Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression DOI Open Access
Roosa Kaarijärvi, Heidi Kaljunen, Kirsi Ketola

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(4), P. 692 - 692

Published: Feb. 9, 2021

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced (t-NEPC) is highly aggressive subtype of castration-resistant which develops for one fifth patients under prolonged androgen deprivation. In recent years, understanding molecular features phenotypic changes in has grown. However, there are still fundamental questions to be answered this emerging research field, example, why how do the treatment-resistant cells acquire neuron-like phenotype. The advantages change role tumor microenvironment controlling cellular emergence forms mostly unknown. Here, we discuss functional links between neurodevelopmental processes progression treatment resistance. We provide an overview neurite-like whether reported t-NEPC pathways proteins relate like neurogenesis axonogenesis during development also novel therapeutic targets modulating plasticity.

Language: Английский

Epigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer DOI Creative Commons
Goutam Chakraborty, Kasmira Gupta, Natasha Kyprianou

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 2, 2023

Prostate cancer is a highly heterogeneous disease. Progression on androgen deprivation therapy (ADT) to castration-resistant (CRPC), or neuroendocrine prostate (NEPC), associated with poor patient survival. This comment highlights recent evidence the epigenetic mechanisms underlying emergence of lineage plasticity and differentiation in treatment-resistant tumors.

Language: Английский

Citations

23
Integrated analysis of single-cell and bulk transcriptomics develops a robust neuroendocrine cell-intrinsic signature to predict prostate cancer progression DOI Creative Commons
Tingting Zhang, Faming Zhao,

Yahang Lin

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 14(3), P. 1065 - 1080

Published: Jan. 1, 2024

Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options.The precise identification of NEPC cells holds paramount significance for both research clinical applications, yet valid biomarker remains to be defined.Methods: Leveraging 11 published NE-related gene sets, single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic 13 experimental models (PCa), we employed multiple advanced algorithms construct validate a robust risk prediction model.Results: Through the compilation comprehensive scRNA-seq reference atlas (comprising total 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets PCa, observed inconsistent inefficient performance among NE sets.Therefore, developed an integrative analysis pipeline, identifying 762 high-quality markers.Subsequently, derived cell-intrinsic signature, R package named NEPAL, predict scores.By applying independent validation datasets, NEPAL consistently accurately assigned feature delineated PCa progression.Intriguingly, demonstrated predictive capabilities prognosis therapy responsiveness, as well potential epigenetic drivers NEPC. Conclusion:The present study furnishes valuable tool monitoring progression through profiles obtained sources.

Language: Английский

Citations

13
EZH2-mediated development of therapeutic resistance in cancer DOI Creative Commons
Parminder Kaur, Eswar Shankar, Sanjay Gupta

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 586, P. 216706 - 216706

Published: Feb. 7, 2024

Language: Английский

Citations

12
The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1 DOI Creative Commons
Rodrigo Romero, Tinyi Chu, Tania J González-Robles

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(11), P. 1641 - 1659

Published: Oct. 11, 2024

Abstract Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate progression. Transplanted mouse organoids with human-relevant driver mutations ( Rb1 − / ; Trp53 cMyc + or Pten ) develop adenocarcinomas, but only those deletion advance aggressive, ASCL1 (NEPC) resistant androgen receptor signaling inhibitors. Notably, transition requires an microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, reveal cells arise from KRT8 luminal cells, progressing into transcriptionally heterogeneous ;KRT8 NEPC. Ascl1 loss established NEPC causes transient regression followed recurrence, its before transplantation abrogates plasticity, resulting castration-sensitive adenocarcinomas. This dynamic model highlights importance timing offers identify additional drivers.

Language: Английский

Citations

12
Prostate Cancer Liver Metastasis: An Ominous Metastatic Site in Need of Distinct Management Strategies DOI Open Access
Audrey Shiner,

Rubens Copia Sperandio,

Mahdi F. Naimi

et al.

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(3), P. 734 - 734

Published: Jan. 27, 2024

Prostate cancer liver metastasis (PCLM), seen in upwards of 25% metastatic castration-resistant PC (mCRPC) patients, is the most lethal site mCRPC with a median overall survival 10–14 months. Despite its ominous prognosis and anticipated rise incidence due to longer contemporary therapy, PCLM understudied. This review aims summarize existing literature regarding risk factors associated development PCLM, identify areas warranting further research. A search was conducted through Ovid MEDLINE from 2000 March 2023. Relevant subject headings text words were used capture following concepts: “Prostatic Neoplasms”, “Liver “Neoplasm Metastasis”. Citation searching identified additional manuscripts. Forty-one studies retained for detailed analysis. The clinical visceral/liver included <70 years, ≥T3 tumor, N1 nodal stage, de novo metastasis, PSA >20 ng/mL, Gleason score >8. Additional comprised elevated serum AST, LDH or ALP, decreased Hb, genetic markers like RB1 PTEN loss, PIK3CB MYC amplification, as well numerous treatments either acting directly indirectly inducing injury. Further research predictive factors, early detection strategies, targeted therapies are critical improving patient outcomes.

