PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity DOI Open Access

Grigor Varuzhanyan,

Chia‐Chun Chen, Jack Freeland

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 13, 2024

ABSTRACT Adenocarcinomas from multiple tissues can evolve into lethal, treatment-resistant small cell neuroendocrine (SCN) cancers comprising subtypes with poorly defined metabolic characteristics. The role of metabolism in directly driving subtype determination remains unclear. Through bioinformatics analyses thousands patient tumors, we identified enhanced PGC-1α—a potent regulator oxidative phosphorylation (OXPHOS)—in various SCN (SCNCs), closely linked differentiation. In a patient-derived prostate tissue SCNC transformation system, the ASCL1-expressing showed elevated PGC-1α expression and increased OXPHOS activity. Inhibition reduced proliferation lung cancer lines blocked tumor formation. Conversely, enhancing PGC- 1α OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled formation rate promoted commitment to ASCL1 lineage. These results establish as driver progression determination, highlighting novel vulnerabilities SCNCs across different tissues. STATEMENT OF SIGNIFICANCE Our study provides functional evidence that reprogramming impact phenotypes establishes PGC-1α-induced lineage determination. mechanistic insights reveal common originating tissues, opening new avenues for pan-SCN therapeutic strategies.

Язык: Английский

Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer DOI Creative Commons
Chengdi Wang, Jingwei Li, Jingyao Chen

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 10, 2025

Post-operative recurrence rates of stage I non-small cell lung cancer (NSCLC) range from 20% to 40%. Nonetheless, the molecular mechanisms underlying hitherto remain largely elusive. Here, we generate genomic, epigenomic and transcriptomic profiles paired tumors adjacent tissues 122 NSCLC patients, among which 57 patients develop after surgery during follow-up. Integrated analyses illustrate that presence predominantly solid or micropapillary histological subtypes, increased genomic instability, APOBEC-related signature are associated with recurrence. Furthermore, TP53 missense mutation in DNA-binding domain could contribute shorter time DNA hypomethylation is pronounced recurrent NSCLC, PRAME significantly hypomethylated overexpressed gene adenocarcinoma (LUAD). Mechanistically, at TEAD1 binding site facilitates transcriptional activation PRAME. Inhibition restrains tumor metastasis via downregulation epithelial–mesenchymal transition-related genes. We also identify enrichment AT2 cells higher copy number variation burden, exhausted CD8 + T Macro_SPP1, along reduced interaction between immune cells, essential for formation ecosystem LUAD. Finally, multi-omics clustering stratify into 4 subclusters varying risk subcluster-specific therapeutic vulnerabilities. Collectively, this study constitutes a promising resource enabling insights biological clinical management post-operative NSCLC. The poorly understood. authors do profiling normal finding processes type proportions

Язык: Английский

Процитировано

5
Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer DOI Creative Commons
Sheng‐Yu Ku,

Yanqing Wang,

Maria Mica Garcia

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(17)

Опубликована: Июль 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).

Язык: Английский

Процитировано

15
The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1 DOI Creative Commons
Rodrigo Romero, Tinyi Chu, Tania J González-Robles

и другие.

Nature Cancer, Год журнала: 2024, Номер 5(11), С. 1641 - 1659

Опубликована: Окт. 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.

Язык: Английский

Процитировано

13
The changing treatment landscape of EGFR-mutant non-small-cell lung cancer DOI
Fei Zhou, Haoyue Guo, Yang Xia

и другие.

Nature Reviews Clinical Oncology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 29, 2024

Язык: Английский

Процитировано

13
The emerging landscape and future perspective of SCLC transformation: from molecular mechanisms to therapeutic strategies DOI
Chenyue Zhang, Kai Wang, Haiyong Wang

и другие.

Critical Reviews in Oncology/Hematology, Год журнала: 2025, Номер 207, С. 104616 - 104616

Опубликована: Янв. 11, 2025

Язык: Английский

Процитировано

2
Neuroendocrine Transformation as a Mechanism of Resistance to Targeted Lung Cancer Therapies: Emerging Mechanisms and Their Therapeutic Implications DOI Open Access

Asim Joshi,

Neeru Bhaskar,

Joel D. Pearson

и другие.

Cancers, Год журнала: 2025, Номер 17(2), С. 260 - 260

Опубликована: Янв. 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.

Язык: Английский

Процитировано

2
Immunogenomic cancer evolution: A framework to understand cancer immunosuppression DOI
Shogo Kumagai,

Yusaku Momoi,

Hiroyoshi Nishikawa

и другие.

Science Immunology, Год журнала: 2025, Номер 10(105)

Опубликована: Март 28, 2025

The process of tumor development involves cells eluding detection and suppression immune responses, which can cause decreased cell antigenicity, expression immunosuppressive molecules, recruitment to the microenvironment (TME). Immunologically genomically integrated analysis (immunogenomic analysis) patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis evasion. In noninflamed cancers such as epidermal growth factor receptor ( EGFR )–mutated lung cancers, genetic abnormalities cancer contribute formation an TME by recruiting cells, cannot be fully explained immunoediting hypothesis. This review summarizes latest findings regarding links between immunosuppression causing clinical resistance immunotherapy. We propose concepts immunogenomic evolution, genomic evolution shapes TME, precision medicine, immunotherapy combined with molecularly targeted reagents modulate TME.

Язык: Английский

Процитировано

2
Small cell lung cancer profiling: an updated synthesis of subtypes, vulnerabilities, and plasticity DOI
Esther Redín, Álvaro Quintanal-Villalonga, Charles M. Rudin

и другие.

Trends in cancer, Год журнала: 2024, Номер 10(10), С. 935 - 946

Опубликована: Авг. 19, 2024

Язык: Английский

Процитировано

9
Spontaneous Transformation from Lung Adenocarcinoma to MYC‐amplified Large Cell Neuroendocrine Carcinoma DOI Open Access
Tetsuhiro Yamakado, Hanako Sato‐Yazawa, Jun Ishii

и другие.

Pathology International, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

Abstract Recent studies suggest that lung adenocarcinoma cells are closely associated with the tumorigenesis of large‐cell neuroendocrine carcinoma via cellular transformation. However, morphological evidence, along genetic abnormalities before, during, and after transformation, is quite limited. We present here a case combined exhibiting acinar solid patterns. Adenocarcinoma abundant mucin, positivity for both napsin‐A markers, were partially found in component extensively observed component. Next‐generation sequencing using extracted genomic DNA from three components revealed homozygous TP53 (missense) STK11 (nonsense) mutations all components, suggesting monoclonal origin. Furthermore, MYC gene amplification, recently presumed to be pivotal driver was components. These findings corresponded pre‐ post‐transformation morphology, providing compelling evidence some kinds adenocarcinomas may serve as precursor carcinoma.

Язык: Английский

Процитировано

1
Current and future therapies for small cell lung carcinoma DOI Creative Commons
Xiaoqian Zhai, Zhengkun Zhang, Yuxin Chen

и другие.

Journal of Hematology & Oncology, Год журнала: 2025, Номер 18(1)

Опубликована: Апрель 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.

Язык: Английский

Процитировано

1