Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.

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Date
2016-06-16Author
Tape, CJ
Ling, S
Dimitriadi, M
McMahon, KM
Worboys, JD
Leong, HS
Norrie, IC
Miller, CJ
Poulogiannis, G
Lauffenburger, DA
Jørgensen, C
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Research team
Signalling & Cancer Metabolism
Cell Communication
Oncogene
Language
eng
Date accepted
2016-03-17
License start date
2016-06
Citation
Cell, 2016, 165 (7), pp. 1818 - ?
Publisher
CELL PRESS