Vincan laboratory: Cancer cell biology
Recent insights from diverse fields of basic and clinical research reveal that the biological processes that govern embryonic development and organogenesis are also commonly involved in the pathologies that arise in that organ or tissue in the adult. This striking parallel between embryonic development and pathology is exemplified by Wnt signalling in the intestinal tract. Wnt signalling is critical throughout embryonic development of the mammalian gut. Moreover, competent Wnt signalling is essential for the homeostatic control of the adult intestinal epithelium. On the other hand, aberrant Wnt signalling in the adult intestine leads to cancer and other pathologies. This critical role of the Wnt pathway in gut development and homeostasis is conserved through evolution, emphasizing the importance of this pathway in this organ. Research in the Cancer Cell Biology lab strongly implicates the Wnt receptor Frizzled7 (FZD7) in transmitting this critical Wnt signal. Notably, FZD7 is an evolutionarily conserved gene in the gut, suggesting that this receptor might be integral to the important role assigned to Wnt signalling in this tissue. Our research goal is to define the role of FZD7 in gut tissues. We employ molecular techniques (qRT-PCR, western blot, confocal immunofluorescence microscopy, immunohistochemistry) and molecular tools (FZD7 promoter reporter plasmid, expression plasmids), and in vivo (conditional knock-out and knock-in mice) and in vitro (organoid and monolayer colon cancer cell lines) models systems.
The small and large (colon) intestines are lined by a specialised epithelium that undergoes constant renewal. This renewal is maintained by stem cells that reside at the bottom of small glands in the epithelium called crypts. LGR5 marks this long-lived population of stem cells exclusively. The crypt base columnar (CBC) LGR5+ stem cells replenish the stem cell population (self renewal) and give rise to progenitor cells which go on to terminally differentiate into the specialised cell types of the intestinal epithelium. The differentiating cells migrate away from the crypt base and are eventually sloughed off into the intestinal lumen. Signalling pathways such as the Wnt pathway delicately regulate the homeostatic control between cell division and death. On the other hand, aberrant Wnt signalling is observed in over 90% of colorectal cancers and in many other types of cancers of epithelial origin and liver. Notably, deregulation of the Wnt pathway specifically in the LGR5+ CBC stem cells of the intestine leads to the initiation of colorectal cancers. Thus, CBC stem cells are the cell-of-origin of colorectal cancer.
Although the importance of the Wnt pathway in the intestine and colorectal cancer is now well established, very little is known about how these Wnt signals are transmitted. Our lab has identified a pivotal role for Fz7 in colorectal cancer morphogenesis, despite constitutive activation of the pathway through mutation of downstream pathway components (e.g. APC, β-catenin). Thus, activation of the Wnt pathway is fine-tuned through several mechanisms to drive cancer. Importantly, inhibiting Fz7 function has potent anti-tumour activity.
- In vivo mouse models of adenoma and cancer formation coupled with the Cre-LoxP system for inducible, conditional gene deletion.
- In vitro 'mini' gut cultures established from mouse and human intestinal tissues (normal, adenoma, cancer and metastases tissues), which are more amenable to molecular manipulation.
- In vitro colorectal cancer morphogenesis model (LIM1863-Mph) that faithfully recapitulates features of EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition) during colorectal cancer metastasis.
To define the function of Fz7 and its Wnt ligands in establishing and maintaining crypt architecture, and the initiation and progression of colorectal cancer.
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For further information about this research, please contact Dr Elizabeth Vincan