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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE55587 | GEO | 2014/07/23

SECONDARY ACCESSION(S): PRJNA240155

REPOSITORIES: GEO

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

Project description: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).

2014-07-23 | E-GEOD-55587 | biostudies-arrayexpress

ATF4 inhibition by p62 represses stromal metabolic reprogramming and tumorigenesis

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ATF4 inhibition by p62 represses stromal metabolic reprogramming and tumorigenesis II

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The lactate-NAD axis activate cancer associated fibroblasts by downregulating p62 [Quantseq]

Project description:Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulate p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impaired poly(ADP-Ribose)-polymerase 1 (PARP1) activity. PARP1 inhibition blocked the poly(ADP-ribosyl)ation of the AP1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ rendered CAFs less active. PARP inhibitors, such as Olaparib, mimicked lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies utilizing Olaparib would benefit from strategies aimed at inhibiting CAF activity.

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The lactate-NAD axis activate cancer associated fibroblasts by downregulating p62 [RNA-seq]

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The lactate-NAD axis activate cancer associated fibroblasts by downregulating p62 [OLA ATAC-seq]

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The lactate-NAD axis activate cancer associated fibroblasts by downregulating p62 [Lactate ATAC-seq]

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Adipocyte p62/SQSTM1 suppresses tumorigenesis through the opposite regulation of metabolism in fat and tumor

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2022-01-19 | GSE146229 | GEO

Comparison of ATG5-/- Bcl-2 tumors expressing p62-GFP versus those expressing EGFP

Project description:Autophagy is a starvation response that facilitates cell survival under metabolic stress and yet defects in autophagy promote tumorigenesis. While the role of understarvation is relatively clearer, its mechanistic role in tumorigenesis is poorly understood. We show that defective autophagy promotes protein damage and accumulation of p62, a marker for protein damage accumulation that is cleared through autophagy pathway. The failure to eliminate p62 in autophagy-defective cells, leads to deregulation of cell signalling and gene expression and ultimately promotes tumorigenesis. Thus defective-autophagy is a mechanism for p62 accumulation commonly observed in human tumors. Keywords: Autophagy, p62, Signal transduction, NF-kB, tumorigenesis.

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