No abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC.Experimental Design: The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n ¼ 163) transcriptomic data. This was followed by independent validation of the gene signature in the International Cancer Genome Consortium (ICGC, n ¼ 95), E-MTAB-6134 (n ¼ 288), and GSE71729 (n ¼ 123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate Cox regression analysis.Results: Our biomarker discovery effort identified a 15-gene immune, stromal, and proliferation (ISP) gene signature that significantly associated with poor OS [HR, 3.90; 95% confidence interval (CI), 2.36-6.41; P < 0.0001]. This signature also robustly predicted survival in three independent validation cohorts ICGC [HR,); P < 0.0001], E-MTAB-6134 [HR, 1.53 (1.14-2.04); P ¼ 0.004], and GSE71729 [HR, 2.33 (1.49-3.63); P < 0.0001]. Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all four cohorts; TCGA (AUC ¼ 0.94), ICGC (AUC ¼ 0.91), E-MTAB-6134 (AUC ¼ 0.80), and GSE71729 (AUC ¼ 0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort [n ¼ 119; HR, 2.62 (1.50-4.56); P ¼ 0.0004]. A nomogram was established which included the ISP, CA19-9, and T-and N-stage for eventual clinical translation.Conclusions: We report a novel gene signature for riskstratification and robust identification of patients with PDAC with poor molecular subtypes.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.