Monocarboxylate Transporters are Involved in Extracellular Matrix Remodelling in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival rate of <8%. PDAC is characterised by desmoplasia with abundant extracellular matrix (ECM) rendering current therapies ineffective. Monocarboxylate transporters (MCTs) are key regulators of cellular metabolism and are upregulated in different cancers, however their role in PDAC desmoplasia is little understood. Here, we investigated MCT and ECM gene expression in primary PDAC patient biopsies using RNA-sequencing data obtained from Gene Expression Omnibus. We generated a hypernetwork model from these data to investigate whether a causal relationship exists between MCTs and ECMs. Our analysis of stromal and epithelial tissues (n=189) revealed 9 differentially expressed MCTs, including upregulation of SLC16A2/6/10 and the non-coding SLC16A1-AS1, and 502 ECMs including collagens, laminins, and ECM remodelling enzymes (false discovery rate<0.05). Causal hypernetwork analysis demonstrated a bidirectional relationship between MCTs and ECMs; 4 MCT and 255 ECM-related transcripts correlated with 90% of differentially expressed ECMs (n=376) and MCTs (n=7), respectively. The hypernetwork model was robust, established by two independent approaches involving iterated sampling and silencing of indirect interactions in the network. This transcriptomic analysis highlights the role of MCTs in PDAC desmoplasia via associations with ECMs, opening novel treatment pathways to improve patient survival. Simple SummaryMonocarboxylate transporters (MCTs) carry a variety of substrates with MCT1-4 being well characterised and involved in proton-coupled transport of monocarboxylates (such as lactate) which can be used as metabolic fuel for cancer cells. Increased acidity of tumour microenvironment via MCTs favours remodelling of extracellular matrix (ECM) leading to desmoplasia associated with tumour metastasis and poor patient outcomes. Although MCT1-2/4 are upregulated in several cancers, their expression and role in pancreatic ductal adenocarcinoma desmoplasia is little understood. Here, we aimed to understand the role of MCTs in desmoplasia through their associations with ECM components. Our analysis using hypernetworks showed the presence of bidirectional associations of MCTs and ECMs, suggesting the presence of a causal relationship and the need to further investigate their functional associations. It confirms the role of MCTs in desmoplasia highlighting their importance as therapeutic targets alone or in combination with key ECM components to potentially improve patient outcomes.