Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.
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ICR Authors
Authors
Tape, CJ
Ling, S
Dimitriadi, M
McMahon, KM
Worboys, JD
Leong, HS
Norrie, IC
Miller, CJ
Poulogiannis, G
Lauffenburger, DA
Jørgensen, C
Ling, S
Dimitriadi, M
McMahon, KM
Worboys, JD
Leong, HS
Norrie, IC
Miller, CJ
Poulogiannis, G
Lauffenburger, DA
Jørgensen, C
Document Type
Journal Article
Date
2016-06-16
Date Accepted
2016-03-17
Date Available
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.
Citation
Cell, 2016, 165 (7), pp. 1818 - ?
Source Title
Publisher
CELL PRESS
ISSN
0092-8674
eISSN
1097-4172
Collections
Research Team
Signalling & Cancer Metabolism
Cell Communication
Oncogene
Cell Communication
Oncogene