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 bidi-rectional 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.

When healing turns into killing – the pathophysiology of pancreatic and hepatic fibrosis

“…monocarboxylate transporter, MCT), fuelling a vicious circle of microenvironmental acidification (Cardone et al., 2005; Michl et al., 2022). And very recently MCTs have been linked to ECM remodelling in pancreatic cancer (Ufuk et al., 2022). In chronic pancreatitis, which often precedes the development of pancreatic cancer, accumulated acidic metabolites associated with pancreatic secretion lower interstitial pH, which was attributed to impaired blood flow (Patel et al., 1995).…”