Life Sciences 79, no. 2 (2022): 117.

[18] S. Elmore, “Apoptosis: A Review of Programmed Cell Death,” Toxicologic Pathology 35, no. 4 (2007): 495–516.

[19] A. Recasens and L. Munoz, “Targeting Cancer Cell Dormancy,” Trends in Pharmacological Sciences 40, no. 2 (2019): 128–141.

[20] C. L. Chaffer, N. D. Marjanovic, T. Lee, et al., “Poised Chromatin at the ZEB1 Promoter Enables Breast Cancer Cell Plasticity and Enhances Tumorigenicity,” Cell 154, no. 1 (2013): 61–74.

[21] X. Yang, X. Liang, M. Zheng, and Y. Tang, “Cellular Phenotype Plasticity in Cancer Dormancy and Metastasis,” Frontiers in Oncology 8 (2018): 505.

[22] G. Gomatou, N. Syrigos, I. A. Vathiotis, and E. A. Kotteas, “Tumor Dormancy: Implications for Invasion and Metastasis,” International Journal of Molecular Sciences 22, no. 9 (2021): 4862.

[23] M. Tufail, C. H. Jiang, and N. Li, “Tumor Dormancy and Relapse: Understanding the Molecular Mechanisms of Cancer Recurrence,” Military Medical Research 12, no. 1 (2025): 7.

[24] T. Matsuoka and M. Tavassoli, “Electron Microscopic Identification of Hemopoietic Progenitor Cells by Exploiting Their Sugar-Recognizing Receptors Using a Newly Developed Minibead Technique,” Experimental Hematology 17, no. 4 (1989): 326–329.

[25] Q. Li, K. Rycaj, X. Chen, and D. G. Tang, “Cancer Stem Cells and Cell Size: A Causal Link?,” Seminars in Cancer Biology 35 (2015): 191–199.

[26] B. Corradetti, A. Lange-Consiglio, M. Barucca, F. Cremonesi, and D. Bizzaro, “Size-Sieved Subpopulations of Mesenchymal Stem Cells From Intervascular and Perivascular Equine Umbilical Cord Matrix,” Cell Proliferation 44, no. 4 (2011): 330–342.

[27] X. Liu, S. Oh, L. Peshkin, and M. W. Kirschner, “Computationally Enhanced Quantitative Phase Microscopy Reveals Autonomous Oscillations in Mammalian Cell Growth,” Proceedings of the National Academy of Sciences of the United States of America 117, no. 44 (2020): 27388–27399.

[28] S. Oh, C. Lee, W. Yang, et al., “Protein and Lipid Mass Concentration Measurement in Tissues by Stimulated Raman Scattering Microscopy,” Proceedings of the National Academy of Sciences of the United States of America 119, no. 17 (2022): e2117938119.

[29] M. Godin, F. F. Delgado, S. Son, et al., “Using Buoyant Mass to Measure the Growth of Single Cells,” Nature Methods 7, no. 5 (2010): 387–390.

[30] S. Son, A. Tzur, Y. Weng, et al., “Direct Observation of Mammalian Cell Growth and Size Regulation,” Nature Methods 9, no. 9 (2012): 910–912.

[31] C. Cadart, E. Zlotek-Zlotkiewicz, L. Venkova, et al., “Fluorescence eXclusion Measurement of Volume in Live Cells,” Methods in Cell Biology 139 (2017): 103–120.

[32] A. Sakaue-Sawano, H. Kurokawa, T. Morimura, et al., “Visualizing Spatiotemporal Dynamics of Multicellular Cell-Cycle Progression,” Cell 132, no. 3 (2008): 487–498.

[33] E. Zatulovskiy and J. M. Skotheim, “On the Molecular Mechanisms Regulating Animal Cell Size Homeostasis,” Trends in Genetics 36, no. 5 (2020): 360–372.

[34] T. P. Miettinen, H. K. Pessa, M. J. Caldez, et al., “Identification of Transcriptional and Metabolic Programs Related to Mammalian Cell Size,” Current Biology 24, no. 6 (2014): 598–608.

[35] A. P. Pérez, M. H. Artés, D. F. Moreno, J. Clotet, and M. Aldea, “Mad3 Modulates the G1 Cdk and Acts as a Timer in the Start Network,” Science Advances 8, no. 18 (2022): eabm4086.

[36] M. B. Ginzberg, N. Chang, H. D'Souza, N. Patel, R. Kafri, and M. W. Kirschner, “Cell Size Sensing in Animal Cells Coordinates Anabolic Growth Rates and Cell Cycle Progression to Maintain Cell Size Uniformity,” eLife 7 (2018): e26957.

[37] I. Soifer, L. Robert, and A. Amir, “Single-Cell Analysis of Growth in Budding Yeast and Bacteria Reveals a Common Size Regulation Strategy,” Current Biology 26, no. 3 (2016): 356–361.

[38] M. C. Lanz, S. Zhang, M. P. Swaffer, et al., “Genome Dilution by Cell Growth Drives Starvation-Like Proteome Remodeling in Mammalian and Yeast Cells,” Nature Structural & Molecular Biology 31, no. 12 (2024): 1859–1871.

[39] C. Cadart, S. Monnier, J. Grilli, et al., “Size Control in Mammalian Cells Involves Modulation of Both Growth Rate and Cell Cycle Duration,” Nature Communications 9, no. 1 (2018): 3275.

[40] C. Cadart, L. Venkova, M. Piel, and M. Cosentino Lagomarsino, “Volume Growth in Animal Cells Is Cell Cycle Dependent and Shows Additive Fluctuations,” eLife 11 (2022): e70816.

[41] D. Martínez-Alonso and M. Malumbres, “Mammalian Cell Cycle Cyclins,” Seminars in Cell & Developmental Biology 107 (2020): 28–35.

[42] W. Stallaert, S. R. Taylor, K. M. Kedziora, et al., “The Molecular Architecture of Cell Cycle Arrest,” Molecular Systems Biology 18, no. 9 (2022): e11087.

[43] M. Malumbres and M. Barbacid, “Cell Cycle, CDKs and Cancer: A Changing Paradigm,” Nature Reviews. Cancer 9, no. 3 (2009): 153–166.

[44] S. Goel, M. J. DeCristo, S. S. McAllister, and J. J. Zhao, “CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest,” Trends in Cell Biology 28, no. 11 (2018): 911–925.

[45] N. B. La Thangue and P. W. Rigby, “An Adenovirus E1A-Like Transcription Factor Is Regulated During the Differentiation of Murine Embryonal Carcinoma Stem Cells,” Cell 49, no. 4 (1987): 507–513.

[46] L. N. Kent and G. Leone, “The Broken Cycle: E2F Dysfunction in Cancer,” Nature Reviews. Cancer 19, no. 6 (2019): 326–338.

[47] D. Chen, Y. Li, Y. Mei, et al., “miR-34a Regulates Mesangial Cell Proliferation via the PDGFR-β/Ras-MAPK Signaling Pathway,” Cellular and Molecular Life Sciences 71, no. 20 (2014): 4027–4042.

