Identification of Molecular Markers Associated with Prostate Cancer Subtypes: An Integrative Bioinformatics Approach DOI Open Access
Ilaria Granata, Paola Barboro

Published: Nov. 16, 2023

Prostate cancer (PCa) is characterised by androgen-dependency. Unfortunately, under anti-androgen treatment pressure, castration-resistant prostate (CRPC) emerges, heterogeneous cell populations that, over time, lead to the development of different androgen-dependent or -independent phenotypes. Despite important advances in therapeutic strategies, CRPC remains incurable. Context-specific essential genes represent valuable candidates for targeted anti-cancer therapies. Through investigation gene and protein annotations integration several published transcriptomic data, we identified two consensus lists stratify PCa patients' risk discriminate phenotypes based on androgen receptor activity. ROC Kaplan-Meier survival analyses were used set validation independent datasets. We further evaluated these their association with dependency. The deregulated expression PCa-related was associated overall disease-specific survival, metastasis and/or high recurrence risk, while CRPC-related clearly discriminated between adeno neuroendocrine Some showed context-specific essentiality. candidate drugs through a computational repositioning approach targeting treating lethal variants PCa. This work provides proof-of-concept use an integrative identify biomarkers involved progression pathogenesis within goal precision medicine.

Language: Английский

Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation DOI Creative Commons
Chia-Chun Chen, Wendy Tran, Kai Song

et al.

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(12), P. 2066 - 2082.e9

Published: Nov. 22, 2023

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of trans-differentiation, we perform multi-omics time course analysis pan-small model (termed PARCB), forward genetic transformation using human prostate basal cells and identify shared developmental, arc-like, entropy-high trajectory among all replicates. Further mapping single resolution reveals two distinct lineages defined by mutually exclusive expression ASCL1 or ASCL2. Temporal regulation groups transcription factors across developmental stages that cellular reprogramming precedes induction neuronal programs. TFAP4 ASCL1/2 feedback are identified as potential regulators ASCL2 expression. Our study provides temporal transcriptional patterns uncovers pan-tissue parallels between lung cancers, well connections normal states.

Language: Английский

Citations

36
A novel exosome based therapeutic intervention against neuroendocrine prostate cancer DOI Creative Commons
Sharanjot Saini,

Amritha Sreekumar,

Sandip Nathani

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 2, 2024

Abstract Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of castration-resistant (CRPC) with poor survival rates. Current treatment options for NEPC are limited to toxic platinum drugs highlighting the urgent need new therapies. This study aimed develop novel therapeutic approach using engineered exosomes against NEPC. Exosomes were modified target CEACAM5, an surface antigen, by attaching CEACAM5 antibodies HEK293T exosomes. These loaded inhibiting EZH2 and androgen receptor (AR) as recent research shows persistent role AR in wherein it plays concerted driving neuronal gene programs. In vitro experiments cell lines demonstrated that CEACAM5-targeted specifically taken up cells, leading reduced cellular viability decreased expression markers. Further vivo tests patient-derived xenograft model (LuCaP145.1) showed significant tumor regression mice treated compared control receiving IgG-labeled results suggest CEACAM5-engineered hold promise targeted therapy Importantly, our exosome engineering strategy versatile can be adapted various antigens other diseases.

Language: Английский

Citations

8
FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer DOI Creative Commons
Zifeng Wang, Scott L. Townley, Songqi Zhang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 8, 2024

Abstract FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the binding of androgen receptor (AR) in both normal prostate epithelial cells and luminal subtype cancer (PCa). Recent studies have highlighted emergence FOXA2 an adaptive response to AR signaling inhibition treatments. However, role transition regulating lineage plasticity remains unclear. Our study demonstrates that binds distinct classes developmental enhancers multiple AR-independent PCa subtypes, with its depending on LSD1. Moreover, we reveal collaborates JUN at promotes transcriptional reprogramming AP-1 lineage-plastic cells, thereby facilitating cell state transitions lineages. Overall, our findings underscore pivotal a pan-plasticity driver rewires induce differential necessary plasticity.

Language: Английский

Citations

7
Castration-resistant prostate cancer monitoring by cell-free circulating biomarkers DOI Creative Commons

Eva Chrenková,

Hana Študentová, Kateřina Holá

et al.

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Sept. 10, 2024

Prostate cancer is the second leading cause of male cancer-related deaths in Western countries, which predominantly attributed to metastatic castration-resistant stage disease (CRPC). There an urgent need for better prognostic and predictive biomarkers, particularly androgen receptor targeted agents taxanes.

Language: Английский

Citations

4
A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer DOI Creative Commons

Prachi Walke,

Jared D.W. Price,

Frederick S. Vizeacoumar

et al.

