Cancer cells in acidic environment undergo lipid synthesis and accumulation, study finds


Alterations in metabolic processes are a hallmark of cancer and can lead to an acidic tumor environment. Therefore, cancer cells must adapt to survive in this inhospitable environment. In a new study published in the journal Cell reports, Moffitt Cancer Center researchers show that cancer cells in an acidic environment undergo lipid synthesis and accumulation. The team identified the key signaling molecules responsible for these changes and found that these alterations are associated with poor outcomes and disease progression in breast cancer patients.

Cancer cells undergo many changes that promote cell survival and continued growth. One of the characteristic changes of cancer cells is the increased breakdown of the sugar glucose, which, when combined with poor blood circulation, leads to the development of a very acidic surrounding tumor environment. To survive in this environment, cancer cells undergo adaptations, such as the activation of the self-degradation and recycling process called autophagy, and the accumulation of lipid fat droplets. Lipid droplets play an important role in the regulation of energy, metabolism, and signal transduction; however, scientists do not know how lipid droplets accumulate in tumor cells or what their impact is on cancer survival and progression.

The Moffitt researchers performed a series of laboratory experiments with cell lines and mouse models to improve their understanding of lipid droplets in cancer. They found that breast cancer cell lines grown under acidic conditions accumulate intracellular lipid droplets that express the lipid droplet biomarker protein PLIN2. Lipid droplets formed when a cell membrane protein called OGR1 sensed the presence of the acidic environment. OGR1 then activated downstream signal transduction via phospholipase C and PI3K/AKT proteins, which led to the formation of lipid droplets from the amino acid products that had undergone metabolic degradation into smaller components.

Next, the team wanted to assess the biological effects of lipid droplets and OGR1 on cancer. Interestingly, the acid-sensing receptor OGR1 is highly expressed in breast tumors and strongly associated with disease progression. They demonstrated that by targeting OGR1 they could reduce lipid droplet levels, inhibit stress responses and cell growth under acidic conditions, and decrease tumor growth in mice. Additionally, researchers found that high expression of the lipid droplet biomarker PLIN2 was associated with shorter survival and disease progression in breast cancer patients.

These observations combined suggest that OGR1-mediated lipid droplet formation is an important contributor to tumor development and may be a potential target for anticancer drugs.

Recent studies have established the reprogramming of lipid metabolism as an emerging feature of many cancers, providing opportunities for therapeutic targeting. Many lipid blockers are being studied as anti-cancer drugs in clinical trials. Our studies provide a solid foundation for future investigations that will lead to a more detailed characterization of the role of OGR1 in the ER stress response, autophagy, and lipogenesis in animal models and human breast tumors.


Smitha Pillai, Ph.D., Study Lead Author and Research Scientist, Department of Cancer Physiology, Moffitt

Source:

H. Lee Moffitt Cancer Center and Research Institute

Journal reference:

Pillai, S. et al. (2022) OGR1-mediated lipogenesis regulates metabolic adaptation to acid stress in cancer cells via autophagy. Cell reports. doi.org/10.1016/j.celrep.2022.110796.

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