Prostate cancer is one of the most common cancers worldwide and also the second leading cause of cancer-related death in males in Western countries. Although the majority of human primary prostate cancers have a luminal phenotype, both basal cells and luminal cells can serve as cellular origins of prostate cancer in model systems. However, the stem cell-like plasticity of defined prostate epithelial cells and the cellular origin of prostate cancer under physiological conditions have not been identified. Recently, prostate basal and luminal cell populations were both shown to be self-sustaining, and both cell types could initiate prostate cancer. Luminal cells were shown to have greater tendency to be the cells of origin for prostate cancer in some contexts. In addition, the oncogenic transformation of basal cells requires basal to luminal cell transition. These studies highlight the need to characterize the prostate cell lineage hierarchy and their behaviors in various contexts.

We are studying the prostate cell lineage hierarchy using single-cell RNA sequencing and cell lineage tracing technologies. We have identified a novel prostate luminal progenitor cell population (termed as Luminal-C) which located at the prostate the distal prostate invagination tips (termed as Dist-Luminal-C) and proximal prostate region (termed as Prox-Luminal-C). We are interested in understanding how Luminal-C cells orchestrates its niche signals in normal tissue homeostasis and diseases, and how to control the players in these machineries in vivo, as well as to provide strategies for the purpose of prostate cancer therapies.

(Dist-Luminal-C cells and their role as prostate cancer-initiating cells)

Tumor initiation, progression, and therapy resistance involve genetic/epigenetic reprogramming that leads to aberrant cell lineage specification and transition. It is critical to understand the underlying mechanisms of cancer cell lineage differentiation and transition, which will provide novel insights into anticancer research. Master transcription factors have been widely recognized with the function in cell lineage transdifferentiation and cell fate reprogramming. The identification of master transcription factors in regulation cancer cell lineage specification and transition would provide tremendous insights into the mechanism of lineage plasticity in cancer progression and therapy resistance.

We are studying prostate cell lineage reprogramming at the different stages of prostate tumor initiation, progression, and therapy resistance. We have identified defined ERG as a master transcription factor to regulate prostate luminal lineage through orchestrating chromatin interactions. We are interested in understanding both plasticity of prostate cancer lineages and mechanism of therapy resistances through multi-omics analysis (RNA-seq, ATAC-seq, ChIP-seq and 3D genome analysis) and prostate cancer model analysis (Patients-derived prostate cancer organoids and genetically engineered mouse models).

(ERG drives prostate cell fate reprogramming through orchestrating chromatin interactions)

The lack of in vitro cancer models that recapitulate the diversity of human cancers has hampered progress in understanding cancer cell lineage transition and therapy response. Organoid technology has been remarkably improved in recent years to allow the rapid generation of large repertoire of patient-derived cancer organoids (PDOs) amenable to genetic and pharmacologic studies. PDOs have been used to elucidate crucial scientific questions, including the relationships between genetic/epigenetic alterations and drug responses, cell plasticity during disease progressions, and mechanisms of drug resistances. We have generated patient-derived organoid biobanks of prostate, pancreatic, lung and liver cancers. These tools will help us address the cell origin of cancers, mechanistically study cancer cell lineage transition and therapy response.

For centuries, the attempts have been continuously made to artificially reconstitute counterparts of the in vivo organs from their tissues or cells. Only in the recent decade, organoid technology as a whole technological field systematically has emerged and been shown to play important roles in tissue engineering.

The liver hepatobiliary architecture is critical and essential for proper hepatic function, highlighting the need for an in vitro liver model with the real histological characteristics to study liver diseases and regeneration. We are developing a novel culture system of liver organoids to generate hepatobiliary architecture with hepatic function in vitro and upon transplantation in vivo.