title: Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics.
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.
authors.affiliation: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.forename: Marco
authors.initials: M
authors.lastname: Prisco
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.forename: Zhao
authors.initials: Z
authors.lastname: Lin
authors.forename: Stephanos
authors.initials: S
authors.lastname: Pavlides
authors.forename: Chengwang
authors.initials: C
authors.lastname: Wang
authors.forename: Neal
authors.initials: N
authors.lastname: Flomenberg
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D023281:Genomics; D006019:Glycolysis; D006801:Humans; D007659:Ketones / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism*; D055432:Metabolomics; D008928:Mitochondria / Q000378:metabolism; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation; D057285:Precision Medicine / Q000379:methods; D012008:Recurrence; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D007659:Ketones; D019344:Lactic Acid; D000105:Acetyl Coenzyme A