Language: Английский

Citations

10
Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer DOI Creative Commons
Ziwei Wang, Tao Wang,

Danni Hong

et al.

iScience, Journal Year: 2022, Volume and Issue: 25(7), P. 104576 - 104576

Published: June 13, 2022

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of cancer, with 10% five-year survival rate. However, little known about its origin and the mechanisms governing emergence. Our study characterized ADPC NEPC in tumors from 7 patients using scRNA-seq. First, we identified two gene expression signatures representing different phases trans-differentiation. New marker genes may be used for clinical diagnosis. Second, integrative analyses combining subclonal architecture revealed paths by which diverges original ADPC, either directly treatment-naïve tumor cells or specific intermediate states treatment-resistance. Third, inferred hierarchical transcription factor (TF) network underlying progression, involves constitutive regulation ASCL1, FOXA2, selective NKX2-2, POU3F2, SOX2. Together, these results defined complex profiles advanced our understanding genetic transcriptomic leading to differentiation.

Language: Английский

Citations

37
Monoamine oxidase A (MAOA): A promising target for prostate cancer therapy DOI
Hao Han, Hui Li, Yifan Ma

et al.

Cancer Letters, Journal Year: 2023, Volume and Issue: 563, P. 216188 - 216188

Published: April 17, 2023

Language: Английский

Citations

19
Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution DOI Creative Commons

Jarrell Imamura,

Shinjini Ganguly,

Andrew Muskara

et al.

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: June 30, 2023

Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development castrate-resistant cancer (CRPC) primary cause cancer-related mortality. While CRPC typically develops through gain in androgen receptor (AR) signaling, subset will lose reliance on AR. This process involves genetic, epigenetic, hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine (NEPC) being quintessential example. NEPC enriched following second-generation anti-androgens exhibits resistance endocrine therapy. Loss RB1 , TP53 PTEN expression MYCN AURKA amplification appear be key drivers differentiation. Epigenetic modifications also play an important role transition phenotype. DNA methylation specific gene promoters can regulate lineage commitment Histone suppress AR neuroendocrine-specific expression. Emerging data suggest EZH2 regulator this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably splice variant expression, adrenal-permissive 3βHSD1 allele, glucocorticoid Aberrant regulation promotes radioresistance by altering repair- cell cycle-related genes. Novel therapies are currently developed target these diverse promoting plasticity-driven NEPC.

Language: Английский

Citations

19
Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer DOI
Yasutaka Yamada, Varadha Balaji Venkadakrishnan, Kei Mizuno

et al.

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(722)

Published: Nov. 15, 2023

Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine (NEPC). methyltransferases (DNMTs) are highly expressed, global is dysregulated in NEPC. We identified that deletion DNMT genes decreases expression markers substantially reduced NEPC tumor development metastasis vivo. Decitabine, pan-DNMT inhibitor, attenuated growth patient–derived xenograft models, well retinoblastoma gene ( RB1 )–deficient castration-resistant adenocarcinoma (CRPC) models compared with -proficient CRPC. further found inhibition increased B7 homolog 3 (B7-H3), an emerging druggable target, via demethylation B7-H3. tested DS-7300a (i-DXd), antibody-drug conjugate targeting B7-H3, alone combination decitabine advanced cancer. There was potent single-agent antitumor activity both CRPC bearing high In B7-H3–low therapy plus resulted enhanced response. may therefore be promising therapeutic target for RB1-deficient sensitize through increasing expression. represent subgroups poor prognosis, the biomarker-driven strategies these populations ultimately help improve patient outcomes.

Language: Английский

Citations

19
ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer DOI Creative Commons
Chen Qian, Qian Yang, Mirja Rotinen

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(13), P. 7740 - 7760

Published: June 27, 2024

Abstract Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) NE splicing factor SRRM4, which are key lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate portion AR cistrome epigenetic activation GR. Mechanisms by regulates expression promoter binding, enhancement genome-wide chromatin accessibility, super-enhancer reprogramming. Pharmacologic inhibition suppresses plasticity reprogramming induced signaling inhibitor enzalutamide. These results promotes range drug mechanisms treatment-emergent variation PC support enhanced efforts therapeutically target as means suppressing treatment-resistant disease.

Language: Английский

Citations

8