Epithelial-mesenchymal transition in colorectal cancer metastasis and progression: molecular mechanisms and therapeutic strategies

Abstract

Colorectal cancer (CRC) continues to be a major contributor to cancer-associated death, with metastatic disease posing substantial therapeutic challenges. The epithelial-mesenchymal transition (EMT) orchestrates the transformation of polarized epithelial cells into motile mesenchymal phenotypes, characterized by enhanced migratory capacity and invasive properties. EMT is central to CRC metastasis and progression, particularly concerning its contribution to invasion, internal infiltration, and colonization. Beyond metastasis, EMT facilitates cancer cells' adaptation to diverse microenvironments, gain of stem cell-like characteristics, metabolic reprogramming, and evasion of therapeutic interventions. EMT signatures are emerging as potential prognostic biomarkers, offering valuable insights for real-time disease surveillance and personalized therapeutic strategies. Targeting EMT presents a promising therapeutic avenue to improve drug sensitivity and counteract resistance in CRC. This review systematically examines the molecular mechanisms regulating EMT in CRC, including key transcription factors; post-translational and epigenetic modifications; non-coding RNAs; and pivotal signaling pathways. Additionally, we evaluate the clinical implications of EMT in CRC progression and metastasis and critically assess emerging therapeutic strategies targeting EMT. This study lays the groundwork for developing more efficient interventions to mitigate metastasis and enhance treatment outcomes and patient survival by elucidating the intricate molecular networks that govern EMT and its contributions to CRC pathology.

Fig. 1. From epithelial to mesenchymal.

Cellular Transformation and Plasticity in EMT. Epithelial cells exhibit apical–basal polarity with cell–cell and cell–matrix attachments. Intercellular junctions provide adhesion and communication, maintaining tissue stability and integrity. In contrast, mesenchymal cells lack functional epithelial junctions and exhibit back–front polarity. These cells contain vimentin-based intermediate filaments and use integrin-containing focal adhesions to attach to the extracellular matrix. As intercellular junctions dissolve and cell polarity is lost, cytoskeletal rearrangements transform epithelial cells into mesenchymal cells, enhancing motility and invasiveness. The accumulated loss or gain of epithelial/mesenchymal (E/M) characteristics moves cells into various intermediate states in a reversible manner. These states demonstrate remarkable plasticity, allowing cells to differentiate into various types and migrate collectively.

Fig. 2. The EMT regulatory network in colorectal cancer.

EMT is regulated by a complex network involving transcriptional regulation, post-translational modifications, epigenetic modifications, non-coding RNAs, and signaling pathways. These interconnected mechanisms collectively orchestrate the epithelial-mesenchymal transition in colorectal cancer progression.

Fig. 3. Signaling pathways regulating epithelial-mesenchymal transition in CRC.

Multiple signaling pathways, including Wnt/β-catenin, TGF-β, and PI3K-AKT cascades, regulate EMT in colorectal cancer. These pathways modulate key transcription factors such as SNAIL, ZEB, and TWIST. Additionally, non-coding RNAs play crucial roles in fine-tuning this regulatory network, collectively driving EMT processes.

Fig. 4. The role of EMT in the progression and metastasis of CRC.

Colorectal cancer cells undergoing EMT progressively lose intercellular adhesions and acquire the capacity to degrade the basement membrane and ECM. This enables detachment from the primary tumor and invasion into surrounding tissues. EMT-driven cells enhance vascular permeability, facilitating intravasation into the bloodstream. Surviving circulating tumor cells withstand hemodynamic shear forces and resist anoikis before undergoing extravasation at distant sites, initiating metastatic colonization through MET. Within the tumor microenvironment, interactions between cancer cells and stromal components (immune cells, fibroblasts) generate EMT-inducing signals via cytokines and chemokines. Environmental stressors, such as hypoxia, inflammatory signals, and nutrient competition, drive metabolic adaptations like glycolysis, enhancing survival. EMT also confers stemness properties, enabling self-renewal and multi-lineage differentiation potential, ultimately promoting metastatic colonization.

Fig. 5. Therapeutic strategies for targeting EMT.

There are three main strategies for targeted EMT treatment: I) inhibiting tumorigenesis by blocking upstream signaling pathways, II) targeting the molecular drivers of EMT, and III) targeting mesenchymal markers or inhibiting the MET process.