Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation

Tape, C. J. et al. (2016) Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell, 165(4), pp. 910-920. (doi: 10.1016/j.cell.2016.03.029) (PMID:27087446) (PMCID:PMC4868820)

Abstract

Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumor cell signaling via stromal 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 fibroblasts, 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 and 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Miller, Professor Crispin
• Authors: Tape, C. J., Ling, S., Dimitriadi, M., McMahon, K. M., Worboys, J. D., Leong, H. S., Norrie, I. C., Miller, C., Poulogiannis, G., Lauffenburger, D. A., and Jørgensen, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell
• Publisher: Cell Press
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Published Online: 14 April 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Cell 165:910-920
• Publisher Policy: Reproduced under a Creative Commons Licence