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Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Tape, CJ; Ling, S; Dimitriadi, M; McMahon, KM; Worboys, JD; Leong, HS; Norrie, IC; ... Jorgensen, C; + view all (2016) Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation. Cell , 165 (4) pp. 910-920. 10.1016/j.cell.2016.03.029. Green open access

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Abstract

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.

Type: Article
Title: Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cell.2016.03.029
Publisher version: https://doi.org/10.1016/j.cell.2016.03.029
Language: English
Additional information: © 2016 The Authors This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Pancreatic-Cancer, Induced Apoptosis, Sample Preparation, Hedgehog, Plasticity, Ras, Tumorigenesis, Requirement, Progression, Metabolism
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1563658
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