Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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 tumor epithelium are poorly understood. The signaling adapter p62 has been implicated as a positive regulator of epithelial tumorigenesis; however, its role in the stroma is unknown. We show here that p62 levels are reduced in the stroma of several tumors. Also, orthotopic and organotypic studies demonstrate that the loss of p62 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. Inhibition of the pathway by p62 deficiency results 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 modulation of metabolism in the tumor stroma. C57BL6 syngeneic TRAMP-C2Re3 cells (5×10^4) were injected orthotopically into the prostate of WT (n=6) or p62 KO (n=6) mice (C57BL6 background) and tumor growth was assessed, followed by transcriptome profiling of the orthotopic tumors (n=12).

ORGANISM(S): Mus musculus

SUBMITTER: Jorge Moscat

PROVIDER: E-GEOD-55587 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.

Valencia Tania T Kim Ji Young JY Abu-Baker Shadi S Moscat-Pardos Jorge J Ahn Christopher S CS Reina-Campos Miguel M Duran Angeles A Castilla Elias A EA Metallo Christian M CM Diaz-Meco Maria T MT Moscat Jorge J

Cancer cell 20140704 1

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 a ...[more]

PMID: 25002027

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Project description:The breast tumor microenvironment plays an active role in tumorigenesis. Molecular alterations, including epigenetic modifications to DNA, and changes in RNA and protein expression have been identified in tumor-associated stroma; however, there is considerable debate as to whether the stroma is characterized by genomic instability or whether detection of chromosomal alterations in the breast stroma is a reflection of technological artifact rather than the true genomic content of the tumor microenvironment. Methods: Surgically-removed breast stroma specimens from 112 women undergoing reductive mammoplasty (n=15), prophylactic mastectomy (N=6) or mastectomy for a diagnosis of breast disease (n=92) were frozen in optimal cutting temperature medium. Allelic imbalance (AI) analysis was performed in 484 stromal specimens from 98 women using a panel of 52 microsatellite markers; SNP data was generated from a subset of 86 stromal specimens using 250K SNP arrays (Affymetrix). Copy number alterations were identified using Partek Genomics Suite. Results: AI was not detected in 92% (444/484) of stroma specimens. When compared to previously generated AI data from 77 formalin-fixed, paraffin-embedded stroma specimens (Ellsworth et al., Ann Surg Oncol 2004), 32 (42%) of which harbored at least one detectable AI event, the frequency of AI in the FFPE specimens (4.62%) was significantly higher (P<0.0001) than that found in frozen specimens (0.45%). Of the stroma specimens assayed using SNP arrays 95% (82/86) had no detectable alterations and the 11 copy number changes were small and not shared between specimens. Conclusions: The data presented here support a model in which the tumor microenvironment is genetically stable. The direct comparison of copy number alterations between FFPE and frozen research-grade specimens using identical methodologies suggests that past reports of significant AI in breast stroma, both adjacent to and distant from the tumor, reflects artifact in the archival specimens caused by formalin-fixation, paraffin-embedding and tissue storage. 250K STY data was generated for 86 breast stromal specimens. The tissue specimens were analyzed by paired analysis to the SNP data from matched genomic (blood) DNAs

Dataset Information

Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis

Publications

Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.

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