Uncovering Signalling Pathways Mediating Gastrointestinal Morphogenesis and Tumorigenesis

The gastrointestinal system undergoes remarkable morphogenesis during development, in which a simple, smooth tube rapidly rearranges to form millions of finger-like projections called villi that line the entire intestinal tract. While gastrointestinal development requires precisely coordinated intercellular communication via signalling pathways, mechanisms underlying intestinal morphogenesis remain unclear. The Hedgehog signalling pathway is critical for many aspects of gut development, however, its downstream transcriptional targets allowing for complex cell behaviours during villus formation are poorly understood. By uncovering the Hedgehog targetome in vivo, we revealed GLI2 transcriptional activation of atypical cadherin and planar cell polarity genes in the mesenchyme. Moreover, by using a combination of mouse genetics, live imaging and 3D-culture based approaches, I have demonstrated a requirement for planar cell polarity in instructing organized cell migration for mesenchymal clustering, which is critical for each emerging villus. Therefore, mesenchymal planar cell polarity induced by Hedgehog signaling drives morphogenetic cell behaviours required for proper villus formation. While developmental signalling pathways are essential for instructing the formation of complex organ systems, their reactivation later in life can result in disease. Indeed, recent work has revealed reactivation of developmental signalling pathways in many human gastrointestinal cancers. YAP is a co-transcriptional activator in the Hippo signalling pathway, and is frequently upregulated in gastric cancer, however, its role in tumorigenesis is unclear. By investigating the function of activated-YAP, I have shown its ability to induce gastric adenocarcinoma in a cell type-specific manner. Moreover, Yap deletion in a pre-clinical model of gastric cancer results in suppression of tumorigenesis, implicating YAP as a potential therapeutic target. Together, my results demonstrate that Yap is a potent oncogene in stomach tissue, highlighting the importance for strict regulation of Hippo signalling during adult homeostasis. Collectively, my work has defined the mechanisms by which Hedgehog and planar cell polarity pathways mediate intestinal morphogenesis, as well as YAP in driving gastric adenocarcinoma, which contributes to our understanding of how aberrant developmental signalling can drive disease.

Department dc:contributor.department

Molecular Genetics

Year dc:date.issued

2021

Author dc:creator

• Rao, Abilasha

Advisor dc:contributor.advisor

• Kim, Tae-Hee

• Development
• Gastric cancer
• Morphogenesis
• PCP
• YAP

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/128384

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/128384