Interplay between endolysosomal calcium signalling, EMT, and autophagy in colorectal cancer (CRC): Implications for metastasis and therapeutic strategies.

Abstract

Purpose: Colorectal cancer (CRC) progression and metastasis are driven by coordinated molecular programs, including epithelial-to-mesenchymal transition (EMT) and autophagy. Increasing evidence suggests that calcium (Ca2+) signalling acts as a central regulatory node linking these processes. This review critically synthesises current evidence on Ca2+-dependent regulation of EMT and autophagy in CRC, with emphasis on endolysosomal Ca2+ signalling as a potential therapeutic axis. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, focusing on studies examining calcium signalling, EMT, autophagy, and their interplay in CRC and related cancer models. Results: Multiple Ca2+ signalling pathways, including voltage-gated, store-operated, transient receptor potential, and endolysosomal Ca2+ channels, regulate EMT-associated transcription factors, cytoskeletal dynamics, and autophagic flux. Calcium-dependent signalling hubs such as CAMKK-AMPK, PI3K/AKT/mTOR, and TGF-β pathways emerge as key mediators linking Ca2+ dynamics to EMT and autophagy. Although CRC-specific evidence for certain endolysosomal channels remains limited, findings from CRC models and other solid tumours support their involvement in metastatic behaviour, cellular stress adaptation, and therapy resistance. Conclusion: Calcium signalling represents a critical integrative mechanism connecting EMT and autophagy during CRC progression. Targeting Ca2+-regulated pathways, particularly within endosomal compartments, may offer therapeutic benefit but requires careful consideration of context dependency and tissue specificity. Further CRC-focused mechanistic and translational studies are needed to validate these targets.

Keywords: Colorectal Neoplasms, Epithelial-Mesenchymal Transition, Autophagy, Calcium signalling, Metastasis, TRPML1