Arid1a deficiency sensitises pancreatic cancer to fatty acid synthase inhibition

Abstract

Background: Mutations in the AT-rich interactive domain-containing protein 1A (ARID1A) gene are frequently found in pancreatic cancer. However, the contribution of ARID1A inactivation to pancreatic tumorigenesis remains unclear. Previous work showed that depletion of Arid1a at early developmental stages induces metabolic disturbance and diabetes mellitus in mice.

Methods and Results: In this study, we generated a genetically engineered mouse model harboring both K-ras mutation and Arid1a depletion (KAR mice). We found that the combination of these two genetic alterations induces pancreatic tumor formation. Compared to tumors in K-ras and Tp53-mutant mice (KPC mice), KAR tumors showed increased immune cell infiltration and reduced stromal activation. Transcriptomic analysis revealed significant upregulation of fatty acid metabolism and fatty acid synthase (FASN) in KAR tumors, with ARID1A directly regulating Fasn expression. Pharmacological inhibition of FASN reduced tumor cell viability and slowed tumor progression in vivo. Analysis of clinical datasets showed an inverse correlation between ARID1A and FASN expression, with high FASN levels predicting worse patient survival.

Conclusion: ARID1A deficiency promotes fatty acid metabolism to accelerate pancreatic tumorigenesis. FASN is a potential therapeutic target for ARID1A-deficient pancreatic cancer.Mutations in AT-rich interactive domain-containing protein 1A (ARID1A) gene are frequently found in pancreatic cancer. However, the contribution of ARID1A inactivation to pancreatic tumourigenesis is not well-characterised. Previously, we generated genetically engineered mice with specific depletion of Arid1a gene in the pancreas and found that depletion of Arid1a at early developmental stage induced metabolic disturbance and diabetes mellitus. In this study, we established a mouse model with K-ras mutation and Arid1a depletion (KAR mice) in the pancreas and showed that the combination of these two genetic alterations induced pancreatic tumour formation. Compared to the tumours developed in mice with K-ras mutation and Tp53 deficiency (KPC mice), KAR tumours exhibited increased immune cell infiltration and reduced stromal activation. Our results demonstrated a significant upregulation of fatty acid metabolism and fatty acid synthase (FASN) in the KAR tumours, with ARID1A directly regulating FASN expression. Inhibition of FASN by chemical inhibitor reduced tumour cell viability and slowed tumour progression in mice. Clinical data revealed a negative correlation between ARID1A expression and FASN, with high FASN levels associated with worse patient survival. Collectively, ARID1A deficiency upregulates fatty acid metabolism to accelerate pancreatic tumourigenesis and FASN is a potential therapeutic target for ARID1A-deficient pancreatic cancer.

Keywords

ARID1A / fatty acid metabolism / fatty acid synthase (FASN) / K-ras mutation / pancreatic cancer / tumour microenvironment

References

[1] Lee JC, Ahn S, Paik KH, et al. Clinical impact of neoadjuvant treatment in resectable pancreatic cancer: a systematic review and meta-analysis protocol. BMJ Open. 2016; 6: e010491.

[2] Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011; 364: 1817-1825.

[3] Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012; 491: 399-405.

[4] Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015; 518: 495-501.

[5] Witkiewicz AK, McMillan EA, Balaji U. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015; 6: 6744.

[6] Wu JN, Roberts CW. ARID1A mutations in cancer: another epigenetic tumor suppressor?. Cancer Discov. 2013; 3: 35-43.

[7] Zhu YP, Sheng LL, Wu J, et al. Loss of ARID1A expression is associated with poor prognosis in patients with gastric cancer. Hum Pathol. 2018; 78: 28-35.

[8] Bitler BG, Wu S, Park PH, et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol. 2017; 19: 962-973.

[9] Zhang X, Sun Q, Shan M, et al. Promoter hypermethylation of ARID1A gene is responsible for its low mRNA expression in many invasive breast cancers. PLoS ONE. 2013; 8: e53931.

[10] Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 1996; 10: 2117-2130.

[11] Jiang C, Pugh BF. Nucleosome positioning and gene regulation: advances through genomics. Nat Rev Genet. 2009; 10: 161-172.

[12] Nagarajan S, Rao SV, Sutton J, et al. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat Genet. 2020; 52: 187-197.

