Therapy-Induced Developmental Reprogramming of Prostate Cancer Cells and Acquired Resistance
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE66852 | GEO | 2016/03/11
SECONDARY ACCESSION(S): PRJNA278087
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-03-11 | E-GEOD-66852 | biostudies-arrayexpress
Project description:Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.
| S-EPMC5386661 | biostudies-literature
Project description: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. Gene expression profiles were obtained for RNAs extracted from biological replicates of parental LNCaP cells or from Neuroendocrine-like LNCaP (LNCaP-NE) cells grown for 15 days in CSS-media with no androgen.
2016-03-11 | E-GEOD-66851 | biostudies-arrayexpress
Project description: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.
2016-03-11 | E-GEOD-66850 | biostudies-arrayexpress
Project description:Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.
2016-03-11 | GSE66850 | GEO
Project description:Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.
2016-03-11 | GSE66851 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-05-01 | E-GEOD-39418 | biostudies-arrayexpress
Project description:Androgen deprivation therapy (ADT) is standard-of-care for advanced-stage prostate cancer, and enzalutamide (Xtandi®, Astellas, Northbrook, IL, USA), a second generation antiandrogen, is prescribed in this clinical setting. The response to this medication is usually temporary with the rapid emergence of drug resistance. A better understanding of gene expression changes associated with enzalutamide resistance will facilitate circumventing this problem. We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-2B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation. Next-Gen sequencing detected 9409 and 7757 genes differentially expressed in LNCaP and C4-2B cells, compared to their parental counterparts. A subset of differentially expressed genes were validated by qRT-PCR. Analysis by the i-pathway revealed membrane transporters including solute carrier proteins, ATP-binding cassette transporters, and drug metabolizing enzymes as the most prominent genes dysregulated in resistant cell lines. RNA-Seq data demonstrated predominance of solute carrier genes SLC12A5, SLC25A17, and SLC27A6 during metabolic reprogramming and development of drug resistance. Upregulation of these genes were associated with higher uptake of lactic/citric acid and lower glucose intake in resistant cells. Our data suggest the predominance of solute carrier genes during metabolic reprogramming of prostate cancer cells in an androgen-deprived environment, thus signifying them as potentially attractive therapeutic targets.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2013-05-01 | GSE39418 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-09-01 | E-GEOD-55860 | biostudies-arrayexpress