TY - JOUR
T1 - Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation
AU - Tape, Christopher J.
AU - Ling, Stephanie
AU - Dimitriadi, Maria
AU - McMahon, Kelly M.
AU - Worboys, Jonathan D.
AU - Leong, Hui Sun
AU - Norrie, Ida C.
AU - Miller, Crispin J.
AU - Poulogiannis, George
AU - Lauffenburger, Douglas A.
AU - Jørgensen, Claus
N1 - This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Open Access funded by Wellcome Trust.
Tape et al., Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation, Cell 165, 1-11,( May 5, 2016), copyright 2016 The Authors,
http://dx.doi.org/10.1016/j.cell.2016.03.029.
PY - 2016/5/5
Y1 - 2016/5/5
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2016.03.029
DO - 10.1016/j.cell.2016.03.029
M3 - Article
C2 - 27087446
SN - 0092-8674
VL - 165
SP - 910
EP - 920
JO - Cell
JF - Cell
IS - 4
ER -