Saturday, September 7, 2024
9/7/2024
The goal of this research is to characterize Ras-driven and KSR1-dependent mechanisms that modulate tumor initiation, drug resistance and the epithelial-to-mesenchymal transition (EMT) in colorectal cancer. Tumor initiating cells (TICs) are a subpopulation of tumor cells defined by their ability to self-renew and regenerate the entire heterogeneous tumor population and are believed to be a reservoir of drug resistant persister cells. EMT- like behavior contributes to tumor initiation, invasion, and metastasis. Partial reversal of EMT to a “hybrid” state is necessary for efficient TIC formation and metastatic colonization. In turn, TICs lose clonogenicity and self- renewal and acquire the invasive behavior of mesenchymal cells that drives their dissemination. While the interconversion of tumor cells to migratory and invasive mesenchymal cells from self-renewing TICs is necessary for metastasis, little is known about the mechanisms that direct tumor cells between these phenotypes. We combined targeting of genes encoding key effectors of Ras signaling with polysome profiling and computational analysis to discover that the molecular scaffold KSR1 mediates resistance to clinically approved drugs and regulates TIC formation and EMT via RNA binding protein SRSF9. Our preliminary data suggest the hypothesis that KSR1- dependent signaling in KRAS-mutated CRC promotes the splicing and translation of mRNAs critical to CRC tumor initiation, drug resistance, and EMT. Using genetically modified CRC organoids, mouse models, and cells, the synergistic expertise of our team will characterize these novel pathways controlling CRC behavior in vitro and in vivo by 1) Characterizing the KSR1-dependent pathway(s) necessary for tumor initiation and resistance, 2) Defining the KSR1-dependent mechanism(s) driving cells from partial EMT toward invasive mesenchymal behavior, and 3) Determining how KSR1-dependent splicing promotes translation of proteins critical for EMT. Completion of this research will reveal novel mechanisms that may be targeted to improve therapeutic response and inhibit tumor initiation and metastasis.
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