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

Publication date: 5 December 2017
Source:Cell Metabolism, Volume 26, Issue 6
Author(s): Juan F. Linares, Thekla Cordes, Angeles Duran, Miguel Reina-Campos, Tania Valencia, Christopher S. Ahn, Elias A. Castilla, Jorge Moscat, Christian M. Metallo, Maria T. Diaz-Meco
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.

Graphical abstract

Teaser

Tumors suffer nutrient stress and need to reprogram their metabolism to survive. Linares et al. elucidate a key role for p62 in rewiring the metabolism of tumor stromal fibroblasts to sustain growth of both stromal and epithelial tumor cells, thus making p62 a novel cancer vulnerability point.


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