Single-cell characterization of differentiation trajectories and drug resistance features in gastric cancer with peritonealmetastasis

Abstract

	•MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential and exhibiting spatial proximity to fibroblasts and endothelial cells constitute the driving force of gastric cancer peritoneal metastasis (GCPM).
	•Higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates within the peritoneal microenvironment in therapeutic failure cases.
	•Co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at diagnosis.

Keywords

drug resistance / gastric cancer peritoneal metastasis / single-cell RNA sequencing / spatial transcriptomics

References

[1] BrayF, Laversanne M, SungH, et al. Global cancer statistics 2022: gLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229-263.

[2] HuangJ, Lucero-Prisno DE, ZhangL, et al. Updated epidemiology of gastrointestinal cancers in East Asia. Nat Rev Gastroenterol Hepatol. 2023; 20(5): 271-287.

[3] GretschelS, SiegelR, Estévez-SchwarzL, HünerbeinM, Schneider U, SchlagPM. Surgical strategies for gastric cancer with synchronous peritoneal carcinomatosis. Br J Surg. 2006; 93(12): 1530-1155.

[4] ThomassenI, van Gestel YR, van RamshorstB, et al. Peritoneal carcinomatosis of gastric origin: a population-based study on incidence, survival and risk factors. Int J Cancer. 2014; 134(3): 622-628.

[5] FosterJM, ZhangC, RehmanS, Sharma P, HRAlexander. The contemporary management of peritoneal metastasis: a journey from the cold past of treatment futility to a warm present and a bright future. CA Cancer J Clin. 2023; 73(1): 49-71.

[6] GuanW-L, HeY, XuR-H. Gastric cancer treatment: recent progress and future perspectives. J Hematol Oncol. 2023; 16(1): 57.

[7] FucàG, CohenR, LonardiS, et al. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. J Immunother Cancer. 2022; 10(2): e004001.

[8] GweeYX, ChiaDKA, SoJ, et al. Integration of genomic biology into therapeutic strategies of gastric cancer peritoneal metastasis. J Clin Oncol. 2022; 40(24): 2830.

[9] WangR, SongS, QinJ, et al. Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression. Cancer Cell. 2023; 41(8): 1407-1426.e9.

[10] ZhangJ, ChenY, ChenT, et al. Single-cell transcriptomics provides new insights into the role of fibroblasts during peritoneal fibrosis. Clin Transl Med. 2021; 11(3): e321.

[11] SiM, WangQ, LiY, et al. Inhibition of hyperglycolysis in mesothelial cells prevents peritoneal fibrosis. Sci Transl Med. 2019; 11(495): eaav5341.

[12] FuX, WangQ, DuH, HaoH. CXCL8 and the peritoneal metastasis of ovarian and gastric cancer. Front Immunol. 2023; 14: 1159061.

[13] HuangX-Z, PangM-J, LiJ-Y, et al. Single-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis. Nature Communications. 2023; 14(1): 822.

[14] WangR, SongS, HaradaK, et al. Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response. Gut. 2020; 69(1): 18-31.

[15] LiuD, ZhouJ, WangY, et al. Bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial. BMC Med. 2022; 20(1): 408.

[16] JiaK, ChenY, XieY, et al. Helicobacter pylori and immunotherapy for gastrointestinal cancer. Innovation (Camb). 2024; 5(2): 100561.

[17] World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013; 310(20): 2191-2194.

[18] DuraB, ChoiJ-Y, ZhangK, et al. scFTD-seq: freeze-thaw lysis based, portable approach toward highly distributed single-cell 3’ mRNA profiling. Nucleic Acids Res. 2019; 47(3): e16.

[19] AranD, LooneyAP, LiuL, et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2): 163-172.

[20] KangB, CampsJ, FanB, et al. Parallel single-cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment. Genome Biol. 2022; 23(1): 265.

[21] KumarV, Ramnarayanan K, SundarR, et al. Single-cell atlas of lineage states, tumor microenvironment, and subtype-specific expression programs in gastric cancer. Cancer Discov. 2022; 12(3): 670-691.

[22] LiuB, LiC, LiZ, WangD, RenX, ZhangZ. An entropy-based metric for assessing the purity of single cell populations. Nature Communications. 2020; 11(1): 3155.

[23] PatelAP, TiroshI, TrombettaJJ, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014; 344(6190): 1396-1401.

[24] QiuX, MaoQ, TangY, et al. Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10): 979-982.

[25] JinS, Guerrero-Juarez CF, ZhangL, et al. Inference and analysis of cell-cell communication using CellChat. Nature Communications. 2021; 12(1): 1088.

[26] YuanxinW, Ruiping W, ShaojunZ, et al. iTALK: an R package to characterize and illustrate intercellular communication. bioRxiv. 2019:507871.

[27] BrowaeysR, Saelens W, SaeysY. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods. 2020; 17(2): 159-162.

[28] HeY, JiangZ, ChenC, Wang X. Classification of triple-negative breast cancers based on immunogenomic profiling. J Exp Clin Cancer Res. 2018; 37(1): 327.