[48] Q. Wang, S. Wu, Y. Gu, et al., “RASAL2 Regulates the Cell Cycle and Cyclin D1 Expression Through PI3K/AKT Signalling in Prostate Tumorigenesis,” Cell Death Discovery 8, no. 1 (2022): 275.

[49] M. Fang, H. K. Wu, Y. Pei, et al., “E3 ligase MG53 suppresses tumor growth by degrading cyclin D1,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 263.

[50] B. Zhang, Y. L. Li, J. L. Zhao, et al., “Hypoxia-Inducible Factor-1 Promotes Cancer Progression Through Activating AKT/Cyclin D1 Signaling Pathway in Osteosarcoma,” Biomedicine & Pharmacotherapy 105 (2018): 1–9.

[51] L. Zuo, Y. Zhu, L. Hu, et al., “PI3-Kinase/Akt Pathway-Regulated Membrane Transportation of Acid-Sensing Ion Channel 1a/Calcium Ion Influx/Endoplasmic Reticulum Stress Activation on PDGF-Induced HSC Activation,” Journal of Cellular and Molecular Medicine 23, no. 6 (2019): 3940–3950.

[52] S. Y. Wu, S. H. Lan, S. R. Wu, et al., “Hepatocellular Carcinoma-Related Cyclin D1 Is Selectively Regulated by Autophagy Degradation System,” Hepatology 68, no. 1 (2018): 141–154.

[53] M. C. Casimiro, G. Di Sante, A. Di Rocco, et al., “Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis,” Cancer Research 77, no. 13 (2017): 3391–3405.

[54] A. B. Gladden and J. A. Diehl, “Cell Cycle Progression Without Cyclin E/CDK2: Breaking Down the Walls of Dogma,” Cancer Cell 4, no. 3 (2003): 160–162.

[55] G. He, J. Kuang, Z. Huang, et al., “Upregulation of p27 and Its Inhibition of CDK2/Cyclin E Activity Following DNA Damage by a Novel Platinum Agent Are Dependent on the Expression of p21,” British Journal of Cancer 95, no. 11 (2006): 1514–1524.

[56] H. Hochegger, S. Takeda, and T. Hunt, “Cyclin-Dependent Kinases and Cell-Cycle Transitions: Does One Fit all?,” Nature Reviews. Molecular Cell Biology 9, no. 11 (2008): 910–916.

[57] K. Clemm von Hohenberg, S. Müller, S. Schleich, et al., “Cyclin B/CDK1 and Cyclin A/CDK2 Phosphorylate DENR to Promote Mitotic Protein Translation and Faithful Cell Division,” Nature Communications 13, no. 1 (2022): 668.

[58] J. Feng, L. Xie, W. Lu, et al., “Hyperactivation of p53 Contributes to Mitotic Catastrophe in Podocytes Through Regulation of the Wee1/CDK1/Cyclin B1 Axis,” Renal Failure 46, no. 2 (2024): 2365408.

[59] D. Hiraoka, E. Hosoda, K. Chiba, and T. Kishimoto, “SGK Phosphorylates Cdc25 and Myt1 to Trigger Cyclin B-Cdk1 Activation at the Meiotic G2/M Transition,” J Cell Biology 218, no. 11 (2019): 3597–3611.

[60] N. Palmer and P. Kaldis, “Less-Well Known Functions of Cyclin/CDK Complexes,” Seminars in Cell & Developmental Biology 107 (2020): 54–62.

[61] S. Shuai, X. Yan, J. Zhang, et al., “TIP30 Nuclear Translocation Negatively Regulates EGF-Dependent Cyclin D1 Transcription in Human Lung Adenocarcinoma,” Cancer Letters 354, no. 1 (2014): 200–209.

[62] W. Sun, J. Cheng, R. Zhao, et al., “Ku70 Targets BRD3-MYC/Cyclin D1 Axis to Drive Hepatocellular Carcinoma Progression,” Experimental Cell Research 444, no. 2 (2025): 114404.

[63] X. Tang, T. P. W. McMullen, and D. N. Brindley, “Increasing the Low Lipid Phosphate Phosphatase 1 Activity in Breast Cancer Cells Decreases Transcription by AP-1 and Expressions of Matrix Metalloproteinases and Cyclin D1/D3,” Theranostics 9, no. 21 (2019): 6129–6142.

[64] Z. Cai, J. Wang, Y. Li, et al., “Overexpressed Cyclin D1 and CDK4 Proteins Are Responsible for the Resistance to CDK4/6 Inhibitor in Breast Cancer That Can Be Reversed by PI3K/mTOR Inhibitors,” Science China. Life Sciences 66, no. 1 (2023): 94–109.

[65] L. Tuo, J. Xiang, X. Pan, et al., “PCK1 Negatively Regulates Cell Cycle Progression and Hepatoma Cell Proliferation via the AMPK/p27Kip1 Axis,” Journal of Experimental & Clinical Cancer Research 38, no. 1 (2019): 50.

[66] C. Zhang, F. Zhou, J. Zou, et al., “Clinical Considerations of CDK4/6 Inhibitors in HER2 Positive Breast Cancer,” Frontiers in Oncology 13 (2024): 1322078.

[67] C. Liu, Y. Konagaya, M. Chung, et al., “Altered G1 Signaling Order and Commitment Point in Cells Proliferating Without CDK4/6 Activity,” Nature Communications 11, no. 1 (2020): 5305.

[68] Z. Y. Ding, G. N. Jin, W. Wang, et al., “Reduced Expression of Transcriptional Intermediary Factor 1 Gamma Promotes Metastasis and Indicates Poor Prognosis of Hepatocellular Carcinoma,” Hepatology 60, no. 5 (2014): 1620–1636.

[69] H. Ungefroren, “PDCD10/CCM3, a potential target for pancreatic ductal adenocarcinoma?,” Clinical Science (London) 139, no. 3 (2025): CS20241916.

[70] S. Poulet, M. Dai, N. Wang, et al., “Genome-Wide In Vivo CRISPR Screen Identifies TGFβ3 as Actionable Biomarker of Palbociclib Resistance in Triple Negative Breast Cancer,” Molecular Cancer 23, no. 1 (2024): 118.

[71] I. Pellarin, A. Dall'Acqua, A. Favero, et al., “Cyclin-Dependent Protein Kinases and Cell Cycle Regulation in Biology and Disease,” Signal Transduction and Targeted Therapy 10, no. 1 (2025): 11.

[72] K. Engeland, “Cell cycle regulation: p53-p21-RB signaling,” Cell Death and Differentiation 29, no. 5 (2022): 946–960.

[73] M. D. Belew, J. Chen, and Z. Cheng, “Emerging Roles of Cyclin-Dependent Kinase 7 in Health and Diseases,” Trends in Molecular Medicine 31, no. 2 (2025): 138–151.

[74] E. Zatulovskiy, S. Zhang, D. F. Berenson, B. R. Topacio, and J. M. Skotheim, “Cell Growth Dilutes the Cell Cycle Inhibitor Rb to Trigger Cell Division,” Science 369, no. 6502 (2020): 466–471.

