Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

Amin H. Nassar; Chul Kim; Tolulope Adeyelu; Elias Bou Farhat; Hassan Abushukair; Mehrdad Rakaee; Kelsey Matteson; Shun-Fat Lau; Yamato Takabe; Antonio Ocejo; Fatemeh Ardeshir-Larijani; Ticiana Leal; Suresh Ramalingam; Sumaiya Alam; Jhanelle E. Gray; James Hicks; David Kaldas; Javier Baena; Maria Zurera Berjaga; Frank Aboubakar Nana; Christian Grohe; Heike Leuders; Fabrizio Citarella; Alessio Cortellini; Emanuele Claudio Mingo; Danny Pancirer; Millie Das; Timothy John Ellis-Caleo; Justin M. Cheung; Jessica J. Lin; Alexander S. Watson; D. Ross Camidge; Arthi Sridhar; Kaushal Parikh; Fionnuala Crowley; Thomas U. Marron; Vanya Aggarwal; Murtaza Ahmed; Kamya Sankar; Hassan Kawtharany; Jun Zhang; Dwight H. Owen; Mingjia Li; Misako Nagasaka; David J. Pinato; Nichola Awosika; Khaled Alhamad; Sonam Puri; Unaiza Zaman; Divya M. Gupta; Chelsea Lau; Hina Khan; Justin Liauw; Ana I. Velazquez; Tyiesha Brown; Laura Moliner; Miguel Mosteiro; Pedro Rocha; Mark Evans; Ari Vanderwalde; Andrew Elliott; Jorge Nieva; Gilberto Lopes; Patrick C. Ma; Hossein Borghaei; Matthew Lee; Lauren Young; Raid Aljumaily; Haris Mirza; David J. Kwiatkowski; Roy S. Herbst; Richard A. Flavell; Abdul Rafeh Naqash; Anne C. Chiang

doi:10.1038/s41467-025-63091-0

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Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

Journal article

Open access

Peer reviewed

Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

Amin H. Nassar, Chul Kim, Tolulope Adeyelu, Elias Bou Farhat, Hassan Abushukair, Mehrdad Rakaee, Kelsey Matteson, Shun-Fat Lau, Yamato Takabe, Antonio Ocejo, …

Nature communications, Vol.16(1), p.7717

2025-08-19

DOI: https://doi.org/10.1038/s41467-025-63091-0

Appears in Miller School of Medicine - Latest Publications

Abstract

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Article

Humanities and Social Sciences

multidisciplinary

Science

Science (multidisciplinary)

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observe comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identifies distinct non-small cell lung cancer-like (NSCLC-like, KEAP1 , KRAS , STK11 mutations) and SCLC-like ( RB1 , TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling reveals stable mutational but shifting transcriptomic landscapes over time. Here we show, elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression in NSCLC-like LCNECs, and higher levels of DLL3 in SCLC-like LCNECs. Immunofluorescence confirms FGL-1 expression in NSCLC-like LCNECs, and H&E slide analyses indicates fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies. Pulmonary large cell neuroendocrine carcinoma is an aggressive subtype of lung cancer. Here, the authors identify distinct subtypes based on genomic alterations and transcriptomic alterations.

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Title: Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma
Creators: Amin H. Nassar - Yale Cancer Center
Chul Kim - Georgetown University
Tolulope Adeyelu - Caris Life Sciences
Elias Bou Farhat - Brigham and Women's Hospital
Hassan Abushukair - University of Oklahoma Health Sciences Center
Mehrdad Rakaee - Brigham and Women's Hospital
Kelsey Matteson - Yale Cancer Center
Shun-Fat Lau - Yale University
Yamato Takabe - Yale University
Antonio Ocejo - Jackson Memorial Hospital
Fatemeh Ardeshir-Larijani - Emory University
Ticiana Leal - Emory University
Suresh Ramalingam - Emory University
Sumaiya Alam - Emory University
Jhanelle E. Gray - Moffitt Cancer Center
James Hicks - Moffitt Cancer Center
David Kaldas - Moffitt Cancer Center
Javier Baena - Department of Medical Oncology, Hospital 12 de Octubre
Maria Zurera Berjaga - Research Institute Hospital 12 de Octubre
Frank Aboubakar Nana - Cliniques Universitaires Saint-Luc
Christian Grohe - Evangelische Lungenklinik Berlin
Heike Leuders - Evangelische Lungenklinik Berlin
Fabrizio Citarella - Università Campus Bio-Medico
Alessio Cortellini - Università Campus Bio-Medico
Emanuele Claudio Mingo - Università Campus Bio-Medico
Danny Pancirer - Stanford Cancer Institute
Millie Das - VA Palo Alto Health Care System
Timothy John Ellis-Caleo - Stanford Cancer Institute
Justin M. Cheung - Massachusetts General Hospital
Jessica J. Lin - Massachusetts General Hospital
Alexander S. Watson - University of Colorado Denver
D. Ross Camidge - University of Colorado Cancer Center
Arthi Sridhar - Mayo Clinic in Arizona
Kaushal Parikh - Mayo Clinic in Arizona
Fionnuala Crowley - Icahn School of Medicine at Mount Sinai
Thomas U. Marron - Icahn School of Medicine at Mount Sinai
Vanya Aggarwal - Georgetown University
Murtaza Ahmed - Cedars-Sinai Medical Center
Kamya Sankar - Cedars-Sinai Medical Center
Hassan Kawtharany - University of Kansas Medical Center
Jun Zhang - University of Kansas Medical Center
Dwight H. Owen - The Ohio State University
Mingjia Li - The Ohio State University
Misako Nagasaka - UC Irvine Health
David J. Pinato - Hammersmith Hospital
Nichola Awosika - Hammersmith Hospital
Khaled Alhamad - Huntsman Cancer Institute
Sonam Puri - Huntsman Cancer Institute
Unaiza Zaman - University of Oklahoma Health Sciences Center
Divya M. Gupta - Northwestern University
Chelsea Lau - Northwestern University
Hina Khan - Brown University
Justin Liauw - Brown University
Ana I. Velazquez - UCSF Helen Diller Family Comprehensive Cancer Center
Tyiesha Brown - UCSF Helen Diller Family Comprehensive Cancer Center
Laura Moliner - Institut Català d'Oncologia
Miguel Mosteiro - Institut Català d'Oncologia
Pedro Rocha - Vall d'Hebron Hospital Universitari
Mark Evans - Caris Life Sciences
Ari Vanderwalde - Caris Life Sciences
Andrew Elliott - Caris Life Sciences
Jorge Nieva - University of Southern California
Gilberto Lopes - Jackson Memorial Hospital
Patrick C. Ma - Pennsylvania State University
Hossein Borghaei - Fox Chase Cancer Center
Matthew Lee - Albert Einstein College of Medicine
Lauren Young - Albert Einstein College of Medicine
Raid Aljumaily - University of Oklahoma Health Sciences Center
Haris Mirza - Yale University
David J. Kwiatkowski - Brigham and Women's Hospital
Roy S. Herbst - Yale Cancer Center
Richard A. Flavell - Yale University
Abdul Rafeh Naqash - University of Oklahoma Health Sciences Center
Anne C. Chiang - Yale Cancer Center
Publication Details: Nature communications, Vol.16(1), p.7717
Publisher: Nature Publishing Group UK
Academic Unit: Miller School of Medicine; UMMG Dept of Medicine - Hematology/Oncology
Language: English
Resource Type: Journal article
Record Identifier: 991032764215102976