Monday, May 6, 2024
5/6/2024
Project Summary/Abstract The objectives of this proposal are to define fundamental mechanisms that drive radiation-induced esophageal squamous cell carcinoma (ESCC). There is compelling evidence linking an increased risk of developing ESCC with a history of therapeutic radiation exposure. Elucidating the machinery that drives tumor susceptibility, is of major import to NCI, as ESCC is the deadliest of all human squamous cell carcinomas. Abnormalities in stress signaling, in proteins such as ATF2 are strongly implicated in cancers. Additionally, a central role of epithelial to mesenchymal transition (EMT) in the promotion of cancer has gained prominence. Knowledge of pathways that translate radiation-induced aberrant signaling to changes in the microenvironment is lacking and essential to assess cancer risk post radiation exposure. This is a major gap in the field, which the current project proposes to bridge. Our preliminary studies suggest a strong association between persistent pATF2ser 490/98 signaling and EMT, both events regulated by transforming growth factor ¿ (TGF¿). Our main objectives are to understand the role of TGFß-mediated pATF2 signaling and its relationship to EMT, to provide insight into how changes in the microenvironment allow radiation-induced tumor initiation and progression and identify biomarkers for ESCC radiation-induced carcinogenesis. We hypothesize that TGF¿ driven persistent pATF2 signaling triggers EMT post radiation exposure, and this signaling network creates a tumor permissive microenvironment. To test this hypothesis, we will use well-characterized normal and transformed cells containing genetic alterations commonly occurring in esophageal cancer, and 3D cell culture systems, closely mimicking the in vivo physiological environment of the esophagus. High and low dose fractionated radiation will be used to simulate the exposure to the esophagus from radiotherapeutic cancer treatments. CRISPR technology will be used to mutate the ATF2 phospho-sites to define dependency of this signaling. Immunofluorescence, immunohistochemistry, and RNA seq will be used to address the specific aims and gain a mechanistic understanding of these events. We will (1) test our hypothesis that EMT induction is a consequence of fractionated radiation-induced aberrant pATF2 signaling, and (2) investigate the effect of pATF2 signaling on tissue architecture, promotion of a tumor phenotype, and transcriptomics post radiation exposure. Our contribution is expected to provide an innovative approach to understand how radiation, through its influence on intercellular communication and interactions with the microenvironment affects levels of biological organization and promotes cancer. This proposal addresses relevant scientific areas of emerging importance such as the contribution of persistent stress signaling, and microenvironment changes in promoting carcinogenesis. These studies are especially significant, as elucidating the underlying mechanisms that promote radiation-induced carcinogenesis could aid in predicting patients at an increased risk of developing ESCC and give mechanistic insights into the radiation-related carcinogenesis of other tumor types including esophageal adenocarcinoma (EAC).
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