[75] H. Li, X. Han, S. Yang, Y. Wang, Y. Dong, and T. Tang, “FOXP1 Drives Osteosarcoma Development by Repressing P21 and RB Transcription Downstream of P53,” Oncogene 40, no. 15 (2021): 2785–2802.

[76] C. A. Febres-Aldana, J. C. Chang, R. Ptashkin, et al., “Rb Tumor Suppressor in Small Cell Lung Cancer: Combined Genomic and IHC Analysis With a Description of a Distinct Rb-Proficient Subset,” Clinical Cancer Research 28, no. 21 (2022): 4702–4713.

[77] C. C. Lin, T. C. Chang, Y. Wang, et al., “PRMT5 Is an Actionable Therapeutic Target in CDK4/6 Inhibitor-Resistant ER+/RB-Deficient Breast Cancer,” Nature Communications 15, no. 1 (2024): 2287.

[78] X. Jin, D. Ding, Y. Yan, et al., “Phosphorylated RB Promotes Cancer Immunity by Inhibiting NF-κB Activation and PD-L1 Expression,” Molecular Cell 73, no. 1 (2019): 22–35.e6.

[79] A. H. Cavanaugh, W. M. Hempel, L. J. Taylor, V. Rogalsky, G. Todorov, and L. I. Rothblum, “Activity of RNA Polymerase I Transcription Factor UBF Blocked by Rb Gene Product,” Nature 374, no. 6518 (1995): 177–180.

[80] D. G. Johnson, J. K. Schwarz, W. D. Cress, and J. R. Nevins, “Expression of Transcription Factor E2F1 Induces Quiescent Cells to Enter S Phase,” Nature 365, no. 6444 (1993): 349–352.

[81] E. Calo, J. A. Quintero-Estades, P. S. Danielian, S. Nedelcu, S. D. Berman, and J. A. Lees, “Rb Regulates Fate Choice and Lineage Commitment In Vivo,” Nature 466, no. 7310 (2010): 1110–1114.

[82] A. Carnero, C. Blanco-Aparicio, O. Renner, W. Link, and J. F. Leal, “The PTEN/PI3K/AKT Signalling Pathway in Cancer, Therapeutic Implications,” Current Cancer Drug Targets 8, no. 3 (2008): 187–198.

[83] T. R. Donahue, L. M. Tran, R. Hill, et al., “Integrative Survival-Based Molecular Profiling of Human Pancreatic Cancer,” Clinical Cancer Research 18, no. 5 (2012): 1352–1363.

[84] C. Y. Chen, J. Chen, L. He, and B. L. Stiles, “PTEN: Tumor Suppressor and Metabolic Regulator,” Frontiers in Endocrinology (Lausanne) 9 (2018): 338.

[85] S. Revathidevi and A. K. Munirajan, “Akt in Cancer: Mediator and More,” Seminars in Cancer Biology 59 (2019): 80–91.

[86] S. R. Datta, A. Brunet, and M. E. Greenberg, “Cellular Survival: A Play in Three Akts,” Genes & Development 13, no. 22 (1999): 2905–2927.

[87] D. H. Kim, D. D. Sarbassov, S. M. Ali, et al., “mTOR Interacts With Raptor to Form a Nutrient-Sensitive Complex That Signals to the Cell Growth Machinery,” Cell 110, no. 2 (2002): 163–175.

[88] D. Mossmann, S. Park, and M. N. Hall, “mTOR Signalling and Cellular Metabolism Are Mutual Determinants in Cancer,” Nature Reviews. Cancer 18, no. 12 (2018): 744–757.

[89] K. Inoki, Y. Li, T. Zhu, J. Wu, and K. L. Guan, “TSC2 Is Phosphorylated and Inhibited by Akt and Suppresses mTOR Signalling,” Nature Cell Biology 4, no. 9 (2002): 648–657.

[90] S. Wang, R. Ma, C. Gao, et al., “Unraveling the Function of TSC1-TSC2 Complex: Implications for Stem Cell Fate,” Stem Cell Research & Therapy 16, no. 1 (2025): 38.

[91] S. Zhang, X. Lin, Q. Hou, Z. Hu, Y. Wang, and Z. Wang, “Regulation of mTORC1 by Amino Acids in Mammalian Cells: A General Picture of Recent Advances,” Animal Nutrition 7, no. 4 (2021): 1009–1023.

[92] A. Glaviano, A. S. C. Foo, H. Y. Lam, et al., “PI3K/AKT/mTOR Signaling Transduction Pathway and Targeted Therapies in Cancer,” Molecular Cancer 22, no. 1 (2023): 138.

[93] S. Li, J. S. Chen, X. Li, X. Bai, and D. Shi, “MNK, mTOR or eIF4E-Selecting the Best Anti-Tumor Target for Blocking Translation Initiation,” European Journal of Medicinal Chemistry 260 (2023): 115781.

[94] V. Panwar, A. Singh, M. Bhatt, et al., “Multifaceted Role of mTOR (Mammalian Target of Rapamycin) Signaling Pathway in Human Health and Disease,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 375.

[95] F. Su and A. Koeberle, “Regulation and Targeting of SREBP-1 in Hepatocellular Carcinoma,” Cancer Metastasis Reviews 43, no. 2 (2024): 673–708.

[96] G. N. Masoud and W. Li, “HIF-1α Pathway: Role, Regulation and Intervention for Cancer Therapy,” Acta Pharmaceutica Sinica B 5, no. 5 (2015): 378–389.

[97] Y. Feng, Y. Chen, X. Wu, et al., “Interplay of Energy Metabolism and Autophagy,” Autophagy 20, no. 1 (2024): 4–14.

[98] G. Xu, Q. Zhang, R. Cheng, J. Qu, and W. Li, “Survival Strategies of Cancer Cells: The Role of Macropinocytosis in Nutrient Acquisition, Metabolic Reprogramming, and Therapeutic Targeting,” Autophagy 21 (2025): 693–718.

[99] S. Tesseraud, P. Avril, M. Bonnet, et al., “Autophagy in Farm Animals: Current Knowledge and Future Challenges,” Autophagy 17, no. 8 (2021): 1809–1827.

[100] A. Sato, N. I. A. Rahman, A. Shimizu, and H. Ogita, “Cell-To-Cell Contact-Mediated Regulation of Tumor Behavior in the Tumor Microenvironment,” Cancer Science 112, no. 10 (2021): 4005–4012.

[101] K. F. Harvey, X. Zhang, and D. M. Thomas, “The Hippo Pathway and Human Cancer,” Nature Reviews. Cancer 13, no. 4 (2013): 246–257.

[102] Y. Kwon, A. Vinayagam, X. Sun, et al., “The Hippo Signaling Pathway Interactome,” Science 342, no. 6159 (2013): 737–740.

[103] S. Ma, Z. Meng, R. Chen, and K. L. Guan, “The Hippo Pathway: Biology and Pathophysiology,” Annual Review of Biochemistry 88 (2019): 577–604.

[104] N. A. Perez-Gonzalez, N. D. Rochman, K. Yao, et al., “YAP and TAZ regulate cell volume,” Journal of Cell Biology 218, no. 10 (2019): 3472–3488.

