Nature Communications (Aug 2025)
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
Affiliations
- Amin H. Nassar
- Department of Medicine (Medical Oncology), Yale School of Medicine and Yale Cancer Center
- Chul Kim
- Division of Hematology and Oncology, Georgetown Cancer Institute
- Tolulope Adeyelu
- Caris Life Sciences
- Elias Bou Farhat
- Division of Pulmonary Medicine, Brigham and Women’s Hospital
- Hassan Abushukair
- Division of Medical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center
- Mehrdad Rakaee
- Division of Pulmonary Medicine, Brigham and Women’s Hospital
- Kelsey Matteson
- Department of Medicine (Medical Oncology), Yale School of Medicine and Yale Cancer Center
- Shun-Fat Lau
- Department of Immunobiology, Yale University
- Yamato Takabe
- Department of Immunobiology, Yale University
- Antonio Ocejo
- Division of Medical Oncology, Jackson Memorial Hospital
- Fatemeh Ardeshir-Larijani
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University
- Ticiana Leal
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University
- Suresh Ramalingam
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University
- Sumaiya Alam
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University
- Jhanelle E. Gray
- Division of Thoracic Oncology, Moffitt Cancer Center
- James Hicks
- Division of Thoracic Oncology, Moffitt Cancer Center
- David Kaldas
- Division of Thoracic Oncology, Moffitt Cancer Center
- Javier Baena
- Department of Medical Oncology, Hospital 12 de Octubre
- Maria Zurera Berjaga
- Department of Medical Oncology, Hospital 12 de Octubre
- Frank Aboubakar Nana
- Division of Pneumology, Cliniques Universitaires Saint Luc
- Christian Grohe
- Klinik für Pneumologie-Evangelische Lungenklinik, Berlin Buch
- Heike Leuders
- Klinik für Pneumologie-Evangelische Lungenklinik, Berlin Buch
- Fabrizio Citarella
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma
- Alessio Cortellini
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma
- Emanuele Claudio Mingo
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma
- Danny Pancirer
- Department of Medicine, Stanford Cancer Institute
- Millie Das
- Department of Medicine, Stanford Cancer Institute
- Timothy John Ellis-Caleo
- Department of Medicine, Stanford Cancer Institute
- Justin M. Cheung
- Department of Medicine, Massachusetts General Hospital
- Jessica J. Lin
- Department of Medicine, Massachusetts General Hospital
- Alexander S. Watson
- Division of Medical Oncology, University of Colorado Cancer Center
- D. Ross Camidge
- Division of Medical Oncology, University of Colorado Cancer Center
- Arthi Sridhar
- Division of Medical Oncology, Mayo Clinic
- Kaushal Parikh
- Division of Medical Oncology, Mayo Clinic
- Fionnuala Crowley
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Thomas U. Marron
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Vanya Aggarwal
- Division of Hematology and Oncology, Georgetown Cancer Institute
- Murtaza Ahmed
- Division of Medical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center
- Kamya Sankar
- Division of Medical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center
- Hassan Kawtharany
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center
- Jun Zhang
- Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center
- Dwight H. Owen
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center
- Mingjia Li
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center
- Misako Nagasaka
- Department of Medicine, UC Irvine
- David J. Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital
- Nichola Awosika
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital
- Khaled Alhamad
- Division of Medical Oncology, Huntsman Cancer Institute
- Sonam Puri
- Division of Medical Oncology, Huntsman Cancer Institute
- Unaiza Zaman
- Division of Medical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center
- Divya M. Gupta
- Division of Medical Oncology, Northwestern University
- Chelsea Lau
- Division of Medical Oncology, Northwestern University
- Hina Khan
- Division of Hematology and Oncology, The Warren Alpert Medical School of Brown University
- Justin Liauw
- Division of Hematology and Oncology, The Warren Alpert Medical School of Brown University
- Ana I. Velazquez
- Division of Medical Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center
- Tyiesha Brown
- Division of Medical Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center
- Laura Moliner
- Division of Medical Oncology, Institut Catala d’Oncologia, L’Hospitalet de Llobregat
- Miguel Mosteiro
- Division of Medical Oncology, Institut Catala d’Oncologia, L’Hospitalet de Llobregat
- Pedro Rocha
- Medical Oncology Department, Vall d’Hebron University Hospital
- Mark Evans
- Caris Life Sciences
- Ari Vanderwalde
- Caris Life Sciences
- Andrew Elliott
- Caris Life Sciences
- Jorge Nieva
- Division of Medical Oncology, Norris Cancer Center, University of Southern California
- Gilberto Lopes
- Division of Medical Oncology, Jackson Memorial Hospital
- Patrick C. Ma
- Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Penn State University
- Hossein Borghaei
- Department of Hematology and Oncology, Fox Chase Cancer Center
- Matthew Lee
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine
- Lauren Young
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine
- Raid Aljumaily
- Division of Medical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center
- Haris Mirza
- Department of Pathology, Yale School of Medicine
- David J. Kwiatkowski
- Division of Pulmonary Medicine, Brigham and Women’s Hospital
- Roy S. Herbst
- Department of Medicine (Medical Oncology), Yale School of Medicine and Yale Cancer Center
- Richard A. Flavell
- Department of Immunobiology, Yale University
- Abdul Rafeh Naqash
- Division of Medical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center
- Anne C. Chiang
- Department of Medicine (Medical Oncology), Yale School of Medicine and Yale Cancer Center
- DOI
- https://doi.org/10.1038/s41467-025-63091-0
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 15
Abstract
Abstract 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.
