The implication of lactate in carcinogenesis has become increasingly important, including its role as a tumor-promoting metabolite. In cancer, the acidic environment produced by lactate drives not only tumor progression, invasive ability, and metastasis, but also processes such as angiogenesis and immunosuppression, all of which are associated with negative prognosis.
Particularly, lactate secreted by cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) plays an essential role in the metabolic reprogramming of tumor cells. Lactate sustains different processes within TME, being exploited as a source of energy or acting as an oncometabolite with signaling properties. In prostate cancers (PCa), lactate is one of the major nutrients secreted by CAFs and it is exploited to improve mitochondrial metabolism in PCa cells and their pro-aggressive features.
Lactate is also a crucial driver governing the balance between immune evasion and immune surveillance. Melanoma cells generally rely on Warburg metabolism, characterized by a high glycolytic flux and high lactate dehydrogenase A (LDH-A) expression, accompanied by the secretion of large amounts of lactic acid, that results in the acidification of the TME, thereby concurring to immune escape. Melanoma-bearing patients showed gender disparities that influenced the outcome and response to therapy. Therefore, it is important to clarify if different sexual-dependent microenvironmental factors can selectively shape the immune system, resulting in gender-specific immune composition.
My Ph.D. thesis aimed to study how prostate cancer and melanoma rely on Lactate. To do this, we investigated the impact of the metabolic reprogramming of PCa cells exposed to stromal conditioning on their epigenetic profile and on the metabolic-dependent regulation of gene expression. Instead, regarding melanoma, the research focus consists in better investigating the gender dependence of the metabolic regulation on the immune component, mainly given by a different presence of immunosuppressive metabolites. We hypothesized that different concentrations of lactate with immunosuppressive effects in male and female melanoma microenvironment may elicit different sex-related immune responses.
Results
In PCa model we demonstrated that i) metabolic tumor-stroma crosstalk is driven by CAF-derived lactate that leads to lipid anabolism and LDs accumulation; ii) LDs are used to provide acetyl groups useful for epigenetic modifications (increase of H3K9Ac and H3K27Ac); iii) higher histone acetylation is linked to the lactate-dependent enhancement of PCa invasiveness. These data suggest the close relation between lipid metabolism and epigenetic reprogramming driven by lactate-mediated tumor-stroma crosstalk. iv) Moreover, we observed that interfering with the lactate-dependent increase in lipid anabolism and histone acetylation by BET inhibition impaired CAF-induced PCa cell metabolic rewiring and invasiveness. v) Interestingly, RNAseq analysis revealed that PLIN2 is a direct target of the lactate-dependent histone acetylation and that it is responsible for stromal-induced LDs formation and PCa cell invasiveness. vi) In vivo Bet inhibition impairs lactate-sustained lung metastatic burden in PCa cells. In conclusion, we can firmly sustain that lactate is a mandatory driver to promote metastatic spreading in prostate cancer.
In melanoma our data showed that i) male melanoma cells exhibit a more glycolytic profile (overexpression of key glycolytic enzymes, in particular a higher LDH-A expression, and increase of lactate secretion) with respect to the female counterparts; ii) upon IHC analysis on human samples, male melanoma reveals a more pronounced LDH-A expression, accompanied by an enrichment in CD4+/Treg infiltration, compared to female tissues; iii) interfering with LDH-A expression by both genetic (siLDH-A) and pharmacological (FX-11) approaches, we observed a reduction in Treg polarization in male melanoma cells co-cultured with CD4+ cells. These data suggest a role for lactate in eliciting an immunosuppressive landscape in male melanoma cells/samples with high Treg infiltration.
In conclusion, lactate is an oncometabolite able to increase the metastatic capacity and reshape the immune component, causing a potential impact also in a gender context
