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1) neuroendocrine prostate cancer; 2) AR driven castrate-resistant prostate cancer 3) drug screening novel DNA topoisomerase II inhibitors 4) cell free nucleotide biomarkers from liquid biopsy
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Mar 2019)
While androgen receptor pathway inhibition (ARPI) has significantly increased the survival of metastatic prostate adenocarcinoma (AdPC), accumulating evidence suggests that AdPC can change to a more aggressive subtype, called treatment-induced neuroendocrine prostate cancer (t-NEPC). T-NEPC is androgen receptor (AR) indifferent, and shows a neuroendocrine-like phenotype. Few targeted therapy is currently available for t-NEPC. It is imperative to identify biomarkers for early detection of t-NEPC and molecular targets for drug development.In this work, using whole transcriptome sequencing on t-NEPC from two independent patient cohorts, we have identified a t-NEPC specific splice signature that is predominantly controlled by the RNA splicing factor, serine/arginine repetitive matrix 4 (SRRM4). We have found that SRRM4 is highly expressed in t-NEPC and is strongly correlated with t-NEPC biomarker expression. Significantly, we have, for the first time, shown that SRRM4 can transform LNCaP adenocarcinoma cells into t-NEPC xenografts. We also confirmed that one of SRRM4 target genes was the RE1 silencing transcription factor (REST), a key regulator of neurogenesis. Moreover, The ARPI combined with a gain of SRRM4-induced adenocarcinoma cells to assume multicellular spheroid morphology, and this was essential in establishing progressive NEPC xenografts. We also identified a BHC80 splice variant, BHC80-2, that functions as a key facilitator of t-NEPC development. Functionally reprogrammed by the SRRM4, BHC80-2 does not confer the NEPC phenotype to cancer cells, but rather stimulates cell proliferation and invasion to accelerate tumor progression. In contrast to the epigenetic role of BHC80 in histone demethylation, we defined a novel non-epigenetic action of BHC80-2, whereby cytosolic BHC80-2 proteins trigger the MyD88-p38-TTP pathway to increase the RNA stability of a set of tumor-promoting cytokines. Blocking BHC80-2 signaling suppresses NEPC cell spheroid growth, identifying BHC80-2 as a potential therapeutic target for t-NEPC.Overall, my doctoral studies confirmed that SRRM4 is both a biomarker and a driver of t-NEPC by regulating tumor cell growth and metastasis in addition to its previously reported roles in neuroendocrine differentiation. Our studies not only enhance our understanding of the mechanisms of NEPC development, but also provide insights for personalized medicine-based strategies for prostate cancer patients.
Prostate cancer, the most common malignancy in Canadian men, is a leading cause of cancer-related male mortality. Androgen deprivation therapy is the first-line treatment for advanced prostate cancer. However, a fatal relapse to androgen deprivation therapy is inevitable, which is often characterized by the establishment of an androgen-independent AR signalling that drives the disease to the lethal castration-resistant prostate cancer (CRPC) stage. Defining the mechanisms that promote the reestablishment of AR signaling including the androgen independence is important for therapy development and disease control. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms and its expression has been reported to increase after antiandrogen treatment. Whether UGT2B17 plays a role in the progression of CRPC is unclear. In this work, we demonstrated that the higher expression of UGT2B17 protein is associated with higher Gleason scores, increased metastasis and CRPC progression in prostate tumors. The expression and activity of UGT2B17 were also higher in androgen-independent cell lines compared to androgen-dependent cell lines. Overexpression of UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Furthermore, UGT2B17 not only suppressed androgen-dependent AR transcriptional activity but also enhanced androgen-independent AR transcriptional activity, mainly through activating the c-Src kinase. These results indicate that the UGT2B17-Src-AR signaling contributes to the reestablished AR signaling and expedites CRPC progression and blocking the UGT2B17-Src-AR cascade will be beneficial for overcoming the resistance in CRPC patients. Accordingly, pharmacological targeting of the catalytic domain of DNA topoisomerase II (Topo II), which is known to be essential for AR-mediated transcriptional control, can completely block the transcriptional activity of reestablished AR, mutant ARs and AR splicing variants. Targeting Topo II also strengthened the efficacy of current anti-androgens in suppressing wild type AR activities. Furthermore, catalytic Topo II inhibitors inhibited CRPC and enzalutamide-resistant prostate cancer cell growth and xenograft progression.Overall, my doctoral thesis demonstrates that the UGT2B17-Src-AR signaling axis contributes to the reestablished AR signaling and expedites CRPC progression, and that applying catalytic Topo II inhibitors can block the transcriptional activity of reestablished AR signaling and suppress CRPC progression.
