title: p38MAPK plays a crucial role in stromal-mediated tumorigenesis.
abstract: Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAF) express factors that promote tumorigenesis that are collectively referred to as the senescence-associated secretory phenotype (SASP). Despite their importance in tumorigenesis, the mechanisms that control TME-derived factor expression remain poorly understood. Here, we address a key unanswered question: how the SASP is sustained in senescent fibroblasts and CAFs. We find that the mitogen-activated protein kinase p38 (p38MAPK) controls AUF1 occupancy on SASP mRNAs and thus controls their stability. The importance of this regulatory mechanism is underscored by our findings that stromal-specific p38MAPK inhibition abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Our data suggest that targeting SASP mRNA stability through inhibition of p38MAPK will significantly aid the development of clinical strategies to target the TME.
  
  
  CONCLUSIONS
  The TME plays a key role in tumorigenesis. We demonstrate that p38MAPK governs a posttranscriptional mechanism that sustains the protumorigenic SASP. Inhibition of p38MAPK abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Thus, p38MAPK is a TME-specific Achilles' heel that may be exploited as a new therapeutic target.
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elise
authors.initials: E
authors.lastname: Alspach
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Flanagan
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Ruhland
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ermira
authors.initials: E
authors.lastname: Pazolli
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Donlin
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Timothy
authors.initials: T
authors.lastname: Marsh
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Joseph
authors.initials: J
authors.lastname: Monahan
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: McAllister
authors.affiliation: Authors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Departments of Cell Biology and Physiology, Medicine, and Pathology and Immunology; BRIGHT Institute, Washington University School of Medicine; Departments of Biochemistry & Molecular Biology and Molecular Microbiology & Immunology, Saint Louis University School of Medicine; Confluence Life Sciences, Inc., St. Louis, Missouri; Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Harvard Stem Cell Institute and Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas sheila.stewart@wust
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Stewart
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630987:Hnrpd protein, mouse; D007093:Imidazoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580