[29] XiongD, WangY, YouM. A gene expression signature of TREM2hi macrophages and γδ T cells predicts immunotherapy response. Nature Communications. 2020; 11(1): 5084.

[30] Garrido-MartinEM, Mellows TWP, ClarkeJ, et al. M1hot tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer. J Immunother Cancer. 2020; 8(2): e000778.

[31] PaduaD, ZhangXHF, WangQ, et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008; 133(1): 66-77.

[32] SubramanianA, TamayoP, MoothaVK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43): 15545-15550.

[33] RitchieME, Phipson B, WuD, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43(7): e47.

[34] HänzelmannS, Castelo R, GuinneyJ. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14: 7.

[35] SalménF, Ståhl PL, MollbrinkA, et al. Barcoded solid-phase RNA capture for spatial transcriptomics profiling in mammalian tissue sections. Nat Protoc. 2018; 13(11): 2501-2534.

[36] PengH, WuX, LiuS, et al. Multiplex immunofluorescence and single-cell transcriptomic profiling reveal the spatial cell interaction networks in the non-small cell lung cancer microenvironment. Clin Transl Med. 2023; 13(1): e1155.

[37] JiaK, ChenY, SunY, et al. Multiplex immunohistochemistry defines the tumor immune microenvironment and immunotherapeutic outcome in CLDN18.2-positive gastric cancer. BMC Med. 2022; 20(1): 223.

[38] CarstensJL, Correa de Sampaio P, YangD, et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nature Communications. 2017; 8: 15095.

[39] HuangY-K, WangM, SunY, et al. Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry. Nature Communications. 2019; 10(1): 3928.

[40] Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014; 513(7517): 202-209.

[41] TrouléK, López-Fernández H, García-Martín S, et al. DREIMT: a drug repositioning database and prioritization tool for immunomodulation. Bioinformatics. 2021; 37(4): 578-579.

[42] CampRL, Dolled-Filhart M, RimmDL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004; 10(21): 7252-7259.

[43] LvY, MaX, MaY, DuY, FengJ. A new emerging target in cancer immunotherapy: galectin-9 (LGALS9). Genes Dis. 2023; 10(6): 2366-2382.

[44] CrawfordKS, Volkman BF. Prospects for targeting ACKR1 in cancer and other diseases. Front Immunol. 2023; 14: 1111960.

[45] GalluzziL, VitaleI, WarrenS, et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer. 2020; 8(1): e000337.

[46] GaoJ, LiangY, WangL. Shaping polarization of tumor-associated macrophages in cancer. Immunotherapy Front Immunol. 2022; 13: 888713.

[47] MaR-Y, BlackA, QianB-Z. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends Immunol. 2022; 43(7): 546-563.

[48] SunK, XuR, MaF, et al. scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nature Communications. 2022; 13(1): 4943.

[49] CookME, Bradstreet TR, WebberAM, et al. The ZFP36 family of RNA binding proteins regulates homeostatic and autoreactive T cell responses. Sci Immunol. 2022; 7(76): eabo0981.

[50] YangR, SunL, LiC-F, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nature Communications. 2021; 12(1): 832.

[51] MooreMJ, Blachere NE, FakJJ, et al. ZFP36 RNA-binding proteins restrain T cell activation and anti-viral immunity. Elife. 2018; 7: e33057.

[52] WuY, MaJ, YangX, et al. Neutrophil profiling illuminates anti-tumor antigen-presenting potency. Cell. 2024; 187(6): 1422-1439.e24.

[53] ZhouS-L, ZhouZ-J, HuZ-Q, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to Sorafenib. Gastroenterology. 2016; 150(7): 1646-1658.e17.

[54] RogersT, DeBerardinis RJ. Metabolic plasticity of neutrophils: relevance to pathogen responses and cancer. Trends Cancer. 2021; 7(8): 700-713.

[55] LeJ, ChenY, YangW, Chen L, YeJ. Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus. Acta Pharm Sin B. 2024; 14(2): 437-454.

[56] MeradM, SatheP, HelftJ, Miller J, MorthaA. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013; 31: 563-604.

[57] RébéC, Ghiringhelli F. Interleukin-1β and cancer. Cancers (Basel). 2020; 12(7): 1791.

[58] HeS, WangL, WuY, LiD, ZhangY. CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo. J Exp Clin Cancer Res. 2010; 29(1): 37.

[59] LiX, SongD, SuS, et al. Critical role of guanylate binding protein 5 in tumor immune microenvironment and predictive value of immunotherapy response. Front Genet. 2022; 13: 984615.

[60] FosterDS, Januszyk M, DelittoD, et al. Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer Cell. 2022; 40(11): 1392-1406.e7.

[61] BuechlerMB, FuW, TurleySJ. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity. 2021; 54(5): 903-915.

[62] GeW, YueM, LinR, et al. PLA2G2A+ cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+ cytotoxic T cells. Cancer Lett. 2023; 558: 216095.

[63] TakeharaM, SatoY, KimuraT, et al. Cancer-associated adipocytes promote pancreatic cancer progression through SAA1 expression. Cancer Sci. 2020; 111(8): 2883-2894.

[64] ChenY, McAndrews KM, KalluriR. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021; 18(12): 792-804.