[105] B. Zhao, X. Wei, W. Li, et al., “Inactivation of YAP Oncoprotein by the Hippo Pathway Is Involved in Cell Contact Inhibition and Tissue Growth Control,” Genes & Development 21, no. 21 (2007): 2747–2761.

[106] L. Müller and M. Hatzfeld, “Emerging Functions of Plakophilin 4 in the Control of Cell Contact Dynamics,” Cell Communication and Signaling: CCS 23, no. 1 (2025): 109.

[107] S. Li, L. Hao, N. Li, et al., “Targeting the Hippo/YAP1 Signaling Pathway in Hepatocellular Carcinoma: From Mechanisms to Therapeutic Drugs (Review),” International Journal of Oncology 65, no. 3 (2024): 88.

[108] H. Yang, J. Yang, X. Zheng, et al., “The Hippo Pathway in Breast Cancer: The Extracellular Matrix and Hypoxia,” International Journal of Molecular Sciences 25, no. 23 (2024): 12868.

[109] F. Zhang, B. Huang, Y. Xu, et al., “MISP Suppresses Ferroptosis via MST1/2 Kinases to Facilitate YAP Activation in Non-Small Cell Lung Cancer,” Advanced Science 12 (2025): e2415814.

[110] E. H. Ervin, R. French, C. H. Chang, and S. Pauklin, “Inside the Stemness Engine: Mechanistic Links Between Deregulated Transcription Factors and Stemness in Cancer,” Seminars in Cancer Biology 87 (2022): 48–83.

[111] M. J. Perugorria, P. Olaizola, I. Labiano, et al., “Wnt-β-Catenin Signalling in Liver Development, Health and Disease,” Nature Reviews. Gastroenterology & Hepatology 16, no. 2 (2019): 121–136.

[112] H. Saeed, B. J. Leibowitz, L. Zhang, and J. Yu, “Targeting Myc-Driven Stress Addiction in Colorectal Cancer,” Drug Resistance Updates 69 (2023): 100963.

[113] E. V. Prochownik and H. Wang, “Normal and Neoplastic Growth Suppression by the Extended Myc Network,” Cells 11, no. 4 (2022): 747.

[114] M. J. Duffy, S. O'Grady, M. Tang, and J. Crown, “MYC as a Target for Cancer Treatment,” Cancer Treatment Reviews 94 (2021): 102154.

[115] M. Zajac-Kaye, “Myc Oncogene: A Key Component in Cell Cycle Regulation and Its Implication for Lung Cancer,” Lung Cancer 34, no. suppl 2 (2001): S43–S46.

[116] D. Papadopoulos, S. A. Ha, D. Fleischhauer, et al., “The MYCN Oncoprotein Is an RNA-Binding Accessory Factor of the Nuclear Exosome Targeting Complex,” Molecular Cell 84, no. 11 (2024): 2070–2086.e20.

[117] M. W. Gramling and C. M. Eischen, “Suppression of Ras/Mapk Pathway Signaling Inhibits Myc-Induced Lymphomagenesis,” Cell Death and Differentiation 19, no. 7 (2012): 1220–1227.

[118] F. Fontana, G. Giannitti, S. Marchesi, and P. Limonta, “The PI3K/Akt Pathway and Glucose Metabolism: A Dangerous Liaison in Cancer,” International Journal of Biological Sciences 20, no. 8 (2024): 3113–3125.

[119] L. Yang, P. Shi, G. Zhao, et al., “Targeting Cancer Stem Cell Pathways for Cancer Therapy,” Signal Transduction and Targeted Therapy 5, no. 1 (2020): 8.

[120] L. Bakiri, S. C. Hasenfuss, A. Guío-Carrión, M. K. Thomsen, P. Hasselblatt, and E. F. Wagner, “Liver Cancer Development Driven by the AP-1/c-Jun~Fra-2 Dimer Through c-Myc,” Proceedings of the National Academy of Sciences of the United States of America 121, no. 18 (2024): e2404188121.

[121] S. Suo, D. Zhao, F. Li, et al., “Homoharringtonine Inhibits the NOTCH/MYC Pathway and Exhibits Antitumor Effects in T-Cell Acute Lymphoblastic Leukemia,” Blood 144, no. 12 (2024): 1343–1347.

[122] L. K. Hilton, B. Collinge, S. Ben-Neriah, et al., “Motive and Opportunity: MYC Rearrangements in High-Grade B-Cell Lymphoma With MYC and BCL2 Rearrangements (An LLMPP Study),” Blood 144, no. 5 (2024): 525–540.

[123] Y. Fang, Z. Y. Shen, Y. Z. Zhan, et al., “CD36 Inhibits β-Catenin/c-Myc-Mediated Glycolysis Through Ubiquitination of GPC4 to Repress Colorectal Tumorigenesis,” Nature Communications 10, no. 1 (2019): 3981.

[124] T. Qu, C. Zhang, X. Lu, et al., “8q24 Derived ZNF252P Promotes Tumorigenesis by Driving Phase Separation to Activate c-Myc Mediated Feedback Loop,” Nature Communications 16, no. 1 (2025): 1986.

[125] P. Pouryazdanparast, A. Brenner, Z. Haghighat, J. Guitart, A. Rademaker, and P. Gerami, “The Role of 8q24 Copy Number Gains and c-MYC Expression in Amelanotic Cutaneous Melanoma,” Modern Pathology 25, no. 9 (2012): 1221–1226.

[126] P. Ioannidis, L. Mahaira, A. Papadopoulou, et al., “8q24 Copy Number Gains and Expression of the c-Myc mRNA Stabilizing Protein CRD-BP in Primary Breast Carcinomas,” International Journal of Cancer 104, no. 1 (2003): 54–59.

[127] J. R. P. Knight, C. Alexandrou, G. L. Skalka, et al., “MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression,” Cancer Discovery 11, no. 5 (2021): 1228–1247.

[128] Z. Jing, Q. Liu, X. He, et al., “NCAPD3 Enhances Warburg Effect Through c-Myc and E2F1 and Promotes the Occurrence and Progression of Colorectal Cancer,” Journal of Experimental & Clinical Cancer Research 41, no. 1 (2022): 198.

[129] P. Ren, M. Yue, D. Xiao, et al., “ATF4 and N-Myc Coordinate Glutamine Metabolism in MYCN-Amplified Neuroblastoma Cells Through ASCT2 Activation,” Journal of Pathology 235, no. 1 (2015): 90–100.

[130] J. H. Liang, W. T. Wang, R. Wang, et al., “PRMT5 Activates Lipid Metabolic Reprogramming via MYC Contributing to the Growth and Survival of Mantle Cell Lymphoma,” Cancer Letters 591 (2024): 216877.

[131] R. Ferrarotto, Y. Mitani, D. J. McGrail, et al., “Proteogenomic Analysis of Salivary Adenoid Cystic Carcinomas Defines Molecular Subtypes and Identifies Therapeutic Targets,” Clinical Cancer Research 27, no. 3 (2021): 852–864.

