Dual inhibition of lactate transporters MCT1 and MCT4 in pancreatic neuroendocrine tumors targets metabolic heterogeneity and functional redundancy

Our current understanding of the metabolic landscape of pancreatic neuroendocrine tumors (PanNETs) is very limited. Such knowledge could lead the development of novel therapeutic strategies for subgroups of PanNET patients based on the metabolic profile of their tumor. Here, we investigated the expression of lactate transporters MCT1 and MCT4 in two independent PanNET cohorts (n=93; n=70) and analyzed their association with tumor aggressiveness and therapeutic vulnerability in cell lines, spheroids and patient-derived tumoroids of PanNET. Immunohistochemistry revealed four expressor types: MCT1/4-negative, MCT1-positive, MCT4-positive, and MCT1/4-double positive with frequent regional co-expression. Both homogenous and heterogenous expression patterns were observed, indicating metabolic heterogeneity within the latter subset of PanNETs. MCT4 expression correlated with the hypoxia marker CA9, suggesting a hypoxic and acidic tumor microenvironment. Mechanistic studies revealed that MCT1 and MCT4 operate both as lactate efflux systems in PanNET cell lines, providing functional redundancy to their glycolytic roles. Inhibition of lactate efflux in normoxia and hypoxia using the dual MCT1/4 inhibitor syrosingopine significantly impaired lactate secretion, glycolysis, and proliferation across PanNET cell lines and 3D spheroid and patient-derived tumoroid models. In contrast, selective MCT1 or MCT4 inhibitors showed limited efficacy, underscoring the therapeutic need for co-targeting MCT1 and MCT4 due to functional redundancy and heterogenous expression. This work demonstrates MCT1 and MCT4 as metabolic markers and promising therapeutic targets of a subset of PanNETs with clinical features of aggressiveness.