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 an 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 nine differentially expressed MCTs, including the 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). A causal hypernetwork analysis demonstrated a bidirectional relationship between MCTs and ECMs; four MCT and 255 ECM-related transcripts correlated with 90% of the differentially expressed ECMs (n = 376) and MCTs (n = 7), respectively. The hypernetwork model was robust, established by iterated sampling, direct path analysis, validation by an independent dataset, and random forests. This transcriptomic analysis highlights the role of MCTs in PDAC desmoplasia via associations with ECMs, opening novel treatment pathways to improve patient survival.