Sunday, May 11, 2025
5/11/2025
Tissue Microenvironment ant Tumor Hotspots in Drosophila - PROJECT SUMMARY / ABSTRACT During carcinogenesis, transformed epithelial cells evolve into a malignant neoplasm through a multistep process, whereby the transformed cells acquire traits that enable them to become tumorigenic and ultimately malignant. Although many genes have been identified as involved in different steps of cancer-cell progression, little is known of the initial steps of tumorigenesis, wherein mutant cells deviate from the robustly organized microenvironment to undergo uncontrolled overgrowth. In this proposal we will use the Drosophila model to dissect genetically how endogenous tissue microenvironment contributes to tumor formation. This work is part of our long-term effort in deciphering the molecular and cellular mechanisms that govern the early steps of tumorigenesis in epithelial tissues. In our analysis of conserved neoplastic tumor-suppressor genes (nTSGs) using the Drosophila wing imaginal disc model system, we found specific regions in the wing hinge in which tumors always originate. In these specific “tumor hotspots,” nTSG loss-of-function (LOF) pro-tumor cells delaminate from the apical side of the epithelium, and start tumorigenic overgrowth by exploiting endogenous JAK-STAT inflammatory signaling activity. In contrast, the pro-tumor cells in tumor coldspots, the wing pouch area, are extruded from the basal side of the epithelial layer and undergo apoptosis. The wing hinge tumor hotspot area displays a network of specific and robust basal structures, including enriched microtubules, a web of intertwining filopodia, and tightly laminated basement membranes. The epithelial organization in these specific regions is hypothesized to create the “tumor hotspot”, a favorable tissue-intrinsic microenvironment, which forces pro-tumor cells to delaminate from the epithelial layer and enter an environment that is suitable for tumorigenesis. In the proposed studies, we will determine how specific tissue cytoarchitectural traits, local intrinsic signaling and differential cell competition are involved in tumor hotspot formation in the wing disc model by pursuing the following three specific aims: (1) To determine how cytoarchitectural structures regulate the delamination direction of pro-tumor cells in tumor hotspots; (2) To determine how JAK-STAT signaling is involved in hotspot tumorigenesis; and (3) To determine the role of cell competition in tumor hotspot and coldspot differentiation in the wing disc. These three specific aims are independent from each other and can be executed separately. The significance of our proposed studies lies in their implications directly related to early stages of tumorigenesis. Given the conservation of the epithelial cytoarchitectural structures, cell competition mechanisms and the significant role inflammatory signaling pathways play during various types of cancer, tumorigenesis is likely to be initiated from “tumor hotspots” by a similar mechanism in many epithelial tissues. Understanding these regulatory mechanisms will therefore provide new insights into how tissue-intrinsic microenvironment determines whether tumors can actually be induced after cells acquiring cancer-promoting mutations.
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