Gene Expression Profile Can Indicate Aggressive Prostate Cancer Interview with

Dr. Dingxiao Zhang Ph.D Department of Epigenetics and Molecular Carcinogenesis University of Texas MD Anderson Cancer Center Smithville, TX 78957, USA

Dr. Dingxiao Zhang

Dr. Dingxiao Zhang Ph.D
Department of Epigenetics and Molecular Carcinogenesis
University of Texas MD Anderson Cancer Center
Smithville, TX 78957, USA What is the background for this study? What are the main findings?

Dr. Zhang: Prostate cancer (PCa) is a heterogeneous malignancy harboring phenotypically and functionally diverse subpopulations of cancer cells. To better understand PCa cell heterogeneity, it is crucial to dissect the biology of normal prostate epithelial lineages. The background for the current study is to annotate the gene expression profiles of normal prostate epithelial cells, through which we hope to gain insight on Prostate cancer subtypes and the cellular heterogeneity in PCa. The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. In this study, we have performed a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing.

One of our major findings is that the differential gene expression profiles in basal versus luminal prostate epithelial cells account for their distinct functional properties. Specifically, basal cells preferentially express gene categories associated with stem cells, MYC-transcriptional program, neurogenesis, and ribosomal RNA (rRNA) biogenesis regulated by Pol I. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene expression profile is enriched in advanced, anaplastic, castration-resistant, and metastatic prostate cancers.

Therefore, we link the cell-type specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. What should clinicians and patients take away from your report?

Dr. Zhang: It is well known that the majority of untreated primary prostate cancer present as adenocarcinomas while a small subset (1–5%) of patient tumors is classified as undifferentiated or anaplastic PCa variants termed as small cell PCa or neuroendocrine PCa. These tumors have a clinically aggressive behavior, lack androgen receptor expression, and are refractory to androgen-deprivation therapy. Significantly, such aggressive variants markedly increase in castration-resistant prostate cancer patients, and currently there is no effective treatment for these aggressive PCa variants, mainly due to the fact that they are poorly characterized molecularly. As our study reveals the molecular resemblance of basal cells to anaplastic PCa and its castration-resistant counterpart, clinicians can think that if a patient’s tumor possesses a basal cell gene expression profile, it would suggest that the tumor will be aggressive and not respond well to anti-androgens. For both clinicians and patients, our results suggest a rationale for treating prostate tumors with a basal cell gene expression profile with a combination of Pol-I and MYC inhibitors. What recommendations do you have for future research as a result of this study?

Dr. Zhang: Our basal cell gene signature can be developed as a clinical biomarker for stratifying the  prostate cancer patients according to the aggressiveness of the disease. Further characterizing these differences in gene expression patterns of basal and luminal cell lineages will shed fresh lights on the etiology of and developing novel therapies against both adenocarcinomas and variantprostate cancer. Is there anything else you would like to add?

Dr. Zhang: Proneural genes are those that are normally expressed in and play important functions in neural cells including neurons, astrocytes, and oligodendrocytes. We surprisingly find that the adult human prostate basal stem cells are greatly enriched in such genes (12%). The unique gene expression pattern in basal stem cells confers on them functional versatilities, and implicate basal cells as the cell of origin for these aggressive variants of prostate cancer.


Dingxiao Zhang et al. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer, Nature Communications (2016). DOI: 10.1038/ncomms10798

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Dr. Dingxiao Zhang (2016). Gene Expression Profile Can Indicate Aggressive Prostate Cancer