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Cell. 2016 May 5;165(4):910-20. doi: 10.1016/j.cell.2016.03.029. Epub 2016 Apr 14.

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.

Author information

1
The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
3
Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
4
The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
5
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
6
The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Electronic address: claus.jorgensen@cruk.manchester.ac.uk.

Abstract

Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRAS(G12D)) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRAS(G12D) signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRAS(G12D) 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 KRAS(G12D). Consequently, reciprocal KRAS(G12D) produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRAS(G12D) 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. VIDEO ABSTRACT.

PMID:
27087446
PMCID:
PMC4868820
DOI:
10.1016/j.cell.2016.03.029
[Indexed for MEDLINE]
Free PMC Article

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