Abstract A34: Oncogenic KRAS regulates pancreatic cancer cell signaling via stromal reciprocation

Abstract

Abstract Pancreatic Ductal Adenocarcinoma is characterized by a reactive stroma, which modifies tumor progression and response to therapy. Oncogenic mutations regulate signaling both within tumor cells and adjacent stromal cells. However, defining whether oncogenes can regulate tumor cell signaling and phenotypic behavior via stromal cells is of importance to understand mechanisms of disease progression and response to therapy. Here we show that oncogenic KRAS (KRASG12D) regulates pancreatic cancer cell signaling via stromal stellate cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic stellate cells, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation, apoptosis, and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Citation Format: Christopher Tape, Stephanie Ling, Maria Dimitriadi, Kelly McMahon, Jonathan Worboys, Hui S. Leong, Ida Norrie, Crispin Miller, George Poulogiannis, Douglas Lauffenburger, Claus Jorgensen.{Authors}. Oncogenic KRAS regulates pancreatic cancer cell signaling via stromal reciprocation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A34.