[65] GobinE, Bagwell K, WagnerJ, et al. A pan-cancer perspective of matrix metalloproteases (MMP) gene expression profile and their diagnostic/prognostic potential. BMC Cancer. 2019; 19(1): 581.

[66] GuoS, WuX, LeiT, et al. The role and therapeutic value of syndecan-1 in cancer metastasis and drug resistance. Front Cell Dev Biol. 2021; 9: 784983.

[67] CohenAD, Garfall AL, StadtmauerEA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019; 129(6): 2210-2221.

[68] NixonBG, GaoS, WangX, MO Li. TGFβ control of immune responses in cancer: a holistic immuno-oncology perspective. Nat Rev Immunol. 2023; 23(6): 346-362.

[69] SaraivaM, VieiraP, O’GarraA. Biology and therapeutic potential of interleukin-10. J Exp Med. 2020; 217(1): e20190418.

[70] SiddiquiJA, Pothuraju R, KhanP, et al. Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. Cytokine Growth Factor Rev. 2022; 64: 71-83.

[71] OladejoM, NguyenH-M, WoodL. CD105 in the progression and therapy of renal cell carcinoma. Cancer Lett. 2023; 570: 216327.

[72] WangL, LiuY, DaiY, et al. Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment. Gut. 2022.

[73] EumHH, KwonM, RyuD, et al. Tumor-promoting macrophages prevail in malignant ascites of advanced gastric cancer. Exp Mol Med. 2020; 52(12): 1976-1988.

[74] OsmanS, RazaA, Al-ZaidanL, et al. Anti-cancer effects of Tranilast: an update. Biomed Pharmacother. 2021; 141: 111844.

[75] BrownJS. Treatment of cancer with antipsychotic medications: pushing the boundaries of schizophrenia and cancer. Neurosci Biobehav Rev. 2022; 141: 104809.

[76] FilippouPS, Karagiannis GS, ConstantinidouA. Midkine (MDK) growth factor: a key player in cancer progression and a promising therapeutic target. Oncogene. 2020; 39(10): 2040-2054.

[77] NathS, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014; 20(6): 332-342.

[78] YangX-J, HuangC-Q, SuoT, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011; 18(6): 1575-1581.

[79] BonnotP-E, Piessen G, KepenekianV, et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastases (CYTO-CHIP study): a propensity score analysis. J Clin Oncol. 2019; 37(23): 2028-2040.

[80] DesiderioJ, ChaoJ, MelstromL, et al. The 30-year experience-A meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer. Eur J Cancer. 2017: 79.

[81] RauB, LangH, KoenigsrainerA, et al. Effect of hyperthermic intraperitoneal chemotherapy on cytoreductive surgery in gastric cancer with synchronous peritoneal metastases: the phase III GASTRIPEC-I trial. J Clin Oncol. 2024; 42(2): 146-156.

[82] YuP, DingG, HuangX, et al. Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: a retrospective cohort study. Int J Surg. 2024; 110(6): 3504-3517.

[83] ChengS, LiZ, GaoR, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021; 184(3): 792-809.e23.

[84] HeH, ChenS, FanZ, et al. Multi-dimensional single-cell characterization revealed suppressive immune microenvironment in AFP-positive hepatocellular carcinoma. Cell Discov. 2023; 9(1): 60.

[85] ReisES, Mastellos DC, RicklinD, MantovaniA, Lambris JD. Complement in cancer: untangling an intricate relationship. Nat Rev Immunol. 2018; 18(1): 5-18.

[86] RevelM, Sautès-Fridman C, FridmanW-H, RoumeninaLT. C1q+ macrophages: passengers or drivers of cancer progression. Trends Cancer. 2022; 8(7): 517-526.

[87] LiY, JiangL, ChenY, et al. Specific lineage transition of tumor-associated macrophages elicits immune evasion of ascitic tumor cells in gastric cancer with peritoneal metastasis. Gastric Cancer. 2024; 27(3): 519-538.

[88] ZhangS, PengW, WangH, et al. C1q+ tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion. J Immunother Cancer. 2023; 11(8): e007441.

[89] LiljedahlE, Konradsson E, GustafssonE, et al. Combined anti-C1-INH and radiotherapy against glioblastoma. BMC Cancer. 2023; 23(1): 106.

[90] DingP, LiL, LiL, et al. C5aR1 is a master regulator in colorectal tumorigenesis via immune modulation. Theranostics. 2020; 10(19): 8619-8632.

[91] XiaX, ZhangZ, ZhuC, et al. Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications. Nature Communications. 2022; 13(1): 1017.

[92] LiX, HuaiQ, ZhuC, et al. GDF15 ameliorates liver fibrosis by metabolic reprogramming of macrophages to acquire anti-inflammatory properties. Cell Mol Gastroenterol Hepatol. 2023; 16(5): 711-734.

[93] StraussJ, HeeryCR, SchlomJ, et al. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ in advanced solid tumors. Clin Cancer Res. 2018; 24(6): 1287-1295.

[94] NiuM, YiM, WuY, et al. Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy. J Hematol Oncol. 2023; 16(1): 94.

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