Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer

Abstract

Previously, we showed that high-energy metabolites (lactate and ketones) "fuel" tumor growth and experimental metastasis in an in vivo xenograft model, most likely by driving oxidative mitochondrial metabolism in breast cancer cells. To mechanistically understand how these metabolites affect tumor cell behavior, here we used genome-wide transcriptional profiling. Briefly, human breast cancer cells (MCF7) were cultured with lactate or ketones, and then subjected to transcriptional analysis (exon-array). Interestingly, our results show that treatment with these high-energy metabolites increases the transcriptional expression of gene profiles normally associated with "stemness," including genes upregulated in embryonic stem (ES) cells. Similarly, we observe that lactate and ketones promote the growth of bonafide ES cells, providing functional validation. The lactate- and ketone-induced "gene signatures" were able to predict poor clinical outcome (including recurrence and metastasis) in a cohort of human breast cancer patients. Taken together, our results are consistent with the idea that lactate and ketone utilization in cancer cells promotes the "cancer stem cell" phenotype, resulting in significant decreases in patient survival. One possible mechanism by which these high-energy metabolites might induce stemness is by increasing the pool of Acetyl-CoA, leading to increased histone acetylation, and elevated gene expression. Thus, our results mechanistically imply that clinical outcome in breast cancer could simply be determined by epigenetics and energy metabolism, rather than by the accumulation of specific "classical" gene mutations. We also suggest that high-risk cancer patients (identified by the lactate/ketone gene signatures) could be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the anti-oxidant and "mitochondrial poison" metformin. Finally, we propose that this new approach to personalized cancer medicine be termed "Metabolo-Genomics," which incorporates features of both 1) cell metabolism and 2) gene transcriptional profiling. Importantly, this powerful new approach directly links cancer cell metabolism with clinical outcome, and new therapeutic strategies for inhibiting the TCA cycle and mitochondrial oxidative phosphorylation in cancer cells.

Ketone body utilization drives tumor growth and metastasis

“…8 Similarly, treatment of MCF7 breast cancer cells with 3-hydroxy-butyrate was combined with genome-wide transcriptional profiling to generate a novel gene signature that effectively predicts tumor recurrence, metastasis and poor clinical outcome in human breast cancer patients. 9 However, these results do not establish a direct cause-effect relationship between ketone body production, re-utilization and tumor progression.…”

Mitochondrial dysfunction in breast cancer cells prevents tumor growth

“…45 Moreover, ketone-treated human breast cancer cells (MCF7) were subjected to genome-wide transcriptional profiling and used to generate prognostic gene signatures. 46 These ketoneinduced gene signatures accurately predicted increased tumor recurrence, metastasis and poor clinical outcome in human breast cancer patients. 46 Similarly, genetic induction of ketone body production in cancer-associated fibroblasts (by expression of ATG16L1 or HMGCS2, or via silencing of the BRCA1 gene) promotes both tumor growth and/or metastasis.…”

“…46 These ketoneinduced gene signatures accurately predicted increased tumor recurrence, metastasis and poor clinical outcome in human breast cancer patients. 46 Similarly, genetic induction of ketone body production in cancer-associated fibroblasts (by expression of ATG16L1 or HMGCS2, or via silencing of the BRCA1 gene) promotes both tumor growth and/or metastasis. 27,32,47 Finally, genetic induction of mitochondrial biogenesis in cancer cells (by expression of PGC1-α/β; POLRMT; or MitoNEET) promotes tumorigenesis.…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…Lisanti et al [46] found that ketones and lactate stimulate stem cell markers in breast carcinoma cells, expressing an oxidative mitochondrial metabolism. This suggests that an appropriate mitochondrial antagonist, such as metformin, could eradicate cancer stem cell subpopulation.…”