title: Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.
abstract: 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. VIDEO ABSTRACT.
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Tape
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ling
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Dimitriadi
authors.affiliation: Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McMahon
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Worboys
authors.affiliation: Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Leong
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Ida C
authors.initials: IC
authors.lastname: Norrie
authors.affiliation: Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Crispin J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: George
authors.initials: G
authors.lastname: Poulogiannis
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Electronic address: claus.jorgensen@cruk.manchester.ac.uk.
authors.forename: Claus
authors.initials: C
authors.lastname: Jørgensen
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology*; D002450:Cell Communication; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism; D020543:Proteome / Q000032:analysis / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; D020543:Proteome; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)