[13] Kimura Y, Fukuda A, Ogawa S, et al. ARID1A maintains differentiation of pancreatic ductal cells and inhibits development of pancreatic ductal adenocarcinoma in mice. Gastroenterology. 2018; 155: 194-209.

[14] Wang W, Friedland SC, Guo B, et al. ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas. Gut. 2019; 68: 1245-1258.

[15] Wang SC, Nassour I, Xiao S, et al. SWI/SNF component ARID1A restrains pancreatic neoplasia formation. Gut. 2019; 68: 1259-1270.

[16] Ferri-Borgogno S, Barui S, McGee AM, et al. Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis. Cancers (Basel). 2020; 12: 2695.

[17] Kuo TL, Cheng KH, Chen LT, Hung WC. ARID1A loss in pancreas leads to islet developmental defect and metabolic disturbance. iScience. 2023; 26: 105881.

[18] Celen C, Chuang JC, Shen S, et al. Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling. Cell Rep. 2022; 41: 111581.

[19] Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer—clinical challenges and opportunities. Nat Rev Clin Oncol. 2020; 17: 527-540.

[20] Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020; 30: R921-R925.

[21] Ren B, Cui M, Yang G, et al. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer. 2018; 17: 108.

[22] Baron M, Veres A, Wolock SL, et al. A single-cell transcriptomic map of the human and mouse pancreas reveals inter- and intra-cell population structure. Cell Syst. 2016; 3: 346-360.

[23] Shen J, Peng Y, Wei L, et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 2015; 5: 752-767.

[24] Williamson CT, Miller R, Pemberton HN, et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat Commun. 2016; 7: 13837.

[25] Li R, Xiong G, Zhao J, Yang L. Targeting the alterations of ARID1A in pancreatic cancer: tumorigenesis, prediction of treatment, and prognostic value. Am J Transl Res. 2022; 14: 5952-5964.

[26] Rehman H, Chandrashekar DS, Balabhadrapatruni C, et al. ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors. JCI Insight. 2022; 7(16): e155899.

[27] Yang L, Yang G, Ding Y, et al. Inhibition of PI3K/AKT signaling pathway radiosensitizes pancreatic cancer cells with ARID1A deficiency in vitro. J Cancer. 2018; 9: 890-900.

[28] Alldredge JK, Eskander RN. EZH2 inhibition in ARID1A mutated clear cell and endometrioid ovarian and endometrioid endometrial cancers. Gynecol Oncol Res Pract. 2017; 4: 17.

[29] O'Farrell M, Duke G, Crowley R, et al. FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models. Sci Rep. 2022; 12: 15661.

[30] Wang J, Lin W, Li R, et al. The deubiquitinase USP13 maintains cancer cell stemness by promoting FASN stability in small cell lung cancer. Front Oncol. 2022; 12: 899987.

[31] Ruiz-Perez MV, Sainero-Alcolado L, Oliynyk G, et al. Inhibition of fatty acid synthesis induces differentiation and reduces tumor burden in childhood neuroblastoma. iScience. 2021; 24: 102128.

[32] Zaytseva YY, Rychahou PG, Le AT. Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer. Oncotarget. 2018; 9: 24787-24800.

[33] Gouw AM, Eberlin LS, Margulis K. Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proc Natl Acad Sci. 2017; 114: 4300-4305.

[34] Kadry YA, Lee JY, Witze ES. Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis. Open Biol. 2021; 11: 210033.

[35] Bi L, Chiang JY, Ding WX, Dunn W, Roberts B, Li T. Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice. J Lipid Res. 2013; 54: 2754-2762.

[36] Goswami S, Chen Y, Anandhan S, et al. ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC. Sci Transl Med. 2020; 12(548): eabc4220.

[37] Sarshekeh AM, Alshenaifi J, Roszik J, et al. ARID1A mutation may define an immunologically active subgroup in patients with microsatellite stable colorectal cancer. Clin Cancer Res. 2021; 27: 1663-1670.

[38] Botta GP, Kato S, Patel H, et al. SWI/SNF complex alterations as a biomarker of immunotherapy efficacy in pancreatic cancer. JCI Insight. 2021; 6(18): e150453.

[39] Kuo TL, Cheng KH, Shan YS, Chen LT, Hung WC. β-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer. Theranostics. 2019; 9: 324-336.

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.