Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(17)

Published: July 18, 2024

Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the type and cellular context. While be early prostate cancer, we identified significant downregulation of pathway during progression from adenocarcinoma to neuroendocrine (NE) where it functions as a tumor suppressor. Activation NE Rb1/Trp53-deficient models led phenotypic conversion toward more indolent, non-NE state with glandular features expression luminal lineage markers. This was accompanied by upregulation MHC I IFN immune cell infiltration. Overall, these data support suppressor differentiation advanced provide insights into how influences plasticity microenvironment (TME).

Language: Английский

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The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1

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

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The changing treatment landscape of EGFR-mutant non-small-cell lung cancer

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 29, 2024

Language: Английский

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The emerging landscape and future perspective of SCLC transformation: from molecular mechanisms to therapeutic strategies

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: 207, P. 104616 - 104616

Published: Jan. 11, 2025

Language: Английский

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Current and future therapies for small cell lung carcinoma

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: April 1, 2025

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid proliferation and high metastatic potential. It universal inactivation of RB1, overexpression the MYC family dysregulation multiple oncogenic signaling pathways. Among different patients, SCLCs are similar at genetic level but exhibit significant heterogeneity molecular level. The classification SCLC has evolved from a simple neuroendocrine (NE)/non-neuroendocrine (non-NE) system to transcription factor-based subtype system; lineage plasticity adds further complexity poses challenges for therapeutic development. While initially sensitive platinum-based chemotherapy, resistance develops rapidly, leading dismal prognosis. Various antibodies, including PD-1/PD-L1 inhibitors antibody‒drug conjugates, have been introduced into clinical practice or being evaluated in trials. However, their benefits patients remain limited. This review summarizes carcinogenic mechanisms, tumor heterogeneity, immune microenvironment SCLC, with focus on recent advances metastasis mechanisms. Additionally, corresponding progress tackling these discussed.

Language: Английский

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Small cell lung cancer profiling: an updated synthesis of subtypes, vulnerabilities, and plasticity

Trends in cancer, Journal Year: 2024, Volume and Issue: 10(10), P. 935 - 946

Published: Aug. 19, 2024

Language: Английский

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EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non–small cell lung cancer

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(23)

Published: May 30, 2024

The transformation of lung adenocarcinoma to small cell cancer (SCLC) is a recognized resistance mechanism and hindrance therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). paucity pretranslational/posttranslational clinical samples limits the deeper understanding mechanisms exploration effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) models. Next, identified transcriptional reprogramming that drives erlotinib in NE lines cell-derived xenograft mice. We observed enhanced expression genes involved EHMT2 WNT/β-catenin pathways. In addition, demonstrated increases methylation SFRP1 promoter region reduce expression, followed by activation pathway TKI-mediated transformation. Notably, similar alterations were transformed SCLC obtained from patients. Importantly, suppression with selective restored sensitivity delayed identify process provide potential target for overcoming erlotinib.

Language: Английский

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Neuroendocrine Transformation as a Mechanism of Resistance to Targeted Lung Cancer Therapies: Emerging Mechanisms and Their Therapeutic Implications

Cancers, Journal Year: 2025, Volume and Issue: 17(2), P. 260 - 260

Published: Jan. 15, 2025

Lung cancer is the leading cause of cancer-related deaths worldwide, highlighting a major clinical challenge. broadly classified into two histologically distinct subtypes, termed small cell lung (SCLC) or non-small (NSCLC). Identification various oncogenic drivers NSCLC has facilitated development targeted therapies that have dramatically improved patient outcomes. However, acquired resistance to these common, which ultimately results in relapse. Several on-target and off-target mechanisms been described for NSCLC. One common mechanism histological transformation initial SCLC, highly aggressive form exhibits neuroendocrine histology. This presents significant challenge, since there are very few treatments available relapsed patients. Although phenomenon NSCLC-to-SCLC was almost 20 years ago, only recently we begun understand underlying this therapy-driven response. These recent discoveries will be key identifying novel biomarkers therapeutic strategies improve outcomes patients undergo transformation. Here, highlight advances discuss potential they uncovered target resistance.

Language: Английский

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Single‐Cell RNA Sequencing Reveals the Cellular Origin and Evolution of Small‐Cell Neuroendocrine Carcinoma of the Cervix

Journal of Medical Virology, Journal Year: 2025, Volume and Issue: 97(1)

Published: Jan. 1, 2025

Small-cell neuroendocrine cancer (SCNEC) of the uterine cervix is an exceedingly rare, highly aggressive tumor with extremely poor prognosis. The cellular heterogeneity, origin, and tumorigenesis trajectories SCNEC remain largely unclear. We performed single-cell RNA sequencing whole-exome on tissues adjacent normal cervical from two patients diagnosed cervix. Here, we provide first comprehensive insights into composition, HPV infection-related features, gene expression profiles at resolution. Correlation analyses suggested that may originate squamous epithelial cells, this observation was validated bulk RNA-seq data external cancer. Furthermore, sex-determining region Y-box 2 (SOX2), a key transcription factor functions in direct neural differentiation, located copy number gain expressed cells both patients. Notable, distributions HPV-infected epithelium SOX2 were consistent each other. Therefore, supposed high-risk infection amplification contribute to progression small-cell

Language: Английский

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Gene mutation, clinical characteristics and pathology in resectable lung adenocarcinoma

World Journal of Surgical Oncology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 22, 2025

With the wide use of CT scan in clinical practice, more lung cancer was diagnosed resectable stage. Pathological examination and genetic testing have become a routine procedure for adenocarcinoma following radical resection. This study analyzed special pathological components gene mutations to explore their relationship with characteristics overall survival. Clinical, pathological, mutation data from 1,118 patients were collected. All underwent surgery at Department Thoracic Surgery, Second Xiangya Hospital Central South University. Patients grouped based on mutations. Differences features survival as well. mucinous, neuroendocrine, poor-differentiated presented prognostic risk factors, including pleural invasion, carcinothrombosis, STAS, advanced stages, along varying frequencies These factors significantly shortened ALK KRAS also associated such solid nodules, later stages. However, significant reduction observed only mutation. Relationship between still requires further investigation. Special (mucinous, poor-differentiated) had an influence biological behavior tumors, resulting different prognosis.

Language: Английский

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