Paloma Bravo, a junior biology major at Carleton College, identified biomarker features for cancer contexts in which RTCP1 is required.
The lack of effective therapies contributes to the high cancer mortality rates. Precision medicine will help identify new therapeutic strategies to target specific cancer contexts. BSRP has been a truly transformative experience in preparing me as a future scientist, leader, and collaborator. I could have never imagined the amount of growth and progress I could make in a single summer before coming to the Broad from entering a completely new field to the final presentation. The BSRP and the cohort’s dedication to each other’s success along with the collaborative nature of the Broad made this possible and completely exceeded my expectations of what research can look like. I am beyond grateful and more excited than ever to apply the skills that I have learned to future research experiences and to my career!There have recently been large efforts to systematically identify novel therapeutic targets by deploying genome-scale CRISPR-Cas9 loss-of-function screens across multiple cancer cell models. Systematic analysis of this dataset identified the gene RTCP1 (Receptor Trafficking Candidate Protein 1), involved in the deubiquitination of internalized receptor cargo resulting in their degradation, as a novel selective dependency. Upon knockdown of RTCP1 in dependent cells we observed decreased cell viability and endosome accumulation which could be a promising target for therapeutics. However, RTCP1 dependence is variable and difficult to detect. Our goal was to identify biomarker features for cancer contexts in which RTCP1 is required by using functional genomic and RNA-seq data. We found that the absence of PBMA (Potential Biomarker A) , a protein involved in receptor recycling in cells, was the top correlated feature of RTCP1 dependency. Further analysis identified absence of the endosomal trafficking protein PBMB (Potential Biomarker B) as a potential additional biomarker for RTCP1 dependency in downregulated PBMA cancers. Future work includes validation of these biomarkers by knocking down RTCP1 in dependent cell lines and overexpressing PBMA and PBMB to investigate potential rescue pathways and cell viability. A better understanding of endosomal trafficking pathways as biomarkers of RTCP1 dependency will support the development of more effective targeted therapeutics.
Project: Aberrant endosomal trafficking in cancer results in dependency on RTCP1
Mentor: Jason Kwon, Cancer Program