Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

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...

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Bibliographic Details
Published in:Cell 2016-05, Vol.165 (4), p.910-920
Main Authors: Tape, Christopher J., Ling, Stephanie, Dimitriadi, Maria, McMahon, Kelly M., Worboys, Jonathan D., Leong, Hui Sun, Norrie, Ida C., Miller, Crispin J., Poulogiannis, George, Lauffenburger, Douglas A., Jørgensen, Claus
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Cell Communication
Humans
Mice
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Phosphoproteins - analysis
Phosphoproteins - metabolism
Proteome - analysis
Proteome - metabolism
Proto-Oncogene Proteins p21(ras) - metabolism
Signal Transduction
Stromal Cells - metabolism
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Summary: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. [Display omitted] [Display omitted] •KRASG12D establishes a reciprocal signaling axis via heterotypic stromal cells•Reciprocal signaling further regulates tumor cell signaling downstream of KRASG12D•Reciprocal signaling regulates tumor cell behavior via AXL/IGF1R-AKT•Heterocellularity expands tumor cell signaling beyond cell-autonomous pathways Cell-specific proteome labeling reveals that oncogenic KRAS stimulates stromal cells to initiate reciprocal signaling back to pancreatic tumor cells, thereby enabling signaling capacity beyond the traditionally studied cell-autonomous pathways.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2016.03.029