[132] J. van Riggelen, A. Yetil, and D. W. Felsher, “MYC as a Regulator of Ribosome Biogenesis and Protein Synthesis,” Nature Reviews. Cancer 10, no. 4 (2010): 301–309.

[133] M. Schaechter, O. Maaloe, and N. Kjeldgaard, “Dependency on Medium and Temperature of Cell Size and Chemical Composition During Balanced Grown of Salmonella typhimurium,” Journal of General Microbiology 19, no. 3 (1958): 592–606.

[134] A. González and M. N. Hall, “Nutrient Sensing and TOR Signaling in Yeast and Mammals,” EMBO Journal 36, no. 4 (2017): 397–408.

[135] R. Loewith and M. N. Hall, “Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control,” Genetics 189, no. 4 (2011): 1177–1201.

[136] D. R. Kellogg and P. A. Levin, “Nutrient Availability as an Arbiter of Cell Size,” Trends in Cell Biology 32, no. 11 (2022): 908–919.

[137] F. Kallinowski, P. Vaupel, S. Runkel, et al., “Glucose Uptake, Lactate Release, Ketone Body Turnover, Metabolic Micromilieu, and pH Distributions in Human Breast Cancer Xenografts in Nude Rats,” Cancer Research 48, no. 24 Pt 1 (1988): 7264–7272.

[138] P. Fantes and P. Nurse, “Control of Cell Size at Division in Fission Yeast by a Growth-Modulated Size Control Over Nuclear Division,” Experimental Cell Research 107, no. 2 (1977): 377–386.

[139] R. A. Saxton and D. M. Sabatini, “mTOR Signaling in Growth, Metabolism, and Disease,” Cell 168, no. 6 (2017): 960–976, https://doi.org/10.1016/j.cell.2017.02.004.

[140] H. Su, F. Yang, R. Fu, et al., “Cancer Cells Escape Autophagy Inhibition via NRF2-Induced Macropinocytosis,” Cancer Cell 39, no. 5 (2021): 678–693.e11.

[141] Y. Q. Wu, C. S. Zhang, J. Xiong, et al., “Low Glucose Metabolite 3-Phosphoglycerate Switches PHGDH From Serine Synthesis to p53 Activation to Control Cell Fate,” Cell Research 33, no. 11 (2023): 835–850.

[142] R. Mehdizadeh, A. Madjid Ansari, F. Forouzesh, et al., “P53 Status, and G2/M Cell Cycle Arrest, Are Determining Factors in Cell-Death Induction Mediated by ELF-EMF in Glioblastoma,” Scientific Reports 13, no. 1 (2023): 10845.

[143] P. S. Hodkinson, A. Mackinnon, and T. Sethi, “Targeting Growth Factors in Lung Cancer,” Chest 133, no. 5 (2008): 1209–1216.

[144] C. R. Chong and P. A. Jänne, “The Quest to Overcome Resistance to EGFR-Targeted Therapies in Cancer,” Nature Medicine 19, no. 11 (2013): 1389–1400.

[145] D. Hanahan, “Hallmarks of Cancer: New Dimensions,” Cancer Discovery 12, no. 1 (2022): 31–46.

[146] I. J. Conlon, G. A. Dunn, A. W. Mudge, and M. C. Raff, “Extracellular control of cell size,” Nature Cell Biology 3, no. 10 (2001): 918–921.

[147] H. T. Lee and E. P. Kay, “FGF-2 Induced Reorganization and Disruption of Actin Cytoskeleton Through PI 3-Kinase, Rho, and Cdc42 in Corneal Endothelial Cells,” Molecular Vision 9 (2003): 624–634.

[148] K. A. McClellan, J. L. Vanderluit, L. M. Julian, et al., “The p107/E2F Pathway Regulates Fibroblast Growth Factor 2 Responsiveness in Neural Precursor Cells,” Molecular and Cellular Biology 29, no. 17 (2009): 4701–4713.

[149] K. L. Zhang, W. W. Zhu, S. H. Wang, et al., “Organ-Specific Cholesterol Metabolic Aberration Fuels Liver Metastasis of Colorectal Cancer,” Theranostics 11, no. 13 (2021): 6560–6572.

[150] M. N. González, W. de Mello, G. S. Butler-Browne, et al., “HGF Potentiates Extracellular Matrix-Driven Migration of Human Myoblasts: Involvement of Matrix Metalloproteinases and MAPK/ERK Pathway,” Skeletal Muscle 7, no. 1 (2017): 20.

[151] M. De Piano, V. Manuelli, G. Zadra, et al., “Lipogenic Signalling Modulates Prostate Cancer Cell Adhesion and Migration via Modification of Rho GTPases,” Oncogene 39, no. 18 (2020): 3666–3679.

[152] L. Liu, E. Aleksandrowicz, P. Fan, et al., “Enrichment of c-Met+ Tumorigenic Stromal Cells of Giant Cell Tumor of Bone and Targeting by Cabozantinib,” Cell Death & Disease 5, no. 10 (2014): e1471.

[153] Y. Xiao and D. Yu, “Tumor Microenvironment as a Therapeutic Target in Cancer,” Pharmacology & Therapeutics 221 (2021): 107753.

[154] G. Caligiuri and D. A. Tuveson, “Activated Fibroblasts in Cancer: Perspectives and Challenges,” Cancer Cell 41, no. 3 (2023): 434–449.

[155] D. A. Fletcher and R. D. Mullins, “Cell Mechanics and the Cytoskeleton,” Nature 463, no. 7280 (2010): 485–492.

[156] J. H. Shi, L. N. Liu, D. D. Song, et al., “TRAF3/STAT6 Axis Regulates Macrophage Polarization and Tumor Progression,” Cell Death and Differentiation 30, no. 8 (2023): 2005–2016.

[157] A. L. Correia, J. C. Guimaraes, P. Auf der Maur, et al., “Hepatic Stellate Cells Suppress NK Cell-Sustained Breast Cancer Dormancy,” Nature 594, no. 7864 (2021): 566–571.

[158] N. Jiang, A. Saftics, E. Romano, et al., “Multiparametric Profiling of HER2-Enriched Extracellular Vesicles in Breast Cancer Using Single Extracellular VEsicle Nanoscopy,” Journal of Nanobiotechnology 22, no. 1 (2024): 589.

[159] S. Zhao, Y. Mi, B. Zheng, et al., “Highly-Metastatic Colorectal Cancer Cell Released miR-181a-5p-Rich Extracellular Vesicles Promote Liver Metastasis by Activating Hepatic Stellate Cells and Remodelling the Tumour Microenvironment,” Journal of Extracellular Vesicles 11, no. 1 (2022): e12186.

[160] J. L. Galeano Niño, H. Wu, K. D. LaCourse, et al., “Effect of the Intratumoral Microbiota on Spatial and Cellular Heterogeneity in Cancer,” Nature 611, no. 7937 (2022): 810–817.

[161] M. R. Rubinstein, X. Wang, W. Liu, Y. Hao, G. Cai, and Y. W. Han, “Fusobacterium nucleatum Promotes Colorectal Carcinogenesis by Modulating E-Cadherin/β-Catenin Signaling via Its FadA Adhesin,” Cell Host & Microbe 14, no. 2 (2013): 195–206.

