Metabolic Reprogramming of Stromal Fibroblasts through p62-mTORC1 Signaling Promotes Inflammation and Tumorigenesis

• Published in: Cancer cell Vol. 26; no. 1; pp. 121 - 135
• Main Authors: Valencia, Tania, Kim, Ji Young, Abu-Baker, Shadi, Moscat-Pardos, Jorge, Ahn, Christopher S., Reina-Campos, Miguel, Duran, Angeles, Castilla, Elias A., Metallo, Christian M., Diaz-Meco, Maria T., Moscat, Jorge
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.07.2014
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acids - metabolism; Animals; Cell Communication; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Coculture Techniques; Energy Metabolism; Fibroblasts - enzymology; Fibroblasts - metabolism; Glucose - metabolism; Heat-Shock Proteins - deficiency; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HEK293 Cells; Humans; Inflammation - enzymology; Inflammation - genetics; Inflammation - pathology; Inflammation Mediators - metabolism; Interleukin-6 - metabolism; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neoplasm Invasiveness; Oxidative Stress; Prostatic Hyperplasia - enzymology; Prostatic Hyperplasia - genetics; Prostatic Hyperplasia - pathology; Prostatic Intraepithelial Neoplasia - enzymology; Prostatic Intraepithelial Neoplasia - genetics; Prostatic Intraepithelial Neoplasia - pathology; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; RNA Interference; Sequestosome-1 Protein; Signal Transduction; Stromal Cells - enzymology; Stromal Cells - pathology; Time Factors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transfection; Tumor Microenvironment
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2014.05.004

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. [Display omitted] •p62 levels are reduced in mouse and human tumor stroma•p62 loss in stromal fibroblasts resulted in increased epithelial tumorigenesis•p62 regulates stromal inflammation by mTor/c-Myc metabolic reprogramming•Stromal metabolic reprogramming is essential for IL-6-driven epithelial tumorigenesis Valencia et al. show that reduced levels of p62 in cancer-associated fibroblasts increase prostate epithelial cell cancer tumorigenesis. They show that p62 modulates stromal cell glucose and amino acid metabolism through an mTORC1/c-Myc pathway, resulting in increased secretion of tumor-promoting IL-6.