ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma.

TitleATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma.
Publication TypeJournal Article
Year of Publication2017
AuthorsLinares JF, Cordes T, Duran A, Reina-Campos M, Valencia T, Ahn CS, Castilla EA, Moscat J, Metallo CM, Diaz-Meco MT
JournalCell Metab
Volume26
Issue6
Pagination817-829.e6
Date Published2017 Dec 05
ISSN1932-7420
KeywordsActivating Transcription Factor 4, Animals, Asparagine, Cancer-Associated Fibroblasts, Carcinogenesis, Cell Line, Tumor, Glucose, Glutamine, HEK293 Cells, Humans, Male, Mice, Prostatic Neoplasms, RNA-Binding Proteins, Stress, Physiological, Stromal Cells, Tumor Microenvironment, Ubiquitination
Abstract

Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.

DOI10.1016/j.cmet.2017.09.001
Alternate JournalCell Metab
PubMed ID28988820
PubMed Central IDPMC5718961
Grant ListR01 DK108743 / DK / NIDDK NIH HHS / United States
R01 CA192642 / CA / NCI NIH HHS / United States
R01 CA218254 / CA / NCI NIH HHS / United States
R01 CA172025 / CA / NCI NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
R01 CA188652 / CA / NCI NIH HHS / United States
Related Faculty: 
Juan Francisco Linares Rodriguez, Ph.D. Maria Diaz-Meco Conde, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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