Saturday, April 20, 2024
4/20/2024
Project Summary Many types of cancer harbor disease-sustaining tumor cells, or tumor-initiating cells (TICs), that play a pivotal role in cancer development. TICs have been implicated in drug resistance and tumor recurrence, making them a rational target for therapeutic intervention. However, methods for destabilizing TICs have not been as evident as was initially hoped. The long-term goal of my research program is to identify cellular crosstalk and molecular pathways involved in the regulation of stem cells in tissue homeostasis and cancer development. Just as normal stem cells are regulated by external cues derived from specialized microenvironments or stem cell niches, the stem-like state and malignant properties of TICs are controlled by various factors emanating from the TIC-associated microenvironment, the so-called TIC niche. Therefore, targeting the crosstalk between TICs and the niche is an attractive avenue for durable cancer therapy. While solid tumors are known to recruit immune cells in the stroma and create favorable conditions for their growth and survival, little is known about how TICs regulate the localization and function of tumor-supportive immune cells in their spatial proximity. Our incomplete understanding of the complexity of the niche and the plasticity of TICs is a significant barrier to improving therapeutic efficacy. Invasive squamous cell carcinoma (SCC) exhibits high rates of recurrence driven by therapy-resistant TICs at the tumor-stroma interface, making it a rational model to study the crosstalk between TICs and the potential niche cells. We previously devised a de novo SCC mouse model that allows us to label and lineage trace TGF-¿-responding tumor cells. Through this approach, we have demonstrated that tumor cells responding to paracrine TGF-¿ signaling promote invasive tumor progression. Moreover, TGF-¿- responding tumor cells function as drug-resistant TICs through activation of NRF2-mediated antioxidant metabolism and drive tumor recurrence. Therefore, the mechanisms that lead to “TGF-¿-rich” tumor microenvironments may precede the development of TIC–niche interactions, which could potentially be exploited as a new target for destabilizing TICs. Recently, we found that TICs release IL-33 through TIC- intrinsic stress-resistant activities, which induces the accumulation of a subset of macrophages in close proximity of TICs. These IL-33-responding macrophages are alternatively-activated and send reciprocal TGF-¿ signaling to induce invasive and drug-resistant properties in TICs. Based on our preliminary data, our central hypothesis is that the IL-33–TGF-¿ paracrine signaling loop constitutes a feedforward mechanism that promotes the formation of a robust TIC niche, in which both tumor-promoting functions of macrophages and malignant properties of TICs are induced. Here we will determine the mechanism of tumor-promoting niche formation and malignant transformation of TICs, which could help identify the vulnerability of TICs to combat therapy-resistant cancers.
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