Colorectal cancer progression: lessons from Drosophila?

Area of Science:

• Cell Biology
• Developmental Biology
• Cancer Biology

Background:

• Colorectal cancers progress from benign adenomas to malignant adenocarcinomas and carcinomas.
• Carcinomas often involve epithelial-to-mesenchymal transition (EMT), mediated by transcription factors like Twist and Snail, leading to E-cadherin downregulation.
• Adenocarcinomas retain E-cadherin but disrupt epithelium via cyst formation, involving Crumbs/CRB3, Stardust/PALS1, and Bazooka/PAR3.

Purpose of the Study:

• To investigate the mechanisms underlying adenocarcinoma formation in human colorectal cancers.
• To explore the role of intratumour heterogeneity in epithelial disruption and cyst formation.
• To compare adenocarcinoma development with carcinoma development and identify potential model systems.

Main Methods:

• Comparative analysis of human colorectal adenocarcinomas and carcinomas.
• Investigation of epithelial gene expression, including E-cadherin.
• Utilisation of Drosophila models to study cyst formation induced by signalling pathway heterogeneity (Wnt, Smad, Ras).

Main Results:

• Adenocarcinomas retain E-cadherin, unlike carcinomas which undergo EMT.
• Epithelial disruption in adenocarcinomas involves formation of small cysts with specific apical protein localization.
• Drosophila studies demonstrate that clonal heterogeneity in signalling pathways induces cyst formation and cell extrusion.

Conclusions:

• Intratumour heterogeneity is a potential driver of human adenocarcinoma formation through cystogenesis and cell extrusion.
• The mechanisms of adenocarcinoma development, involving cyst formation, differ from EMT-driven carcinoma development.
• Drosophila border cell migration offers a potential model for studying invasive adenocarcinoma cell migration.