Oncogene, Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

Language: Английский

Citations

0
Identification of Molecular Markers Associated with Prostate Cancer Subtypes: An Integrative Bioinformatics Approach DOI Creative Commons
Ilaria Granata, Paola Barboro

Biomolecules, Journal Year: 2024, Volume and Issue: 14(1), P. 87 - 87

Published: Jan. 10, 2024

Prostate cancer (PCa) is characterised by androgen dependency. Unfortunately, under anti-androgen treatment pressure, castration-resistant prostate (CRPC) emerges, heterogeneous cell populations that, over time, lead to the development of different androgen-dependent or -independent phenotypes. Despite important advances in therapeutic strategies, CRPC remains incurable. Context-specific essential genes represent valuable candidates for targeted anti-cancer therapies. Through investigation gene and protein annotations integration published transcriptomic data, we identified two consensus lists stratify PCa patients’ risk discriminate phenotypes based on receptor activity. ROC Kaplan–Meier survival analyses were used set validation independent datasets. We further evaluated these their association with The deregulated expression PCa-related was associated overall disease-specific survival, metastasis and/or high recurrence risk, while CRPC-related clearly discriminated between adeno neuroendocrine Some showed context-specific essentiality. candidate drugs through a computational repositioning approach targeting treating lethal variants PCa. This work provides proof-of-concept use an integrative identify biomarkers involved progression pathogenesis within goal precision medicine.

Language: Английский

Citations

3
Treatment-induced stemness and lineage plasticity in driving prostate cancer therapy resistance DOI Creative Commons
Anmbreen Jamroze, Xiaozhuo Liu, Dean G. Tang

et al.

Published: Aug. 25, 2024

Most human cancers are heterogeneous consisting of cancer cells at different epigenetic and transcriptional states with distinct phenotypes, functions, drug sensitivities. This inherent cell heterogeneity contributes to tumor resistance clinical treatment, especially the molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) androgen receptor signaling (ARSIs). Therapeutic interventions, in turn, induce lineage plasticity (also called infidelity) that also drives therapy resistance. In this Perspective, we focus our discussions on manifested treatment-induced switching epithelial basal/stem-like, mesenchymal, neural lineages. We employ prostate (PCa) prime example highlight ARSI-induced during towards development castration-resistant PCa (CRPC). further discuss how microenvironment (TME) influences therapy-induced plasticity. Finally, offer an updated summary regulators mechanisms driving infidelity, which should be therapeutically extend therapeutic window improve patients' survival.

Language: Английский

Citations

2
Subtype Transdifferenziation in Human Cancer: The Power of Tissue Plasticity in Tumor Progression DOI Open Access
Monica Fedele, Laura Cerchia, Sabrina Battista

et al.

Published: Jan. 26, 2024

The classification of tumors in subtypes, characterized by phenotypes determined specific differentiation pathways, aids diagnosis and directs therapy towards targeted approaches. However, with the advent explosion next-generation sequencing, cancer are turning out to be far more heterogenous than initially thought, is continually being updated include subtypes. Tumors indeed highly dynamic they can evolve undergo various changes their characteristics during disease progression. picture becomes even complex when tumor responds a therapy. In all these cases, cells acquire ability trans-differentiate, changing subtype, adapt microenvironments. These modifications affect tumor's growth rate, invasiveness, response treatment, overall clinical behavior. Studying subtype transitions crucial for understanding evolution, predicting outcomes, developing personalized treatment strategies. We discuss this emerging hallmark molecular mechanisms involved at crossroads between microenvironment, focusing on four different human cancers which tissue plasticity causes switch: breast cancer, prostate glioblastoma pancreatic adenocarcinoma.

Language: Английский

Citations

1
Subtype Transdifferentiation in Human Cancer: The Power of Tissue Plasticity in Tumor Progression DOI Creative Commons
Monica Fedele, Laura Cerchia, Sabrina Battista

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(4), P. 350 - 350

Published: Feb. 17, 2024

The classification of tumors into subtypes, characterized by phenotypes determined specific differentiation pathways, aids diagnosis and directs therapy towards targeted approaches. However, with the advent explosion next-generation sequencing, cancer are turning out to be far more heterogenous than initially thought, is continually being updated include subtypes. Tumors indeed highly dynamic, they can evolve undergo various changes in their characteristics during disease progression. picture becomes even complex when tumor responds a therapy. In all these cases, cells acquire ability transdifferentiate, changing subtype, adapt microenvironments. These modifications affect tumor’s growth rate, invasiveness, response treatment, overall clinical behavior. Studying subtype transitions crucial for understanding evolution, predicting outcomes, developing personalized treatment strategies. We discuss this emerging hallmark molecular mechanisms involved at crossroads between microenvironment, focusing on four different human cancers which tissue plasticity causes switch: breast cancer, prostate glioblastoma, pancreatic adenocarcinoma.

Language: Английский

Citations

1
A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer DOI Open Access

Prachi Walke,

Jared D.W. Price,

Frederick S. Vizeacoumar

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Summary Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance conventional therapies. A key driver of NEPC is the overexpression MYCN , well-established oncogene associated with neuroendocrine tumors. However, efforts directly inhibit N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome obstacle, we conducted unbiased genome-wide screening using isogenic cell lines identify synthetic vulnerabilities . Among identified candidates, NEUROG2 emerged as significant candidate. Neurog2 proneural transcription factor (PTF) known for role developmental processes trans-differentiation adult cells. Our findings demonstrate that depletion does not affect non-malignant cells, but significantly suppresses growth -overexpressing cells tumors orthotopic models. Furthermore, our observations indicate Neurog2-mediated regulation PTFs can facilitate development. Thus, targeting holds promise an effective strategy NEPC.

Language: Английский

Citations

0