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 (KRAS[superscript G12D]) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed h...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/107657 https://orcid.org/0000-0001-7004-8227 |
| _version_ | 1811090698146938880 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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 |
| author_sort | Ling, Stephanie |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T14:50:27Z |
| format | Article |
| id | mit-1721.1/107657 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:50:27Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1076572022-10-01T22:51:47Z Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation 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 Massachusetts Institute of Technology. Department of Biological Engineering Tape, Christopher Lauffenburger, Douglas A 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. Wellcome Trust (London, England) (Sir Henry Wellcome Fellowship 098847/Z/12/Z) National Institutes of Health (U.S.) (Grants U54-CA112967 and R01-CA96504) Rosetrees Trust (M286) 2017-03-22T20:08:18Z 2017-03-22T20:08:18Z 2016-04 2016-02 Article http://purl.org/eprint/type/JournalArticle 0092-8674 http://hdl.handle.net/1721.1/107657 Tape, Christopher J. et al. “Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.” Cell 165.4 (2016): 910–920. https://orcid.org/0000-0001-7004-8227 en_US http://dx.doi.org/10.1016/j.cell.2016.03.029 Cell Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | 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 Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation |
| title | Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation |
| title_full | Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation |
| title_fullStr | Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation |
| title_full_unstemmed | Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation |
| title_short | Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation |
| title_sort | oncogenic kras regulates tumor cell signaling via stromal reciprocation |
| url | http://hdl.handle.net/1721.1/107657 https://orcid.org/0000-0001-7004-8227 |
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