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Cancer Cell. 2018 Apr 9;33(4):770-784.e6. doi: 10.1016/j.ccell.2018.03.001.

Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor.

Author information

1
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Sanford Burnham Prebys Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
3
Institute for Diabetes and Obesity, Helmholtz Diabetes Center & German Center for Diabetes Research (DZD), Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
4
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: jmoscat@sbpdiscovery.org.
5
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: mdmeco@sbpdiscovery.org.

Abstract

Obesity is a leading risk factor for cancer. However, understanding the crosstalk between adipocytes and tumor cells in vivo, independently of dietary contributions, is a major gap in the field. Here we used a prostate cancer (PCa) mouse model in which the signaling adaptor p62/Sqstm1 is selectively inactivated in adipocytes. p62 loss in adipocytes results in increased osteopontin secretion, which mediates tumor fatty acid oxidation and invasion, leading to aggressive metastatic PCa in vivo. Furthermore, p62 deficiency triggers in adipocytes a general shutdown of energy-utilizing pathways through mTORC1 inhibition, which supports nutrient availability for cancer cells. This reveals a central role of adipocyte's p62 in the symbiotic adipose tissue-tumor collaboration that enables cancer metabolic fitness.

KEYWORDS:

CPT1; adipocyte; cancer; fatty acid oxidation; metabolic reprogramming; obesity; osteopontin; p62; prostate; sequestosome-1

PMID:
29634950
PMCID:
PMC5896786
DOI:
10.1016/j.ccell.2018.03.001
[Indexed for MEDLINE]
Free PMC Article

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