Mucinous carcinoma upregulates targets of small molecule inhibitors of cancers: implications for targeting oncogenic mucins in the colorectal cancer microenvironment
Henry Ebili, Adesoji Ebenezer Adetona, Patrick Akintunde Akintola, Uchenna Simon Ezenkwa, Kazeem Adeyinka Adegboyejo, Ayotunde O. Ale, Yusuf AbdullahiBackground: Mucinous colorectal carcinoma (CRC) is a distinct histological subtype associated with abundant extracellular mucin production, adverse clinicopathological features, chemoresistance, and poor prognosis. However, the tumour microenvironment (TME) signalling characteristics of mucinous CRC and its potential vulnerabilities to anti-mucin small molecule inhibitors (SMIs) remain incompletely understood. Objective: To investigate the signalling characteristics of mucinous CRC, interrogate the relationship between mucinous histology and TME signalling pathways, and identify potential anti-mucin SMIs enriched in mucinous CRC. Methods: This retrospective multi-cohort study analysed clinicopathological, transcriptomic, and copy number data from the TCGA, Sidra-LUMC, and CPTAC2 CRC cohorts. Gene Set Enrichment Analysis, pathway ontology enrichment analysis, drug ontology enrichment analysis, differential ontology enrichment analyses, and protein–protein interaction analyses were performed to identify enriched signalling pathways and therapeutic targets associated with mucinous histology. Results: Of 984 CRC cases with histological data, 15.7% were mucinous adenocarcinomas. Mucinous CRC was significantly associated with female gender, younger age, right-sided tumour location, advanced pathological tumour stage, microsatellite instability, BRAF mutation positivity, high tumour mutation burden, and low chromosomal instability indices. Enrichment analyses demonstrated preferential activation of multiple oncogenic and TME-related pathways in mucinous CRC, including PDGF, Ras, VEGF, EGF receptor, Integrin, Angiogenesis, Hypoxia/HIF, and Insulin/IGF signalling pathways. Differential ontology analyses confirmed preferential enrichment of Integrin and Angiogenesis signalling in mucinous CRC. Protein–protein interaction analyses demonstrated significant interactions between mucin genes and signalling pathway components, suggesting that mucins function as hubs in TME signalling networks. Importantly, mucinous CRC exhibited significant enrichment of responses to calcium channel blockers, mucolytic drugs, N-glycosylation inhibitors, and Bosutinib. Conclusion: Mucinous CRC demonstrates a signalling-rich TME characterized by extensive mucin-associated oncogenic interactions and preferential enrichment of anti-mucin drug targets. These findings support multitargeted anti-mucin therapeutic strategies in mucinous CRC.