[162] F. Paolini, M. Zaccarini, A. Francesconi, et al., “Beta HPV Type 15 Can Interfere With NF-κB Activity and Apoptosis in Human Keratinocytes,” Frontiers in Cellular and Infection Microbiology 10 (2020): 111.

[163] X. Zhong, X. He, Y. Wang, et al., “Warburg Effect in Colorectal Cancer: The Emerging Roles in Tumor Microenvironment and Therapeutic Implications,” Journal of Hematology & Oncology 15, no. 1 (2022): 160.

[164] C. Stock, B. Gassner, C. R. Hauck, et al., “Migration of Human Melanoma Cells Depends on Extracellular pH and Na+/H+ Exchange,” Journal of Physiology 567, no. Pt 1 (2005): 225–238.

[165] E. Boedtkjer and S. F. Pedersen, “The Acidic Tumor Microenvironment as a Driver of Cancer,” Annual Review of Physiology 82 (2020): 103–126.

[166] S. Ju, F. Wang, Y. Wang, and S. Ju, “CSN8 Is a Key Regulator in Hypoxia-Induced Epithelial-Mesenchymal Transition and Dormancy of Colorectal Cancer Cells,” Molecular Cancer 19, no. 1 (2020): 168.

[167] J. Barbazan, C. Pérez-González, M. Gómez-González, et al., “Cancer-Associated Fibroblasts Actively Compress Cancer Cells and Modulate Mechanotransduction,” Nature Communications 14, no. 1 (2023): 6966.

[168] A. W. Holle, N. Govindan Kutty Devi, K. Clar, et al., “Cancer Cells Invade Confined Microchannels via a Self-Directed Mesenchymal-To-Amoeboid Transition,” Nano Letters 19, no. 4 (2019): 2280–2290.

[169] I. Dickson, “Pancreatic Cancer: Between ROCK and a Hard Place,” Nature Reviews. Gastroenterology & Hepatology 14, no. 6 (2017): 324–325.

[170] A. Elosegui-Artola, I. Andreu, A. E. M. Beedle, et al., “Force Triggers YAP Nuclear Entry by Regulating Transport Across Nuclear Pores,” Cell 171, no. 6 (2017): 1397–1410.e14.

[171] A. Claude-Taupin and N. Dupont, “To Squeeze or Not: Regulation of Cell Size by Mechanical Forces in Development and Human Diseases,” Biology of the Cell 116, no. 2 (2024): e2200101.

[172] J. Luo, H. Zou, Y. Guo, et al., “The Oncogenic Roles and Clinical Implications of YAP/TAZ in Breast Cancer,” British Journal of Cancer 128, no. 9 (2023): 1611–1624.

[173] Y. Huang, J. Su, J. Liu, et al., “YAP Activation in Promoting Negative Durotaxis and Acral Melanoma Progression,” Cells 11, no. 22 (2022): 3543.

[174] X. Zhang, L. Yang, P. Szeto, et al., “The Hippo Pathway Oncoprotein YAP Promotes Melanoma Cell Invasion and Spontaneous Metastasis,” Oncogene 39, no. 30 (2020): 5267–5281.

[175] H. Vignes, C. Vagena-Pantoula, M. Prakash, et al., “Extracellular mechanical forces drive endocardial cell volume decrease during zebrafish cardiac valve morphogenesis,” Developmental Cell 57, no. 5 (2022): 598–609.e5.

[176] Y. Li, M. Chen, J. Hu, et al., “Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wnt/β-Catenin Signaling,” Cell Stem Cell 28, no. 1 (2021): 63–78, https://doi.org/10.1016/j.stem.2020.09.012.

[177] U. Smith, “Effect of Cell Size on Lipid Synthesis by Human Adipose Tissue In Vitro,” Journal of Lipid Research 12, no. 1 (1971): 65–70.

[178] W. F. Marshall, “Scaling of Subcellular Structures,” Annual Review of Cell and Developmental Biology 36 (2020): 219–236.

[179] S. Marguerat and J. Bähler, “Coordinating Genome Expression With Cell Size,” Trends in Genetics 28, no. 11 (2012): 560–565.

[180] M. P. Swaffer, G. K. Marinov, H. Zheng, et al., “RNA Polymerase II Dynamics and mRNA Stability Feedback Scale mRNA Amounts With Cell Size,” Cell 186, no. 24 (2023): 5254–5268.e26.

[181] C. W. Sandlin, S. Gu, J. Xu, C. Deshpande, M. D. Feldman, and M. C. Good, “Epithelial Cell Size Dysregulation in Human Lung Adenocarcinoma,” PLoS One 17, no. 10 (2022): e0274091.

[182] T. P. Miettinen and M. Björklund, “Mitochondrial Function and Cell Size: An Allometric Relationship,” Trends in Cell Biology 27, no. 6 (2017): 393–402.

[183] T. P. Miettinen and M. Björklund, “Cellular Allometry of Mitochondrial Functionality Establishes the Optimal Cell Size,” Developmental Cell 39, no. 3 (2016): 370–382.

[184] S. Manohar and G. E. Neurohr, “Too Big Not to Fail: Emerging Evidence for Size-Induced Senescence,” FEBS Journal 291, no. 11 (2024): 2291–2305.

[185] T. P. Miettinen, M. J. Caldez, P. Kaldis, and M. Björklund, “Cell Size Control - a Mechanism for Maintaining Fitness and Function,” BioEssays 39, no. 9 (2017): 1700058.

[186] A. A. Amodeo and J. M. Skotheim, “Cell-Size Control,” Cold Spring Harbor Perspectives in Biology 8, no. 4 (2016): a019083.

[187] J. Hao, A. Ma, L. Wang, et al., “General Requirements for Stem Cells,” Cell Proliferation 53, no. 12 (2020): e12926.

[188] A. Kreso and J. E. Dick, “Evolution of the Cancer Stem Cell Model,” Cell Stem Cell 14, no. 3 (2014): 275–291.

[189] S. J. Morrison and J. Kimble, “Asymmetric and Symmetric Stem-Cell Divisions in Development and Cancer,” Nature 441, no. 7097 (2006): 1068–1074.

[190] R. Lamb, B. Ozsvari, G. Bonuccelli, et al., “Dissecting Tumor Metabolic Heterogeneity: Telomerase and Large Cell Size Metabolically Define a Sub-Population of Stem-Like, Mitochondrial-Rich, Cancer Cells,” Oncotarget 6, no. 26 (2015): 21892–21905.

[191] C. R. Jeter, T. Yang, J. Wang, H. P. Chao, and D. G. Tang, “Concise Review: NANOG in Cancer Stem Cells and Tumor Development: An Update and Outstanding Questions,” Stem Cells 33, no. 8 (2015): 2381–2390.

[192] H. Ida, N. Taira, Y. Nashimoto, A. Kumatani, Y. Takahashi, and H. Shiku, “EMT-Induced Morphological Variations on Living Cell Membrane Surface,” Analytical Chemistry 97, no. 1 (2025): 312–318.

