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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2017)

Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy in men and the second leading cause of cancer-related deaths in the US. Men with PCa that has recurred after surgery or radiation therapy usually respond to androgen deprivation therapy (ADT); however despite initial responses rate of 80 to 90 percent, nearly all men eventually develop progressive disease following ADT; this is referred to as castration-resistant prostate cancer (CRPC), which remains an incurable disease. It has been reported that neuroendocrine (NE) cell type in prostate cancer is highly associated with castration-resistant disease. However, the exact role of NE cells in promoting the transition from castration-sensitive cancer to castration-resistant disease is not fully understood. The goal of this study was to investigate the gene expression profile, cellular function and therapeutic resistant properties of NE cells purified through CXCR2 surface marker from prostate adenocarcinoma. We further investigated the role of CXCR2 in mediating CRPC carcinogenesis and explore the use of CXCR2 inhibitor combine with Enzalutamide as a potential therapy for advanced prostate cancer. In this research, we have identified a novel cross-talk between neuroendocrine cells in hormone na�ve prostate cancer with both prostate cancer progression and hormonal therapy resistance. We have demonstrated that C-X-C motif chemokine receptor 2 (CXCR2) is a unique surface marker of neuroendocrine cells in prostate cancer and it is over-expressed in metastatic castration resistant, high grade, and NEPC patient cases. Importantly, we discovered that CXCR2 plays a critical role in facilitating this intercellular communication and NEPC transformation from typical prostate adenocarcinoma. CXCR2 overexpression led to enzalutamide resistance, loss of AR expression, and lineage plasticity with acquisition of stem cell-like properties. We further demonstrated that CXCR2 inhibition can prevent/delay enzalutamide resistance and restore AR function, leading to reductions in tumor burden. This research provides the mechanism for the first time of therapeutic resistance mediated by NE cells and raises the possibility to the final cure of lethal prostate cancer through CXCR2 blocker.

  • 1 supplemental file
Cover page: Targeting CXCR2+ Neuroendocrine-like Cells for the Treatment of Castration-resistant Prostate Cancer
  • Article
  • Peer Reviewed
UCLA Previously Published Works (2016)
mtDNA sequence alterations are challenging to generate but desirable for basic studies and potential correction of mtDNA diseases. Here, we report a new method for transferring isolated mitochondria into somatic mammalian cells using a photothermal nanoblade, which bypasses endocytosis and cell fusion. The nanoblade rescued the pyrimidine auxotroph phenotype and respiration of ρ0 cells that lack mtDNA. Three stable isogenic nanoblade-rescued clones grown in uridine-free medium showed distinct bioenergetics profiles. Rescue lines 1 and 3 reestablished nucleus-encoded anapleurotic and catapleurotic enzyme gene expression patterns and had metabolite profiles similar to the parent cells from which the ρ0 recipient cells were derived. By contrast, rescue line 2 retained a ρ0 cell metabolic phenotype despite growth in uridine-free selection. The known influence of metabolite levels on cellular processes, including epigenome modifications and gene expression, suggests metabolite profiling can help assess the quality and function of mtDNA-modified cells.
    Cover page: Mitochondrial Transfer by Photothermal Nanoblade Restores Metabolite Profile in Mammalian Cells
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2019)
    Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2019)
      Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
        Cover page: Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2016)
        Selection of an optimal donor pancreas is the first key task for successful islet isolation. We conducted a retrospective multicenter study in 11 centers in North America to develop an islet donor scoring system using donor variables. The data set consisting of 1,056 deceased donors was used for development of a scoring system to predict islet isolation success (defined as postpurification islet yield >400,000 islet equivalents). With the aid of univariate logistic regression analyses, we developed the North American Islet Donor Score (NAIDS) ranging from 0 to 100 points. The c index in the development cohort was 0.73 (95% confidence interval 0.70-0.76). The success rate increased proportionally as the NAIDS increased, from 6.8% success in the NAIDS < 50 points to 53.7% success in the NAIDS ≥ 80 points. We further validated the NAIDS using a separate set of data consisting of 179 islet isolations. A comparable outcome of the NAIDS was observed in the validation cohort. The NAIDS may be a useful tool for donor pancreas selection in clinical practice. Apart from its utility in clinical decision making, the NAIDS may also be used in a research setting as a standardized measurement of pancreas quality.
          Cover page: A Multicenter Study: North American Islet Donor Score in Donor Pancreas Selection for Human Islet Isolation for Transplantation
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