Saturday, November 23, 2024
11/23/2024
Project Summary Most cancers develop from premalignant lesions that progress to malignancy in response to further mutations or epigenetic changes. A better understanding of malignant progression may enable approaches to suppress tumorigenesis, especially in individuals with specific cancer predispositions. This project aims to define mechanisms through which premalignant lesions form and progress to malignancy in the childhood retinal cancer, retinoblastoma. In this cancer, biallelic loss of RB1 is thought to enable the aberrant proliferation of early maturing cone precursors (emCPs), which then form largely quiescent premalignant lesions in utero, followed by emergence of retinoblastoma foci in the perinatal and postnatal periods. The earliest retinoblastomas appear to lack clonal mutations beyond RB1, implying that entrance into and escape from premalignancy is enabled by epigenetic changes. In preliminary studies, we developed stem cell-derived retinal organoid models that display initial emCP proliferation, a largely quiescent premalignant stage, and emergence of retinoblastoma-like foci at tissue ages similar to those of retinoblastomas in patients. Accordingly, the models provide an opportunity to define mechanisms underlying the production and progression of premalignant retinoblastoma in an experimentally tractable setting. Although numerous aspects may be considered, the project focuses on: a) the emCPs’ proliferation dynamics and mitotic behavior at each tumorigenesis stage, along with gene expression changes that overcome initially highly impaired mitoses to enable production of premalignant lesions; b) gene expression changes that mediate exit from the cell cycle into a series of premalignant cell states; c) gene expression and underlying epigenetic changes that mediate transitions between premalignant states and the emergence of retinoblastoma-like foci, and finally d) characterization of the retinal organoid-derived retinoblastoma-like foci, including definitive tests of their emCP origin, their malignant potential, and their similarity to retinoblastomas in patients. Together, the studies aim to provide sufficient knowledge of malignant progression to enable approaches to prevent this process in children with highly penetrant retinoblastoma predisposition.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
