Abstract SY22-02: Tumor suppression by p62 through the metabolic reprogramming of the stroma
Authors: Moscat Jorge 
Published: July 2017

Abstract
Large-scale genomic and transcriptomic interrogation of cancer has underscored the complexity of its genetic landscape, revealing a massive number of genetic alterations that results in the impossibility of distinguishing ‘‘driver’’ from ‘‘passenger’’ mutations. This makes oncogene-targeting therapies extremely challenging. This variability is well exemplified in hepatocellular carcinoma (HCC), in which more than 28,000 different somatic mutations have been identified. HCC development is a relatively long and complex process including chronic hepatitis, fibrosis, cirrhosis, and stromal activation, which are key mediators of a microenvironment conducive to tumorigenesis. Infection with hepatitis B and C viruses (HBV and HCV) has been considered the major HCC risk factor. Not surprisingly, obesity-induced nonalcoholic fatty liver disease (NAFLD), and its more severe consequence nonalcoholic steatohepatitis (NASH), have progressively become critical promoters of HCC. Chronic liver injury sets in motion a vicious circle of hepatocyte cell death, inflammation, and fibrosis that results in cirrhosis and cancer. A critical player in that process is hepatic stellate cells (HSCs). Recent reports highlight the potential central role of HSCs in the generation of proinflammatory signals important for HCC development. More recently, the study of pancreatic cancer suggests that pancreatic stellate cell reprogramming by targeting the vitamin D receptor (VDR) might improve therapeutic responses. Nononcogenic addiction can reveal new tumor vulnerabilities that can be exploited therapeutically for cancer treatment. In this regard, metabolic reprogramming and autophagy are progressively being considered as a new, rich source of possible therapeutic targets in cancer irrespective of the genetic landscape of the tumor. p62 is a signaling and autophagy adaptor that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). p62 was the first identified autophagy adaptor; however, at least other four other proteins have similar functions, including NBR1, TAX1BP1, NDP52, and OPTN. Importantly, p62 is a signaling regulator residing in the late endosome lysosome, and unlike other autophagy adaptors except for NBR1, p62 is also a central regulator of signaling pathways controlling cell survival and growth. This is because it interacts with key signaling proteins through well-defined structural elements. Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Importantly, we show that the upregulation of p62 in hepatocytes during HCC initiation is necessary and sufficient for tumor induction in mice and is highly expressed in human HCC patients. The mechanism for this relies on the ability of p62 to activate hepatocyte NRF2 and mTORC1 pathways and differs from its protumorigenic role in lung adenocarcinomas that mostly relies on the activation of NF-κB. However, although p62 is a protumorigenic molecule in epithelial cancer cells, more recent results reveal that it plays a tumor-suppressor role in the stroma. Interestingly, most studies addressing the role of p62 in cancer have focused on its function in transformed epithelial cells, but only very recently has the concept of p62 as a tumor suppressor in the cancer stroma emerged from our studies of prostate cancer. We discuss recent observations demonstrating a novel role of p62 as a promoter of stromal reprogramming in both prostate cancer and HCC due to its ability to repress the stromal activation of prostate fibroblasts and HSCs in the liver, through different mechanisms. This suggests that in parallel to epithelial cancer heterogeneity, there is a completely unexplored diversity of stromal cells that utilize distinct mechanisms to impact tumor initiation and progression. We propose that therapies aimed at repressing the downregulation of stromal p62, and likely that of other autophagy adaptors, will positively impact therapies targeting the tumor epithelium.
Citation Format: Jorge Moscat. Tumor suppression by p62 through the metabolic reprogramming of the stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY22-02. doi:10.1158/1538-7445.AM2017-SY22-02