Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Tumor evolution is based on the ability to constantly mutate and activate different pathways under the selective pressure of targeted therapies. Epigenetic alterations including those of the chromatin structure are associated with tumor initiation, progression and drug resistance. Many cancers, including prostate cancer, present enlarged nuclei, and chromatin appears altered and irregular. These phenotypic changes are likely to result from epigenetic dysregulation. High-throughput sequencing applied to bulk samples and now to single cells has made it possible to study these processes in unprecedented detail. It is therefore timely to review the impact of chromatin relaxation and increased DNA accessibility on prostate cancer growth and drug resistance, and their effects on gene expression. In particular, we focus on the contribution of chromatin-associated proteins such as the bromodomain-containing proteins to chromatin relaxation. We discuss the consequence of this for androgen receptor transcriptional activity and briefly summarize wider gain-of-function effects on other oncogenic transcription factors and implications for more effective prostate cancer treatment.

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Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽

10.1182/blood-2018-11-835405 ◽

2019 ◽

Vol 133 (13) ◽

pp. 1436-1445 ◽

Cited By ~ 6

Author(s):

Jyoti Nangalia ◽

Emily Mitchell ◽

Anthony R. Green

Keyword(s):

Somatic Mutations ◽

Clonal Selection ◽

Single Cells ◽

Driver Mutations ◽

Great Promise ◽

Tumor Evolution ◽

Disease Development ◽

Hematopoietic Tissue ◽

The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

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Modeling Prostate Cancer Treatment Responses in the Organoid Era: 3D Environment Impacts Drug Testing

Biomolecules ◽

10.3390/biom11111572 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1572

Author(s):

Annelies Van Hemelryk ◽

Lisanne Mout ◽

Sigrun Erkens-Schulze ◽

Pim J. French ◽

Wytske M. van Weerden ◽

...

Keyword(s):

Prostate Cancer ◽

Treatment Effect ◽

Drug Testing ◽

Nuclear Translocation ◽

Single Cells ◽

Great Promise ◽

Preclinical Research ◽

3D Scaffolds ◽

The Impact

Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organoid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Matrigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin stabilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects.

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Investigating Human Mitochondrial Genomes in Single Cells

Genes ◽

10.3390/genes11050534 ◽

2020 ◽

Vol 11 (5) ◽

pp. 534

Author(s):

Maria Angela Diroma ◽

Angelo Sante Varvara ◽

Marcella Attimonelli ◽

Graziano Pesole ◽

Ernesto Picardi

Keyword(s):

Exome Sequencing ◽

High Throughput Sequencing ◽

Single Cells ◽

Somatic Mosaicism ◽

Cellular Heterogeneity ◽

Tumor Evolution ◽

Whole Genome ◽

Sequencing Data ◽

Experimental Conditions ◽

Mtdna Mutations

Mitochondria host multiple copies of their own small circular genome that has been extensively studied to trace the evolution of the modern eukaryotic cell and discover important mutations linked to inherited diseases. Whole genome and exome sequencing have enabled the study of mtDNA in a large number of samples and experimental conditions at single nucleotide resolution, allowing the deciphering of the relationship between inherited mutations and phenotypes and the identification of acquired mtDNA mutations in classical mitochondrial diseases as well as in chronic disorders, ageing and cancer. By applying an ad hoc computational pipeline based on our MToolBox software, we reconstructed mtDNA genomes in single cells using whole genome and exome sequencing data obtained by different amplification methodologies (eWGA, DOP-PCR, MALBAC, MDA) as well as data from single cell Assay for Transposase Accessible Chromatin with high-throughput sequencing (scATAC-seq) in which mtDNA sequences are expected as a byproduct of the technology. We show that assembled mtDNAs, with the exception of those reconstructed by MALBAC and DOP-PCR methods, are quite uniform and suitable for genomic investigations, enabling the study of various biological processes related to cellular heterogeneity such as tumor evolution, neural somatic mosaicism and embryonic development.

