Abstract 3714: Role of miR-29a in pancreatic stellate cell mediated stromal remodeling in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of malignancy with nearly equal incidence and mortality rates in patients. The disease is characterized by dense desmoplastic tumor-associated stroma, which prevents effective therapeutic delivery to the tumor core and confers resistance to chemotherapy. The central effectors of such characteristic stroma in PDAC are the pancreatic stellate cells (PSCs), which are activated by autocrine and paracrine signaling of the tumor cells and deposit excessive amounts of extracellular matrix (ECM) proteins- the major component of the stroma. This interaction of the PSCs with the cancer cells greatly promote tumor progression and metastasis. In our previous work, we demonstrated that microRNA (miRNA) 29a plays a key role in PSC-mediated stromal reaction, and that the loss of the molecule in PSCs accelerates ECM protein accumulation and cancer growth. To understand the mechanistic regulation of miR-29a in PDAC stroma, we performed RNA-seq analysis with human PSCs (hPSCs), which identified 197 genes that differentially expressed with miR-29a overexpression at a false discovery rate less than 0.05. This included 19 downregulated and one upregulated direct miR-29a targets. Of these, expression of six key targets with the highest fold changes, namely, ADAMTS2, IGF1, E2F7, LAMC1, CLDN1 and ITGA6 by miR-29a were validated at the protein level in hPSCs. In addition, canonical pathways associated with the target genes and their network interactions were assessed, which identified the association of the key targets with pathways such as collagen synthesis, insulin signaling, TGF-β and PI3K/Akt pathways. ADAMTS2, E2F7, LAMC1 and CLDN1 expressions were significantly upregulated in PDAC patient pancreas compared to that in healthy individuals. Together, the current study presents a comprehensive understanding of miR-29a mediation in stromal remodeling, and elucidates associated pathways in regulating PSCs9 function in PDAC desmoplasia and pancreatic carcinogenesis. Citation Format: Shatovisha Dey, Sheng Liu, Tricia D. Factora, Solaema Taleb, Primavera Riverahernandez, Lata Udari, Xiaoling Zhong, Jun Wan, Janaiah Kota. Role of miR-29a in pancreatic stellate cell mediated stromal remodeling in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3714.