title: Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.
abstract: The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Valencia
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: University of Cincinnati Medical College, Cincinnati, OH 45267, USA.
authors.forename: Shadi
authors.initials: S
authors.lastname: Abu-Baker
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat-Pardos
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Ahn
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Reina-Campos
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.affiliation: University of Cincinnati Medical College, Cincinnati, OH 45267, USA.
authors.forename: Elias A
authors.initials: EA
authors.lastname: Castilla
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.|Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002450:Cell Communication; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D004734:Energy Metabolism; D005347:Fibroblasts / Q000201:enzymology* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D006360:Heat-Shock Proteins; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; C489427:MYC protein, human; D046912:Multiprotein Complexes; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C577686:interleukin-6, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D005947:Glucose