Most recent update: Friday, April 20, 2018 - 07:35

Bariatric News - Cookies & privacy policy

You are here

Fat cells and tumour growth

Breakthrough in how fat cells communicate with tumour tissue

The researchers reveal a central role of p62 in fat tissue-tumour communication, which supports cancer metabolic fitness

Researchers from Sanford Prebys Medical Discovery Institute (SBP) have revealed that inactivation of a protein called p62 in fat cells fuels aggressive, metastatic prostate cancer in mice. The deficiency of p62 triggers a shutdown of energy-consuming processes in fat tissue, thereby increasing the availability of nutrients for cancer cells.

"This work could lead to better therapies that consider cancer not just as a genetic or cellular disease, but as a whole-body process where tumours communicate with metabolic organs to maintain their unlimited appetite for nutrients," said co-senior study author, Dr Maria Diaz-Meco, a professor in the Cancer Metabolism and Signaling Networks Program at SBP. "This is a vulnerability that can be targeted therapeutically."

The paper, ‘Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor’, published in Cancer Cell, sought to understand how the molecular mechanisms by which fat cells communicate with tumour tissue.

"Most of the studies addressing the role of adiposity and obesity in cancer use mice fed a high-fat diet," said co-senior study author, Dr Jorge Moscat, director and professor of the Cancer Metabolism and Signaling Networks Program at SBP. "Although this mimics some of the situations in patients, it prevents a real understanding of the signalling pathways that control the bidirectional communication between tumours and adipocytes or fat cells. This is essential if we want to identify therapeutic targets that can be harnessed to prevent the pro-tumorigenic signals emanating from the adipose tissue."

To address this problem, Diaz-Meco and Moscat turned to a mouse model of obesity they previously helped to develop. These mice specifically lack p62 in fat cells, leading to increased adiposity and metabolic problems without altering food intake. In this study, the researchers reveal a central role of p62 in fat tissue-tumour communication, which supports cancer metabolic fitness.

Specifically, they found that p62 deficiency in fat cells promotes the progression and metastasis of prostate cancer in mice by inhibiting a protein complex called mTORC1. The tumours suppress energy-consuming activities such as fat cell development, a metabolic process called oxidative phosphorylation, and fatty acid metabolism in white fat tissue. As a result, more fatty acids and other nutrients are available to support tumour growth.

"This metabolic reprograming orchestrated by the loss of p62 in adipocytes appears to help tumours cope with the high-energy demands of an aggressive cancer," said Diaz-Meco.

Additional experiments showed that p62 deficiency in fat tissue promotes the synthesis of proteins called osteopontin and Cpt1a, which are critical for prostate cancer proliferation, migration and invasion. These findings are clinically relevant because high levels of osteopontin and Cpt1a are associated with aggressive, metastatic castration-resistant prostate cancer in humans.

"The significance is huge because we identify a new set of therapeutic targets that, if modulated, should block the ability of activated adipose tissue to promote tumour malignancy," said Moscat.

According to the authors, the findings suggest that mTOR inhibitors currently used to treat a wide range of cancers may have the unintended consequence of shutting down fat tissue metabolism and fuelling tumour growth, at least under certain circumstances. However, this possibility needs to be evaluated in future studies. For their own part, the authors plan to further investigate the p62 signalling pathway in patients and identify druggable targets that could be evaluated for their therapeutic potential.

"We need to consider other aspects of cancer therapeutics beyond the better-known genetics," said Diaz-Meco. "That is, we need to invest more in the research of cancer metabolism, which deals with the identification of metabolic vulnerabilities that should be common to all types of cancers. This will ultimately lead to better therapies that are less susceptible to resistance, which is an all-too-common problem in oncogene-target approaches."

Want more stories like this? Subscribe to Bariatric News!

Bariatric News
Keep up to date! Get the latest news in your inbox. NOTE: Bariatric News WILL NOT pass on your details to 3rd parties. However, you may receive ‘marketing emails’ sent by us on behalf of 3rd parties.