Master's Student Supervision (2010-2017)
Treatment-induced neuroendocrine (NE) prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that can arise as a consequence of rigorous androgen receptor pathway inhibition (ARPI) therapies now used to treat castration resistant disease (CRPC). While the PI3K/AKT pathway has been investigated as a co-therapeutic target with ARPI for advanced prostate adenocarcinoma, whether this strategy has implications on t-NEPC progressionremains unknown. Findings from this work indicate that PI3K/AKT inhibition alone reduces protein expression of the RE-1 silencing transcription factor (REST) and induces multiple NE markers in PCa cells. The loss of REST by PI3K/AKT inhibition is through protein degradation mediated by the E3-ubiquitin ligase β-TRCP and REST phosphorylations at the S1024, S1027, and S1030 sites. Since AR inhibition was previously reported to deplete REST, results from this project reveal that the combined inhibition of PI3K/AKT and AR further aggravates REST protein reduction. Upon profiling the transcriptomes of AKT inhibition, AR inhibition, and AKT/AR co-inhibition in the LNCaP cell model, Gene Set Enrichment Analysis (GSEA) shows that these transcriptomes are highly correlated with the REST-regulated gene signature. Co-targeting AKT and AR resulted in an even higher correlation comparing to those of single treatment. Comparing these transcriptomes to the RNA-seq gene signature of t-NEPC patients by GSEA, it was observed that adding AKT inhibition to AR blockade enhanced the expression of neurogenesis-related genes and resulted in a stronger and broader upregulation of REST-regulated genes specific to t-NEPC. Collectively, these results indicate that AKT pathway inhibition can induce NE transdifferentiation in PCa cells via REST protein degradation. It delineates a potential risk for the AR and PI3K/AKT co-targeting strategy as it may further facilitate t-NEPC development.
The prostate composes of epithelium and stroma, both of which are kept in balance to maintain normal prostate function. The balance between epithelium and stroma can be disrupted by the abnormal growth of stromal cells which results in prostate diseases such as benign prostatic hyperplasia. The epithelial-stromal interaction plays important roles not only in normal prostate homeostasis maintaining but also in prostate cancer development and progression. In prostate tumor, cancer associated fibroblasts enhance the secretions of cytokines and growth factors to favor cancer cells growth and metastasis. Androgen receptors are reported to regulate the development and maintenance the function of prostate. Progesterone receptor (PR) which belongs to the same steroid hormone receptor family as androgen receptors are little known in prostate. PR was reported to express in prostate, but there is no clear conclusion about the localization and function of PR in human prostate. The objective of this thesis is to investigate the expression and function of PR in human prostate. Two PR isoforms, PRA and PRB, are detected in subsets of the human prostate stromal cells by applying immunohistochemistry assays. Both PR isoforms express specifically in human prostate stromal fibroblasts and smooth muscle cells. Both PRA and PRB are demonstrated to play an inhibitory role in prostate stromal cell proliferation. PR suppresses the expression of cyclin A, cyclinB and cdc25c to delay cell cycle. PRA and PRB are demonstrated to regulate different transcriptomes by gene microarray assay. Immunohistochemistry assays were applied to human prostate cancer tissue biopsies, and PR levels are detected to decrease in the cancer associated stroma compared to the paired normal stroma. The conditioned media from PR positive stromal cell inhibit PC-3 and C4-2B cell motility through down-regulating the secretion of stromal cell derived factor 1 and interleukin 6. We conclude that PRA and PRB express in prostate stromal cells and inhibit the stromal cells proliferation. Decreased expression of PR in cancer associated stroma contributes to prostate tumor progression.