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Chromatin reprogramming as an adaptation mechanism in prostate cancer

European Urology Supplements ◽

10.1016/s1569-9056(19)33312-3 ◽

2019 ◽

Vol 18 (8) ◽

pp. e3063

Author(s):

A. Urbanucci ◽

P. Braadland

Keyword(s):

Prostate Cancer ◽

Adaptation Mechanism ◽

Chromatin Reprogramming

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Wnt/β-catenin signal transduction pathway in prostate cancer and associated drug resistance

Discover Oncology ◽

10.1007/s12672-021-00433-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chunyang Wang ◽

Qi Chen ◽

Huachao Xu

Keyword(s):

Prostate Cancer ◽

Signal Transduction ◽

Drug Resistance ◽

Androgen Receptor ◽

Signal Transduction Pathway ◽

Transduction Pathway ◽

Cancer Pathogenesis ◽

Asian Men ◽

Therapy Development ◽

The Impact

AbstractGlobally, prostate cancer ranks second in cancer burden of the men. It occurs more frequently in black men compared to white or Asian men. Usually, high rates exist for men aged 60 and above. In this review, we focus on the Wnt/β-catenin signal transduction pathway in prostate cancer since many studies have reported that β-catenin can function as an oncogene and is important in Wnt signaling. We also relate its expression to the androgen receptor and MMP-7 protein, both critical to prostate cancer pathogenesis. Some mutations in the androgen receptor also impact the androgen-β-catenin axis and hence, lead to the progression of prostate cancer. We have also reviewed MiRNAs that modulate this pathway in prostate cancer. Finally, we have summarized the impact of Wnt/β-catenin pathway proteins in the drug resistance of prostate cancer as it is a challenging facet of therapy development due to the complexity of signaling pathways interaction and cross-talk.

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Chromatin reprogramming as adaptation mechanism in advanced prostate cancer

European Urology Supplements ◽

10.1016/s1569-9056(18)32987-7 ◽

2018 ◽

Vol 17 (10) ◽

pp. e2505

Author(s):

A. Urbanucci

Keyword(s):

Prostate Cancer ◽

Advanced Prostate Cancer ◽

Adaptation Mechanism ◽

Chromatin Reprogramming

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Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

Cancers ◽

10.3390/cancers13071534 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1534

Author(s):

Marzieh Ehsani ◽

Faith Oluwakemi David ◽

Aria Baniahmad

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Androgen Receptor ◽

Therapy Resistance ◽

Tumor Evolution ◽

Castration Resistance ◽

Main Driver ◽

Additional Resistance ◽

Treatment Onset ◽

High Degree

Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2–3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR‑dependent and contribute to PCa drug resistance will be discussed.

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Fluorescent potentiometric dyes for membrane-potential imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100168566 ◽

1994 ◽

Vol 52 ◽

pp. 166-167

Author(s):

Leslie M. Loew

Keyword(s):

Membrane Potential ◽

Single Cells ◽

Quantitative Imaging ◽

Optical Recording ◽

Biological Processes ◽

Major Focus ◽

The Past ◽

Excitable Systems ◽

Major Application ◽

The Impact

A major application of potentiometric dyes has been the multisite optical recording of electrical activity in excitable systems. After being championed by L.B. Cohen and his colleagues for the past 20 years, the impact of this technology is rapidly being felt and is spreading to an increasing number of neuroscience laboratories. A second class of experiments involves using dyes to image membrane potential distributions in single cells by digital imaging microscopy - a major focus of this lab. These studies usually do not require the temporal resolution of multisite optical recording, being primarily focussed on slow cell biological processes, and therefore can achieve much higher spatial resolution. We have developed 2 methods for quantitative imaging of membrane potential. One method uses dual wavelength imaging of membrane-staining dyes and the other uses quantitative 3D imaging of a fluorescent lipophilic cation; the dyes used in each case were synthesized for this purpose in this laboratory.

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