[193] S. J. Hao, Y. Wan, Y. Q. Xia, X. Zou, and S. Y. Zheng, “Size-Based Separation Methods of Circulating Tumor Cells,” Advanced Drug Delivery Reviews 125 (2018): 3–20.

[194] B. Strilic, L. Yang, J. Albarrán-Juárez, et al., “Tumour-Cell-Induced Endothelial Cell Necroptosis via Death Receptor 6 Promotes Metastasis,” Nature 536, no. 7615 (2016): 215–218.

[195] Q. Sun, W. Li, D. Yang, P. P. Lin, L. Zhang, and H. Guo, “The Presence of Small-Size Circulating Tumor Cells Predicts Worse Prognosis in Non-Small Cell Lung Cancer Patients,” Archives of Pathology & Laboratory Medicine 149, no. 1 (2025): 39–49.

[196] F. Liu, Y. Gao, B. Xu, et al., “PEG10 Amplification at 7q21.3 Potentiates Large-Cell Transformation in Cutaneous T-Cell Lymphoma,” Blood 139, no. 4 (2022): 554–571.

[197] A. Shoari, A. Ashja Ardalan, A. M. Dimesa, and M. A. Coban, “Targeting Invasion: The Role of MMP-2 and MMP-9 Inhibition in Colorectal Cancer Therapy,” Biomolecules 15, no. 1 (2024): 35.

[198] J. L. Duan, B. Ruan, P. Song, et al., “Shear Stress-Induced Cellular Senescence Blunts Liver Regeneration Through Notch-Sirtuin 1-P21/P16 Axis,” Hepatology 75, no. 3 (2022): 584–599.

[199] E. S. Hwang, G. Yoon, and H. T. Kang, “A Comparative Analysis of the Cell Biology of Senescence and Aging,” Cellular and Molecular Life Sciences 66, no. 15 (2009): 2503–2524.

[200] Z. N. Demidenko and M. V. Blagosklonny, “Growth Stimulation Leads to Cellular Senescence When the Cell Cycle Is Blocked,” Cell Cycle 7, no. 21 (2008): 3355–3361.

[201] S. Xie, M. Swaffer, and J. M. Skotheim, “Eukaryotic Cell Size Control and Its Relation to Biosynthesis and Senescence,” Annual Review of Cell and Developmental Biology 38 (2022): 291–319.

[202] R. Katasho, T. Nagano, T. Iwasaki, and S. Kamada, “Nectin-4 Regulates Cellular Senescence-Associated Enlargement of Cell Size,” Scientific Reports 13, no. 1 (2023): 21602.

[203] T. Mammoto, Y. S. Torisawa, M. Muyleart, et al., “Effects of Age-Dependent Changes in Cell Size on Endothelial Cell Proliferation and Senescence Through YAP1,” Aging (Albany NY) 11, no. 17 (2019): 7051–7069.

[204] R. Foy, L. Crozier, A. U. Pareri, et al., “Oncogenic Signals Prime Cancer Cells for Toxic Cell Overgrowth During a G1 Cell Cycle Arrest,” Molecular Cell 83, no. 22 (2023): 4047–4061.e6.

[205] A. B. Heptinstall, I. Adiyasa, C. Cano, and I. R. Hardcastle, “Recent Advances in CDK Inhibitors for Cancer Therapy,” Future Medicinal Chemistry 10, no. 11 (2018): 1369–1388.

[206] C. J. Sherr, D. Beach, and G. I. Shapiro, “Targeting CDK4 and CDK6: From Discovery to Therapy,” Cancer Discovery 6, no. 4 (2016): 353–367.

[207] G. A. Wilson, K. Vuina, G. Sava, et al., “Active Growth Signaling Promotes Senescence and Cancer Cell Sensitivity to CDK7 Inhibition,” Molecular Cell 83, no. 22 (2023): 4078–4092.e6.

[208] H. Zhang, J. Lin, S. Zheng, et al., “CDKL3 Is a Targetable Regulator of Cell Cycle Progression in Cancers,” Journal of Clinical Investigation 134, no. 16 (2024): e178428.

[209] L. Wang, L. Zhang, L. Li, et al., “Small-Molecule Inhibitor Targeting the Hsp90-Cdc37 Protein-Protein Interaction in Colorectal Cancer,” Science Advances 5, no. 9 (2019): eaax2277.

[210] N. C. House, V. E. Brown, M. Chen, et al., “Profiling the Activity of the Potent and Highly Selective CDK2 Inhibitor BLU-222 Reveals Determinants of Response in CCNE1-Aberrant Ovarian and Endometrial Tumors,” Cancer Research 85 (2025): 1297–1309.

[211] U. Platzbecker, J. Chromik, J. Krönke, et al., “Volasertib as a Monotherapy or in Combination With Azacitidine in Patients With Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia: Summary of Three Phase I Studies,” BMC Cancer 22, no. 1 (2022): 569.

[212] W. Fujiwara, M. Yotsukura, Y. Yoshida, et al., “Clinical and Pathologic Differences Between Small-Cell Carcinoma and Large-Cell Neuroendocrine Carcinoma of the Lung,” Annals of Surgical Oncology 31, no. 9 (2024): 5697–5705.

[213] V. Noronha, V. M. Patil, A. Joshi, et al., “Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer,” Journal of Clinical Oncology 38, no. 2 (2020): 124–136.

[214] M. Liu, Q. Liu, K. Hu, et al., “Colorectal Cancer With BRAF V600E Mutation: Trends in Immune Checkpoint Inhibitor Treatment,” Critical Reviews in Oncology/Hematology 204 (2024): 104497.

[215] C. Marchiò, L. Annaratone, A. Marques, L. Casorzo, E. Berrino, and A. Sapino, “Evolving Concepts in HER2 Evaluation in Breast Cancer: Heterogeneity, HER2-Low Carcinomas and Beyond,” Seminars in Cancer Biology 72 (2021): 123–135.

[216] K. M. Khalid, W. S. Ratnayake, C. A. Apostolatos, and M. Acevedo-Duncan, “Dual Inhibition of Atypical PKC Signaling and PI3K/Akt Signaling Dysregulates c-Myc to Induce Apoptosis in Clear Cell Renal Cell Carcinoma,” Frontiers in Oncology 13 (2024): 1213715.

[217] F. André, E. Ciruelos, G. Rubovszky, et al., “Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer,” New England Journal of Medicine 380, no. 20 (2019): 1929–1940.

[218] Y. Li, B. Li, Y. Xu, et al., “GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors,” Cancer Research 82, no. 18 (2022): 3223–3235.

[219] W. Kelly, A. E. Diaz Duque, J. Michalek, et al., “Phase II Investigation of TVB-2640 (Denifanstat) With Bevacizumab in Patients With First Relapse High-Grade Astrocytoma,” Clinical Cancer Research 29, no. 13 (2023): 2419–2425.

[220] J. Bejček, V. Spiwok, E. Kmoníčková, and S. Rimpelová, “Na⁺/K⁺-ATPase Revisited: On Its Mechanism of Action, Role in Cancer, and Activity Modulation,” Molecules 26, no. 7 (2021): 1905.

