Identify genetic regulatory circuitry driving the development of rapamycin tolerance
Awardee: Yan Tang
Institution: Brigham and Women's Hospital
Grant Amount: $73,491
Funding Period: February 1, 2022 - January 31, 2023
Summary:
Rapamycin (and its analogues, rapalogs) are the only effective treatment for TSC-associated diseases, including lymphangioleiomyomatosis (LAM). However, rapalogs can only stabilize lung function in LAM, but lung function continues to decline upon treatment cessation. It’s of paramount importance to understand the mechanisms of why and how LAM cells can survive rapamycin treatment and regrow after treatment cessation. Our single cell RNA-seq analysis of five LAM and six AML (angiomyolipoma, kidney manifestation of TSC) samples identified a subset population of LAM/AML cells with elevated stemness and dormancy programs, two typical features of drug tolerant/resistant tumor persister cells. These cells exhibited stabilized tumor cell phenotypes upon rapamycin treatment, including maintaining high expression of many TSC marker genes, suggesting a rapamycin tolerance mechanism. To identify drivers of development of rapamycin tolerance in a heterogeneous population, we have adopted a high-complex barcoding lineage tracing system that enables simultaneous assessing of each cell’s origin/lineage and transcriptomic/epigenomic profiles at single cell level. This novel approach will enable us to identify lineage-specific drivers for the development of rapamycin tolerance.