Abstract 2414: Retinoic acid induced 14 drives pancreatic cancer progression and metastasis

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with very poor outcomes - fewer than 10 percent of patients survive beyond five years after diagnosis. The primary hurdles facing PDAC patients and clinicians are early dissemination, a lack of therapeutic targets and desmoplasia that renders the primary tumor refractory to chemotherapy. In this regard, we have previously reported that pseudopodium-enriched atypical kinase 1 (PEAK1) and integrin α1 (ITGA1) mediate gemcitabine resistance and metastasis in PDAC. To identify new mechanisms of PDAC progression, we mined the Cancer BioPortal and Human Cell Map BioID databases for additional pseudopodium-enriched (PDE) proteins that predict poor patient outcomes, correlate with PEAK1 and ITGA1 expression in PDAC, and interact with PEAK1 and ITGA1. Here, we identify Retinoic Acid Induced 14 (RAI14, Ankycorbin or NORPEG) as a new candidate driver of PDAC that is a constituent of the KRasG12D PDAC cell autonomous phosphoproteome, localizes to cytoskeleton/adhesion domains in PDAC cells and correlates in expression with ITGA1-binding collagens in PDAC. Knockdown or knockout of RAI14 in KRas mutant PDAC cells impaired adhesion-dependent proliferation/survival in vitro and tumor growth and metastasis in vivo. Single cell cyclic immunofluorescence (CycIF) further revealed that RAI14 supports a subpopulation of PDAC cells positive for proliferation, epithelial to mesenchymal transition (EMT) and antiapoptotic programs. By using a RAI14-focused bioinformatics pipeline in combination with proteomic and immunofluorescence data on the composition of ITGA1-dependent adhesion complexes in PDAC cells, we identified Polo-Like Kinase 1 (PLK1) as a candidate that may control RAI14 function and adhesion-regulated mitosis during PDAC progression. Notably, the potency of volasertib, a PLK1-specific inhibitor, was reduced in RAI14 knockout cells, supporting a model in which RAI14 mediates adhesion-dependent PLK1 functions in PDAC. Taken together, these studies uncover a mechanism for RAI14-driven PDAC progression and the development of strategies to increase chemotherapy sensitivity, reduce primary/metastatic tumor burden and improve patient outcomes. Citation Format: Farhana Runa, Luke Tomaneng, Yvess Adamian, Nathan Cox, Albert-Fred Aquino, Matthew Wallace, Carolina Gonzalez, Kishan Bhakta, Malachia Hoover, Laurelin Wolfenden, Jonathan D. Humphries, Martin J. Humphries, Michael Boyce, Jonathan A. Kelber. Retinoic acid induced 14 drives pancreatic cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2414.