Unknown,Transcriptomics,Genomics,Proteomics

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Therapy-Induced Developmental Reprogramming of Prostate Cancer Cells and Acquired Resistance [Dataset 1]

ABSTRACT: Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). We propose that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) and showed that AR+/PSA+ PCa cell lines were efficiently reprogrammed to and maintained as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed CSCs overexpressed stem genes, had features of N/NC stem cells, high tumor-initiating potential, resistance to anti-androgen and an EMT phenotype. Serum-containing mediums allowed re-differentiation to N-/NC-derived cell lineages or return back to PCa-like cancer cells. Once returned, the cells had increased resistance to androgen signaling inhibition. Finally, a 62-gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. To compare gene expression between parental PCa cells and STM-reprogrammed cells (LNCaP, VCaP, CWR-22rv1 and LAPC4), RNAs from biological triplicate samples of parental cells and corresponding STM-reprogrammed cells (>14 days in STM) were extracted.

ORGANISM(S): Homo sapiens

SUBMITTER: Shawn Anderson

PROVIDER: E-GEOD-66850 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Cancer stem cells (CSCs) drive prostate cancer (PCa) progression and metastasis. These cells exhibit remarkable self-renewal, chemoresistant and invasive potentials, and are thought to participate in the changes in cellular architecture that lead to epithelial-to-mesenchymal transition (EMT). Conventional therapies fail to eliminate CSCs, which results in tumor recurrence and progression to castration resistant PCa (CRPC). Recent evidence suggests that castration itself can induce EMT, which could potentiate the âstemnessâ and number of CSCs within the tumor. Hence, there is an urgent need for EMT- and CSC-targeted therapies that could prevent progression to CRPC. 22Rv1, DU145, LNCaP, and PC3 cells were grown under sphere-forming conditions standardized in our lab. We have previously demonstrated that these enriched PCa cell lines exhibit phenotypic characteristics associated with CSCs in vivo. Over-expression of the stem-associated CD133 biomarker was determined via flow cytometric analysis. Total RNA was isolated from CD133+ prostasphere-derived cells. Gene expression profiling was carried out using the nCounter NanoString system and three different CodeSets associated with cancer or stem cells. Functional annotation was performed using the over-representation analysis tool from ConsensusPathDB. Functional annotation analysis of upregulated transcripts suggests that prostasphere-derived cells undergo a transcriptional reprogramming that triggers a major phenotypic shift. These changes are similar to the mesenchymal shift associated with EMT that drives PCa progression to CRPC. Each cell line exhibited distinct expression profiles that are presented and analyzed individually. Furthermore, our analysis revealed over-represented pathways that were common to all cell lines, which are related to the MAPK/ERK, PI3K/AKT, Notch, and Wnt stem cell fate signaling networks. Transcriptional analysis of induced CSCs not only offers insight into their underlying pathophysiology, but can also be used as a platform for the discovery of therapeutic targets for CSC-specific intervention. In this contribution, we present a flexible in vitro platform for the identification of functionally relevant therapeutic targets, using cell samples with low numbers of malignant stem/progenitors that were enriched in vitro. This approach represents a novel and effective strategy that can be used in the development of therapeutic strategies, which could ultimately be tailored to the biology of individual patients. 22Rv1, DU145, LNCaP and PC3 prostasphere cultures were sampled on Day 4 (P 2), Day 8 (P 3) and Day 12 (P 4), and compared relative to parental monolayers on Day 0 of culture (P 1). Three independent measurements were carried out for monolayers at Day 0 using the CancerReference Kit. Day 12 prostaspheres were enzymatically dissociated and sorted via MACS using the Anti-CD133/2 (293C3)-PE Antibody (Miltenyi) into CD133+ and CD133- fractions. Total RNA was extracted from CD133+ cells and were analyzed using the nCounter GX Cancer Reference kit, the Stem Cell panel and the custom made ITESM CodeSet (14 genes associated with prostate cancer) from NanoString Technologies. This series contains data for the Stem Cell panel.

Dataset Information

Therapy-Induced Developmental Reprogramming of Prostate Cancer Cells and Acquired Resistance [Dataset 1]

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