Proteogenomic characterization of high-grade lung neuroendocrine carcinoma deciphers molecular diversity and potential biomarkers of different histological subtypes in Chinese population DOI Creative Commons
Zicheng Zhang,

Xi Wu,

S. Bao

et al.

Research, Journal Year: 2025, Volume and Issue: 8

Published: Jan. 1, 2025

High-grade lung neuroendocrine carcinomas (Lu-NECs) are clinically refractory malignancies with poor prognosis and limited therapeutic advances. The biological molecular features underlying the histological heterogeneity of Lu-NECs not fully understood. In this study, we present a multi-omics integration whole-exome sequencing deep proteomic profiling in 93 Chinese to establish first comprehensive proteogenomic atlas disease spectrum. Our analyses revealed high degree mutational concordance among subtypes at genomic level; however, distinct profiles enabled clear differentiation subtypes, unveiling subtype-specific related tumor metabolism, immunity, proliferation. Furthermore, RB1 mutations confer divergent prognostic effects through cis- trans- regulation. addition, identified potential protein biomarkers for subtype classification risk stratification, which were validated by immunohistochemistry an independent cohort. This study provides valuable resource insight into Lu-NEC heterogeneity.

Language: Английский

Patient-derived xenograft models in cancer therapy: technologies and applications DOI Creative Commons
Yihan Liu,

Wantao Wu,

Changjing Cai

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: April 12, 2023

Abstract Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority recapitulating the characteristics of cancer, such as spatial structure cancer and intratumor heterogeneity cancer. Moreover, PDX models retain genomic features across different stages, subtypes, diversified treatment backgrounds. Optimized engraftment procedures modern technologies multi-omics deep learning enabled a more comprehensive depiction molecular landscape boosted utilization models. These irreplaceable advantages make an ideal choice studies, preclinical trials novel drugs, validating drug combinations, screening drug-sensitive patients, exploring resistance mechanisms. In this review, we gave overview history process model establishment. Subsequently, review presents strengths weaknesses highlights integration research. Finally, delineated broad application chemotherapy, targeted therapy, immunotherapy, other therapies.

Language: Английский

Citations

181
Radiotherapy in combination with CD47 blockade elicits a macrophage-mediated abscopal effect DOI Creative Commons

Yoko Nishiga,

Alexandros P. Drainas,

Maya Baron

et al.

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(11), P. 1351 - 1366

Published: Nov. 21, 2022

Radiation therapy is a mainstay of cancer treatment but does not always lead to complete tumor regression. Here we combine radiotherapy with blockade the 'don't-eat-me' cell-surface molecule CD47 in small cell lung (SCLC), highly metastatic form cancer. potently enhances local antitumor effects preclinical models SCLC. Notably, also stimulates off-target 'abscopal' inhibiting non-irradiated SCLC tumors mice receiving radiation. These abscopal are independent T cells require macrophages that migrate into sites response inflammatory signals produced by radiation and locally activated phagocytose cells. Similar were observed other treated blockade. The systemic activation following may be particularly important patients who suffer from disease.

Language: Английский

Citations

87
Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation DOI Creative Commons
Smruthy Sivakumar, Jay A. Moore, Meagan Montesion

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(7), P. 1572 - 1591

Published: April 16, 2023

Abstract Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been relative paucity of human tumors studied. Here we provide an integrated analysis 3,600 “real-world” SCLC cases. This large cohort allowed us to identify new recurrent alterations and genetic subtypes, including STK11-mutant (1.7%) TP53/RB1 wild-type (5.5%), as well rare cases that were papillomavirus–positive. In our cohort, gene amplifications on 4q12 are associated increased overall survival, whereas CCNE1 amplification decreased survival. We also more frequent PTEN pathway brain metastases. Finally, profiling containing oncogenic drivers typically NSCLC demonstrates transformation may occur across multiple distinct molecular cohorts NSCLC. These novel unsuspected features help personalize treatment approaches for this fatal form cancer. Significance: Minimal changes therapy outcomes have occurred past four decades. The identification subtypes mutations improved understanding mechanisms from guide development personalized therapies subsets patients SCLC. article highlighted Issue feature, p. 1501

Language: Английский

Citations

72
Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes DOI
Lőrinc Sándor Pongor, Christopher W. Schultz, Lorenzo Rinaldi

