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Oncogenic mutations regulate signaling within both tumour cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumour cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analysed heterocellular KRASG12D signalling in pancreatic ductal adenocarcinoma (PDA) cells.
Tumour cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signalling in the tumour cells. Reciprocal signalling employs additional kinases and doubles the number of regulated signalling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumour cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone.
Reciprocal signalling regulates tumour cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signalling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signalling in cancer.
Oncogenic mutations regulate signaling within both tumour cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumour cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analysed heterocellular KRASG12D signalling in pancreatic ductal adenocarcinoma (PDA) cells.
Tumour cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signalling in the tumour cells. Reciprocal signalling employs additional kinases and doubles the number of regulated signalling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumour cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone.
Reciprocal signalling regulates tumour cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signalling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signalling in cancer.
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Amaya Virós
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“We are so pleased to have received the funding to enable us to test our hypothesis in the lab. If we can create a new medicine that can precisely target a specific type of cell within the tumour, and restore anti-cancer immune responses, this will be a game-changer for oesophageal cancer patients “
Sara Valpione
Former Institute Clinical Fellow and now Clinician in Residence within the CRUK National Biomarker Centre
“My charity bake sales – known as “David’s Great British Bake Off” – are always a hit, home baked products taste so much better than shop bought and are greatly appreciated by staff!”
David Jenkins
Purchasing Officer
“We’ve seen some remarkable responses, with an improvement for some patients within days. This is an early phase trial so there’s a lot more work to do. But the data we have so far is very encouraging and could help many thousands of people in the future”
Tim Somervaille
Senior Group Leader
“It is a pleasure to introduce my team who work to deliver our research goals. We work in a friendly and collaborative environment, supporting each other’s projects. “
Amaya Virós
CRUK Advanced Clinician Scientist Fellow