Research
Our lab is dedicated to uncovering the molecular mechanisms that drive resistance to targeted and immune therapies in prostate and other cancers. We are also pioneering innovative therapeutic strategies to overcome these resistances, utilizing a range of state-of-the-art techniques, including 3D-cultured organoids, single-cell sequencing, and spatial transcriptomics.
Exciting Research Directions in the Lab:
Lineage Plasticity and Resistance
Lineage plasticity is a hallmark of cancer and has emerged as a critical mechanism by which cancer cells circumvent targeted therapies. The pathways through which cancer cells attain lineage plasticity and resistance were previously obscure. We have delineated ectopic activation of JAK-STAT signaling as the pivotal mediator of lineage plasticity and AR therapy resistance (Nature Cancer, 2022).
Novel Tumor Suppressors and Oncogenes
It was previously unclear how cells utilize the epigenetic regulatory machinery to attain lineage plasticity and therapy resistance. We have elucidated a novel molecular switch, ZNF397, that modulates the equilibrium between AR and TET2-driven lineage-specific programs, thereby fostering lineage plasticity and AR therapy resistance in prostate and breast cancers (Cancer Discovery, 2024).
AR therapy resistance is often characterized by sustained or augmented AR protein levels. However, the mechanisms governing ubiquitination-based AR degradation were not well defined. We discovered UBE2J1 as the bona fide E2 ubiquitin-conjugating enzyme that orchestrates AR ubiquitination. The frequent loss of UBE2J1 leads to elevated AR protein levels, reinforcing resistance to antiandrogen treatments (Oncogene, 2023).
Mutagenesis and Tumor Evolution
Investigate the molecular mechanisms that promote mutagenesis, tumor heterogeneity, and tumor evolution. The mutational burden and heterogeneity of tumors propel resistance to targeted therapies. Yet, the mechanisms by which tumor cells enhance genomic heterogeneity were largely enigmatic. We pinpointed SYNCRIP as an intrinsic molecular restraint for APOBEC-driven mutagenesis. The loss of SYNCRIP accelerates tumor mutational burden and heterogeneity, culminating in AR therapy resistance (Cancer Cell, 2023).
Epigenetic Rewiring
mCRPC is marked by substantially increased tumor heterogeneity, presumed to contribute to resistance. Through the utilization of in vivo library screening, we identified the loss of the epigenetic remodeler CHD1 as a predominant event that confers resistance. The absence of CHD1 establishes an altered chromatin landscape, enabling the emergence of heterogeneous resistant subclones (Cancer Cell, 2020).
Tumor Microenvironment and Immune Modulation
Explore how prostate cancer cells alter the tumor microenvironment and immune cells to achieve resistance.
Drug Development
Develop novel therapeutic agents, including small molecular inhibitors and protein degraders, using our established high-throughput platform.