Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY/ABSTRACT Esophageal squamous cell carcinoma (ESCC) accounts for over 80% of esophageal cancer cases and has a poor prognosis, largely due to the absence of symptoms in the early stages. Although an early diagnosis of ESCC may lead to better outcomes in treatment, early detection is challenging since ESCC originates from the basal cell layer and invades the lamina propria. Therefore, understanding the biology of ESCC initiation and developing model systems that recapitulate ESCC neoplasia is crucial. Currently, the mechanism of ESCC initiation and immune landscape remodeling during ESCC initiation and tumorigenesis remain unclear. We have established a genetically engineered murine esophageal organoid model system that has shown significant potential to study ESCC initiation. Through CRISPR-based genetic manipulation of murine esophageal organoids, we identified the key tumor suppressor genes most frequently deleted in ESCC patients and established 32 esophageal organoid lines. Transcriptomics of the neoplastic organoids indicated a transcriptional signature consistent with ESCC patients, and single-cell transcriptomics identified distinct cell lineage, multiple root cells, and critical regulons of such neoplastic organoids. Interestingly, only specific neoplastic organoid- derived cells developed tumors in immunocompetent mice. Our preliminary results suggest that the loss of tumor suppressor genes is a crucial event for ESCC initiation by inducing esophageal neoplasia (cell-autonomous) and remodeling the immune landscape (non-cell-autonomous). Therefore, we hypothesize that the combinatorial loss of tumor suppressor genes initiates ESCC by inducing esophageal neoplasia, cell plasticity, and immune evasion. This hypothesis will be tested through two specific aims: Aim 1. To determine the genetic and transcriptional network initiating ESCC using new model systems; Aim 2. To determine the impact of targeting the ESCC-driven immune landscape remodeling on ESCC initiation and tumorigenesis. The study will fill the current knowledge gap by unveiling the biology of ESCC initiation and providing new models for developing viable therapeutic applications for early ESCC.
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