Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation
Author(s)Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M.; Worboys, Jonathan D.; Leong, Hui Sun; Norrie, Ida C.; Miller, Crispin J.; Poulogiannis, George; Jørgensen, Claus; Tape, Christopher; Lauffenburger, Douglas A; ... Show more Show less
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Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRAS[superscript G12D]) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRAS[superscript G12D] signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRAS[superscript 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[superscript G12D]. Consequently, reciprocal KRAS[superscript G12D] produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRAS[superscript 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.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering
Tape, Christopher J. et al. “Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.” Cell 165.4 (2016): 910–920.
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