[221] A. M. Michaels, A. Zoccarato, Z. Hoare, et al., “Disrupting Na+ Ion Homeostasis and Na+/K+ ATPase Activity in Breast Cancer Cells Directly Modulates Glycolysis In Vitro and In Vivo,” Cancer & Metabolism 12, no. 1 (2024): 15.

[222] L. Zhou, G. Zhou, J. Li, R. Guo, and H. Dong, “NCX1 Interacts With TRPA1 to Promote Cell Proliferation and Tumor Growth of Colon Cancer via Disruption of Calcium Homeostasis,” Journal of Advanced Research (2025).

[223] K. Bera, A. Kiepas, I. Godet, et al., “Extracellular Fluid Viscosity Enhances Cell Migration and Cancer Dissemination,” Nature 611, no. 7935 (2022): 365–373.

[224] S. Li, Z. Wang, R. Geng, et al., “TMEM16A Ion Channel: A Novel Target for Cancer Treatment,” Life Sciences 331 (2023): 122034.

[225] R. Wong, W. Chen, X. Zhong, J. T. Rutka, Z. P. Feng, and H. S. Sun, “Swelling-Induced Chloride Current in Glioblastoma Proliferation, Migration, and Invasion,” Journal of Cellular Physiology 233, no. 1 (2018): 363–370.

[226] N. Rashidi, N. S. Harasymowicz, A. Savadipour, et al., “PIEZO1-Mediated Mechanotransduction Regulates Collagen Synthesis on Nanostructured 2D and 3D Models of Fibrosis,” Acta Biomaterialia 193 (2025): 242–254.

[227] C. Li, S. Rezania, S. Kammerer, et al., “Piezo1 Forms Mechanosensitive Ion Channels in the Human MCF-7 Breast Cancer Cell Line,” Scientific Reports 5 (2015): 8364.

[228] S. Goel, M. J. DeCristo, A. C. Watt, et al., “CDK4/6 Inhibition Triggers Anti-Tumour Immunity,” Nature 548, no. 7668 (2017): 471–475.

[229] J. Wang, R. Zhang, Z. Lin, et al., “CDK7 Inhibitor THZ1 Enhances antiPD-1 Therapy Efficacy via the p38α/MYC/PD-L1 Signaling in Non-Small Cell Lung Cancer,” Journal of Hematology & Oncology 13, no. 1 (2020): 99.

[230] H. Zhang, C. L. Christensen, R. Dries, et al., “CDK7 Inhibition Potentiates Genome Instability Triggering Anti-Tumor Immunity in Small Cell Lung Cancer,” Cancer Cell 37, no. 1 (2020): 37–54.e9.

[231] M. Ingham and G. K. Schwartz, “Cell-Cycle Therapeutics Come of Age,” Journal of Clinical Oncology 35, no. 25 (2017): 2949–2959.

[232] D. J. Slamon, V. Diéras, H. S. Rugo, et al., “Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer,” Journal of Clinical Oncology 42, no. 9 (2024): 994–1000.

[233] M. P. Goetz, M. Toi, M. Campone, et al., “MONARCH 3: Abemaciclib as Initial Therapy for Advanced Breast Cancer,” Journal of Clinical Oncology 35, no. 32 (2017): 3638–3646.

[234] G. N. Hortobagyi, S. M. Stemmer, H. A. Burris, et al., “Overall Survival With Ribociclib Plus Letrozole in Advanced Breast Cancer,” New England Journal of Medicine 386, no. 10 (2022): 942–950.

[235] J. A. Beaver, L. Amiri-Kordestani, R. Charlab, et al., “FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients With Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer,” Clinical Cancer Research 21, no. 21 (2015): 4760–4766.

[236] M. Iorfida, M. Mazza, and E. Munzone, “Fulvestrant in Combination With CDK4/6 Inhibitors for HER2- Metastatic Breast Cancers: Current Perspectives,” Breast Cancer (Dove Med Press) 12 (2020): 45–56.

[237] M. Brandão, R. Caparica, D. Eiger, and E. de Azambuja, “Biomarkers of Response and Resistance to PI3K Inhibitors in Estrogen Receptor-Positive Breast Cancer Patients and Combination Therapies Involving PI3K Inhibitors,” Annals of Oncology 30, no. S10 (2019): 27–42.

[238] A. Bardia, S. A. Hurvitz, A. DeMichele, et al., “Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women With HR+/HER2- Advanced Breast Cancer After Progression on CDK4/6 Inhibitors (TRINITI-1),” Clinical Cancer Research 27, no. 15 (2021): 4177–4185.

[239] C. Sun, Y. Fang, M. Labrie, X. Li, and G. B. Mills, “Systems Approach to Rational Combination Therapy: PARP Inhibitors,” Biochemical Society Transactions 48, no. 3 (2020): 1101–1108.

[240] G. Jerusalem, A. Prat, R. Salgado, et al., “Neoadjuvant Nivolumab + Palbociclib + Anastrozole for Oestrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer: Results From CheckMate 7A8,” Breast 72 (2023): 103580.

[241] A. M. Oza, M. Estevez-Diz, E. M. Grischke, et al., “A Biomarker-Enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women With Platinum-Sensitive TP53-Mutant Ovarian Cancer,” Clinical Cancer Research 26, no. 18 (2020): 4767–4776.

[242] A. Baker, G. P. Gregory, I. Verbrugge, et al., “The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia,” Cancer Research 76, no. 5 (2016): 1158–1169.

[243] A. Rio-Vilariño, A. Cenigaonandia-Campillo, A. García-Bautista, et al., “Inhibition of the AURKA/YAP1 Axis Is a Promising Therapeutic Option for Overcoming Cetuximab Resistance in Colorectal Cancer Stem Cells,” British Journal of Cancer 130, no. 8 (2024): 1402–1413.

[244] J. Murai, S. Y. Huang, B. B. Das, et al., “Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors,” Cancer Research 72, no. 21 (2012): 5588–5599.

[245] X. Zhu, L. Chen, B. Huang, et al., “Efficacy and Mechanism of the Combination of PARP and CDK4/6 Inhibitors in the Treatment of Triple-Negative Breast Cancer,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 122.

[246] H. S. Rugo, F. Lerebours, E. Ciruelos, et al., “Alpelisib Plus Fulvestrant in PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer After a CDK4/6 Inhibitor (BYLieve): One Cohort of a Phase 2, Multicentre, Open-Label, Non-Comparative Study,” Lancet Oncology 25, no. 12 (2024): e629–e638.

[247] C. M. Goodwin, A. M. Waters, J. E. Klomp, et al., “Combination Therapies With CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer,” Cancer Research 83, no. 1 (2023): 141–157.

[248] N. Hara, E. Ichihara, H. Kano, et al., “CDK4/6 Signaling Attenuates the Effect of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer,” Translational Lung Cancer Research 12, no. 10 (2023): 2098–2112.

[249] E. J. Lelliott, S. Mangiola, K. M. Ramsbottom, et al., “Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma,” Cancer Immunology Research 9, no. 2 (2021): 136–146.

RIGHTS & PERMISSIONS

2025 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.