Exploration Of Developmental Signaling Pathways In Tumor Progression And Tissue Regeneration

Abstract

Developmental pathways, including Hedgehog (HH) and Hippo, are involved in cancer and tissue regeneration in various ways. HH signaling from the prostate epithelium was known to regulate mesenchyme expansion during development and regeneration. However, any role of HH signaling in stromal cells during prostate cancer (PCa) progression was poorly understood. I studied both mouse models and human PCa and observed paracrine HH signaling from epithelium to stroma. Genetic fate mapping suggested that the cancer-associated stroma derives from distinct cell types in different mouse models of PCa. Furthermore, I found that increasing HH signaling in the stroma results in decreased tumor progression and the presence of more smooth muscle, which correlated with lower grade PCa in human. Thus, we propose HH signaling restrains tumor progression by maintaining the smooth muscle and preventing invasion by tumor cells. The Hippo pathway has been implicated in the repair of several tissue types. However, any possible role of the Hippo pathway in development or postnatal regeneration of the mouse cerebellum was unknown. I used genetic mouse models involving deletion of the transcriptional co-activators YAP and/or TAZ, and found that YAP, but not TAZ, is an essential regulator of effective recovery of the cerebellum after irradiation-induced injury at birth. Specifically, genetic ablation of Yap in the Nestin-expressing progenitors (NEPs), a progenitor population central to cerebellar regeneration of granule cell precursors (GCPs) following injury, results in significantly impaired cerebellar growth and disruption in the cellular cytoarchitecture. The Yap mutant NEPs respond normally to the injury by migrating to the GCP niche, but then undergo increased cell death. Loss of YAP in NEPs or GCPs during normal development only mildly affects differentiation. Moreover, loss of TAZ does not alter development or regeneration of the cerebellum, or abrogate regeneration of GCPs by Yap mutant NEPs. Instead, Taz ablation seems to partially rescue the poor recovery of GCPs by Yap mutant NEPs, indicating that TAZ and YAP have distinct functions during cerebellar regeneration. In summary, my thesis research provides new insights into the molecular signaling underlying PCa progression and the development and regeneration of the neonatal cerebellum.