Abstract A25: Heterozygous deletion of Dicer promotes anoikis and reduces pancreatic cancer metastasis in vivo

Abstract

Abstract Previous studies have suggested that Dicer acts as a haploinsufficient tumor and metastasis suppressor. In contrast, studies of human pancreatic ductal adenocarcinoma (PDAC) tumors and cell lines demonstrate upregulation of miRNAs with progression. And yet, disagreement exists regarding which miRNA-target relationships are critical to tumor biology. We therefore sought to ascertain the effects of global miRNA suppression on pancreatic tumorigenesis using a conditional loss-of-function allele of Dicer in a mouse model of pancreatic cancer. Given the common observation of elevated miRNA expression in PDAC, we hypothesized that loss of one allele of Dicer would inhibit pancreatic tumorigenesis and prolong overall survival. Ptf1a-Cre-mediated deletion of Dicer in the pancreas demonstrated that homozygous loss is not tolerated, leading to progressive acinar cell atrophy as mice aged and suggesting that Dicer activity is required for the long-term viability of this cell type in the postnatal pancreas. However, mice with heterozygous deletion of Dicer had developmentally normal pancreata that were maintained into adulthood. To assess the impact of Dicer gene deletion on pancreatic tumorigenesis in vivo, we used the RCAS-TVA pancreatic cancer model incorporating polyoma virus middle T antigen (PyMT) expression and p53 gene deletion. We found that heterozygous deletion of Dicer did not impact overall animal survival; primary tumor size, number, or burden; or tumor histology (acinar, ductal, or poorly differentiated carcinomas). However, loss of one copy of Dicer robustly inhibits metastasis of PyMT-driven pancreatic tumors, with metastases seeding from 12.5% of DicerFL/WT tumors versus 54.5% of DicerWT/WT tumors (p<0.05). Intriguingly, cell lines derived from DicerWT/WT and DicerFL/WT tumors also display no differences in their proliferative rate, migration, invasion, soft agar colony formation, or survival following serum-starvation. However, DicerFL/WT cancer cell lines exhibit markedly increased sensitivity to cell death from loss of attachment (anoikis) compared to DicerWT/WT lines (50% survival vs 76% survival at 24 hours; p<0.01). This result provides a potential explanation for the reduced metastasis seen with DicerFL/WT tumors in our mouse model, and it invites further investigation into the precise miRNAs responsible for this phenotype. Importantly, our findings are consistent with observations in human pancreatic cancer, where upregulation of oncogenic miRNAs is commonly seen in late-stage disease. However, our data are in disagreement with published literature implicating Dicer as a tumor suppressor whose expression is decreased during carcinoma progression in other tumor contexts. This discrepancy highlights the importance of cellular context in understanding miRNA biology and the need for more thorough in vivo genetic experimentation to dissect the role of miRNAs in pancreatic carcinogenesis. Citation Format: Brian Quattrochi, Brian C. Lewis. Heterozygous deletion of Dicer promotes anoikis and reduces pancreatic cancer metastasis in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A25.