Lactate and ketone use by tumor cells increases their stemness and drives recurrence and metastasis.

Researchers suggest profiling cancer cells to identify gene-expression signatures associated with the metabolism of lactate and ketones can provide an accurate prognostic indicator of recurrence, metastasis, and poor clinical outcome. Rather than detecting cancer-related gene mutations, the approach, which researchers from Thomas Jefferson University Kimmel Cancer Center call metabolo-genomics, correlates poor disease prognosis with a genetic profile that indicates the cancer is using high-energy metabolites to drive ATP production.

The team claims their previous research has demonstrated that these high-energy metabolites fuel aggressive tumor cell behavior, and their latest work confirms that lactate- and ketone-induced gene signatures in human breast cancer patients are predictive of poor clinical outcome including recurrence and metastasis. They further suggest that high-risk cancer patients identified by these lactate/ketone gene signatures could be treated with therapeutics such as metformin, which specifically target oxidative mitochondrial metabolism.

The research, led by Michael P. Lisanti, M.D., Ph.D., professor and chair of stem cell biology and Regenerative Medicine at Jefferson Medical College, is published in Cell Cycle in a paper titled “Ketones and Lactate Increase Cancer Cell ‘Stemness,’ Driving Recurrence, Metastasis, and Poor Clinical Outcome in Breast Cancer: Achieving Personalized Medicine Via Metabolo-Genomics.”

Dr. Lisanti and colleagues used a breast cancer cell line to study the effects of administering either ketones or lactate the cells’ gene expression. Comparative transciption profiling of cells fed lactate or ketones with untreated cancer cells showed that both the high energy metabolites upregulated the transcription profiles of genes associated with the “stemness” of cells such as neural, embryonic, and hematopoietic stem cells. ” It  appears that the metabolic use of ketones and lactate could fuel the cancer stem cell phenotype, promoting tumor growth and metastasis,” they suggest.

The lactate-  and ketone-related gene signatures did overlap,  but there were also many differences, they report. The lactate-specific profile was most similar to that of neural stem cells, while the ketone-specific gene profile was most akin to hematopoietic stem cells. In contrast, the genes commonly upregulated in both the lactate- and ketone-fed cells were most similar to embryonic stem cells.

Interestingly, supplementing cultures of mouse embryonic stem cells with lactate or ketone led to significantly increased colony size and number. “Thus, both lactate and ketones stimulate the growth of ES cells as predicted, providing functional validation for our observations that these high-energy metabolites may increase cell ‘stemness’,” the authors note.  

They subsequently found lactate- or ketone-specific gene signatures were associated with significant reductions in overall survival in patients with ER-positive tumors and in luminal A breast cancer patients. The expression of lactate or ketone gene signatures in these patients was associated with increased metastasis, tumor recurrence, and dramatic reductions in overall survival.

“Based on this analysis, it appears that lactate and/or ketone utilization by cancer cells may be a general phenomenon that can be exploited to identify aggressive predictive gene signatures for a wide-variety of different types of human cancers,” the team suggests.

They claim the overall results have wide-ranging clinical and translational application and demonstrate the feasibility of generating transcriptional gene signatures that predict poor clinical outcome simply by treating the relevant cancer cell line with lactate or ketones. “This means that many other promising prognostic gene signatures could easily be generated for other types of cancers, by simply treating a given cancer cell line with lactate or ketones,” they write.

Perhaps more importantly, however, the findings suggest that targeting oxidative mitochondrial metabolism in aggressive cancers using appropriate anti-metabolites could help eradicate the cancer stem cell pheotype. “Thus, the Achilles’ heel of the cancer stem cell may be its ability to use lactate and/or ketones as a fuel source for driving oxidative mitochondrial metabolism.”

“Just by feeding cancer cells a particular energy-rich diet, it changes their character, without introducing mutations,” Dr. Lisanti adds. “We’ve only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile. It’s a new biomarker for lethal cancer that we can now treat with the right drugs.”

High lactate production has long been known to be a predictor of poor clinical outcome for a variety of different types of malignancies, the researchers note. This observation, combined with previous research demonstrating that metformin prevents or inhibits tumor formation in both diabetic patients and mouse models, supports the Kimmel team’s suggestion that cancer cells use mitochondrial oxidative phosphorylation for energy production.

Moreover, they conclude, “it is quite ironic that such a potent anticancer drug (metformin) exerts its therapeutic effects by inducing a type of metabolism (aerobic glycolysis) that has been proposed to be the root cause of cancer for the last 85 years. Thus, induction of aerobic glycolysis in cancer cells may not be the cause of cancer, but rather it may be the cure for cancer.”

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