title: p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis.
abstract: Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner. We identified fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Systemic down-regulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor-suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38MAPK-hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis, while blocking this process could have far-reaching therapeutic implications.
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology, and Research), Biopolis, Singapore 138673.
authors.forename: Anna
authors.initials: A
authors.lastname: Brichkina
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertero
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology, and Research), Biopolis, Singapore 138673.
authors.forename: Hui Mun
authors.initials: HM
authors.lastname: Loh
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology, and Research), Biopolis, Singapore 138673.
authors.forename: Nguyet Thi Minh
authors.initials: NT
authors.lastname: Nguyen
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France.|U1081, INSERM (Institut National de la Santé et de la Recherche Médicale), Nice 06107, France.|UMR 7284, CNRS (Centre National de la Recherche Scientifique), Nice 06107, France.|University of Nice-Sophia Antipolis, Nice 06300, France.|Centre Antoine Lacassagne, Nice 06100, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Emelyanov
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France.
authors.forename: Sidwell
authors.initials: S
authors.lastname: Rigade
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France.|U1081, INSERM (Institut National de la Santé et de la Recherche Médicale), Nice 06107, France.|UMR 7284, CNRS (Centre National de la Recherche Scientifique), Nice 06107, France.|University of Nice-Sophia Antipolis, Nice 06300, France.|Centre Antoine Lacassagne, Nice 06100, France.
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France.|U1081, INSERM (Institut National de la Santé et de la Recherche Médicale), Nice 06107, France.|UMR 7284, CNRS (Centre National de la Recherche Scientifique), Nice 06107, France.|University of Nice-Sophia Antipolis, Nice 06300, France.|Centre Antoine Lacassagne, Nice 06100, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France.|U1081, INSERM (Institut National de la Santé et de la Recherche Médicale), Nice 06107, France.|UMR 7284, CNRS (Centre National de la Recherche Scientifique), Nice 06107, France.|University of Nice-Sophia Antipolis, Nice 06300, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Gaggioli
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France.|U1081, INSERM (Institut National de la Santé et de la Recherche Médicale), Nice 06107, France.|UMR 7284, CNRS (Centre National de la Recherche Scientifique), Nice 06107, France.|University of Nice-Sophia Antipolis, Nice 06300, France.|Centre Antoine Lacassagne, Nice 06100, France.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Bulavin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D006820:Hyaluronic Acid; D048051:p38 Mitogen-Activated Protein Kinases
keywords: fibroblasts; hyaluronan; lung cancer; p38MAPK; tumor microenvironment