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(4), P. 928 - 949

Published: Jan. 30, 2023

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of amplification and phenotypic plasticity, characterized by nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA fluorescence in situ hybridization to find extrachromosomal (ecDNA) as a primary source oncogene driver fusions. ecDNAs bring proximity enhancer elements oncogenes, creating transcription-amplifying units, driving exceptionally high gene dosage. We demonstrate that cell-free nucleosome profiling can noninvasively detect ecDNA plasma, facilitating its genome-wide interrogation other cancers. Altogether, our work provides first comprehensive map describes new mechanism governs MYC-driven heterogeneity. ecDNA-enabled transcriptional flexibility may explain significantly worse survival outcomes harboring complex amplifications. drives progression, basis evolution unknown. Using paradigm, report how function MYC-amplifying fostering tumor plasticity degree This article highlighted In Issue feature, p. 799.

Language: Английский

Citations

58
Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade DOI
Barzin Y. Nabet, Habib Hamidi, Myung Chang Lee

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 429 - 443.e4

Published: Feb. 15, 2024

Language: Английский

Citations

45
Lineage-specific intolerance to oncogenic drivers restricts histological transformation DOI
Eric E. Gardner, Ethan M. Earlie, Kate Li

et al.

Science, Journal Year: 2024, Volume and Issue: 383(6683)

Published: Feb. 8, 2024

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models follow conversion of found that barrier histological transformation converges on tolerance Myc, which implicate as a lineage-specific driver pulmonary neuroendocrine cell. Histological transformations frequently accompanied by activation Akt pathway. Manipulating pathway permitted Myc an oncogenic driver, producing rare, stem-like cells transcriptionally resemble basal lineage. These findings suggest may require plasticity inherent stem cell, enabling previously incompatible programs.

Language: Английский

Citations

34
Histopathology images-based deep learning prediction of prognosis and therapeutic response in small cell lung cancer DOI Creative Commons
Yibo Zhang, Zijian Yang,

R. Chen

et al.

npj Digital Medicine, Journal Year: 2024, Volume and Issue: 7(1)

Published: Jan. 18, 2024

Abstract Small cell lung cancer (SCLC) is a highly aggressive subtype of characterized by rapid tumor growth and early metastasis. Accurate prediction prognosis therapeutic response crucial for optimizing treatment strategies improving patient outcomes. In this study, we conducted deep-learning analysis Hematoxylin Eosin (H&E) stained histopathological images using contrastive clustering identified 50 intricate histomorphological phenotype clusters (HPCs) as pathomic features. We two HPCs with significant prognostic value then integrated them into pathomics signature (PathoSig) the Cox regression model. PathoSig showed risk stratification overall survival disease-free successfully patients who may benefit from postoperative or preoperative chemoradiotherapy. The predictive power was validated in independent multicenter cohorts. Furthermore, can provide comprehensive information beyond current TNM staging system molecular subtyping. Overall, our study highlights potential utilizing histopathology images-based deep learning predictions evaluating SCLC. represents an effective tool that aids clinicians making informed decisions selecting personalized SCLC patients.

Language: Английский

Citations

28
Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer DOI
Triparna Sen, Nobuyuki Takahashi,

Subhamoy Chakraborty

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(8), P. 610 - 627

Published: July 4, 2024

Language: Английский

Citations

20
Patient‐derived xenograft model in cancer: establishment and applications DOI Creative Commons

Ao Gu,

Jiatong Li, Mengyao Li

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 19, 2025

Abstract The patient‐derived xenograft (PDX) model is a crucial in vivo extensively employed cancer research that has been shown to maintain the genomic characteristics and pathological structure of patients across various subtypes, metastatic, diverse treatment histories. Various strategies utilized PDX models can offer valuable insights into mechanisms tumor progression, drug resistance, development novel therapies. This review provides comprehensive overview establishment applications models. We present an history current status models, elucidate construction methodologies for different tumors, conduct comparative analysis highlight distinct advantages limitations this relation other are elucidated domain comprehending underlying therapy, which highlights broad fields chemotherapy, targeted delivery systems, combination antibody–drug conjugates radiotherapy. Furthermore, with multiomics single‐cell analyses also emphasized. application clinical personalized medicine additionally

Language: Английский

Citations

5
KDM6A epigenetically regulates subtype plasticity in small cell lung cancer DOI
Leslie Duplaquet, Yixiang Li, Matthew A. Booker

et al.

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(9), P. 1346 - 1358

Published: Aug. 17, 2023

Language: Английский

Citations

36