Liu Lab
Understanding therapy resistance and disease progression in advanced prostate cancer.
Urologic Surgery Research
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Principal InvestigatorChengfei Liu, M.D., Ph.D.
See full physician biographyLiu’s research focuses on therapy resistance and disease progression in advanced prostate cancer. His research interests include nuclear receptor signaling, chaperone-mediated protein regulation, ubiquitin–proteasome pathways, tumor metabolism, steroid hormone biosynthesis, tumor immunology and translational cancer research. His current research program is dedicated to uncovering the mechanisms that drive treatment resistance in lethal prostate cancer, with a strong emphasis on identifying novel therapeutic targets and developing effective therapeutic strategies.
Research Goals
Liu’s long-term research goal is to integrate basic and clinical discoveries to advance translational strategies in urologic oncology, with a focus on understanding and therapeutically targeting mechanisms of prostate cancer progression and treatment resistance. His laboratory aims to define how disruption of protein post-translational regulation and proteostasis drives lineage plasticity and neuroendocrine differentiation in advanced prostate cancer, including the stabilization of oncogenic drivers such as the N-Myc gene and the reprogramming of semaphorin-plexin signaling networks.
In parallel, Liu’s laboratory investigates how androgen receptor pathway inhibition reshapes the tumor immune microenvironment to promote immune evasion and disease aggressiveness. He also seeks to dissect key molecular drivers of anti-androgen resistance, including androgen receptor splice variants, intratumoral androgen biosynthesis, and stress-response pathways involving chaperone systems and ubiquitin-proteasome regulation, with the ultimate goal of identifying convergent vulnerabilities and developing effective combination therapies for lethal castration-resistant and neuroendocrine prostate cancer.
Research Projects
Treatment-induced neuroendocrine prostate cancer (t-NEPC) accounts for 20% of castration-resistant prostate cancer (CRPC) cases and is characterized by rapid proliferation and metastasis with no effective treatment options. The t-NEPC primarily arises from lineage plasticity transformation of adenocarcinoma after long-term androgen deprivation therapy or androgen receptor signaling inhibitor (ARSI) treatment, such as enzalutamide. In this project, the investigators discovered that proteomic equilibrium is profoundly disrupted during prostate cancer lineage plasticity transformation, resulting in impaired protein homeostasis (proteostasis) and widespread oncogenic activation at the protein level. This dysregulated proteostasis is driven by alterations in the chaperone-E3 ubiquitin ligase machinery, which normally ensures proper protein folding, quality control, and degradation. During lineage plasticity, these regulatory networks are rewired, leading to aberrant stabilization of oncogenic proteins. Notably, proteostasis pathways critically govern N-Myc protein turnover, and their dysfunction promotes sustained N-Myc accumulation independent of transcriptional upregulation. This protein-level dysregulation enables N-Myc to act as a central driver of lineage plasticity, therapeutic resistance, and aggressive tumor behavior, highlighting proteostasis imbalance as a previously underappreciated mechanism underlying advanced prostate cancer progression (Xu, Nature Communications, 2024). Additionally, we found that multiple semaphorin-plexin family members were significantly upregulated in NEPC patient datasets. Notably, enzalutamide treatment activated neural lineage transcriptional programs and robustly induced PLXND1 expression, which strongly correlated with aggressive disease features and poor clinical prognosis (Chen, Oncogene, 2024).
Over the past few decades, the new conceptual and technical advances in immunology have led to novel discoveries between the immune system and tumors, including prostate cancer. Literature and data show that castration-resistant prostate cancer (CRPC) treated with enzalutamide may escape the immune surveillance through increasing a cell surface protein called PD-L1, which is the widely used target in immunotherapy for cancer treatment. Emerging data from Liu’s group found that accompanying the PD-L1 overexpression in enzalutamide-resistant prostate cancer cells (Xu, Journal for ImmunoTherapy of Cancer, 2023), another novel cell surface protein, CD200, was also significantly upregulated. Notably, CD200 expression was negatively regulated by androgen receptor signaling. CD200 and its receptor CD200R work together to suppress immune response in multiple diseases, including cancer. Data from Liu’s laboratory further revealed that enzalutamide treatment not only promoted the CD200 expression in tumor cells but also increased its binding receptor-CD200R population in immunosuppressive cells infiltrating into tumors, which may further suppress the immune response (Nip, Biomedicines, 2023).
The goal of this project is to identify novel resistance mechanisms and develop new pharmaceuticals as co-targeted therapy in combination with different agents to treat advanced prostate cancer. Liu’s laboratory has generated and characterized several unique enzalutamide-resistant prostate cancer cell lines, including C4-2B-MDVR (Liu, Cancer Research, 2015) and MycCaP-MDVR (Xu, Journal for ImmunoTherapy of Cancer, 2023). These resistant cell lines provide scientists with unique models to study the mechanisms underlying enzalutamide resistance in metastatic prostate cancer. Researchers detailed the precise mechanisms that contribute to enzalutamide resistance. Working with enzalutamide-resistant cell lines, which Liu created, he established that AKR1C3 (Liu, Cancer Research, 2015), HSP70/STUB1 complex (Liu, Nature Communications, 2018), AR-V7 (Liu, Clinical Cancer Research, 2014), and IL6/STAT3 (Liu, The Prostate, 2014) are all significant participants in the process. He also examined the role of specific enzymes in intratumoral androgen biosynthesis, which is another method that characterizes late-stage drug-resistant prostate cancer (Yang, Oncogene, 2023). Liu’s work on this project has been highlighted several times by Nature Review Urology.