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 () and Anne C. Chiang ()
Additional contact information
Amin H. Nassar: Yale School of Medicine and Yale Cancer Center
Chul Kim: Georgetown Cancer Institute
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 School of Medicine and Yale Cancer Center
Shun-Fat Lau: Yale University
Yamato Takabe: Yale University
Antonio Ocejo: Jackson Memorial Hospital
Fatemeh Ardeshir-Larijani: Winship Cancer Institute of Emory University
Ticiana Leal: Winship Cancer Institute of Emory University
Suresh Ramalingam: Winship Cancer Institute of Emory University
Sumaiya Alam: Winship Cancer Institute of Emory University
Jhanelle E. Gray: Moffitt Cancer Center
James Hicks: Moffitt Cancer Center
David Kaldas: Moffitt Cancer Center
Javier Baena: Hospital 12 de Octubre
Maria Zurera Berjaga: Hospital 12 de Octubre
Frank Aboubakar Nana: Cliniques Universitaires Saint Luc
Christian Grohe: Klinik für Pneumologie-Evangelische Lungenklinik, Berlin Buch
Heike Leuders: Klinik für Pneumologie-Evangelische Lungenklinik, Berlin Buch
Fabrizio Citarella: Università Campus Bio-Medico di Roma
Alessio Cortellini: Università Campus Bio-Medico di Roma
Emanuele Claudio Mingo: Università Campus Bio-Medico di Roma
Danny Pancirer: Stanford Cancer Institute
Millie Das: Stanford Cancer Institute
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 Cancer Center
D. Ross Camidge: University of Colorado Cancer Center
Arthi Sridhar: Mayo Clinic
Kaushal Parikh: Mayo Clinic
Fionnuala Crowley: Icahn School of Medicine at Mount Sinai
Thomas U. Marron: Icahn School of Medicine at Mount Sinai
Vanya Aggarwal: Georgetown Cancer Institute
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 Comprehensive Cancer Center
Mingjia Li: The Ohio State University Comprehensive Cancer Center
Misako Nagasaka: UC Irvine
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: The Warren Alpert Medical School of Brown University
Justin Liauw: The Warren Alpert Medical School of Brown University
Ana I. Velazquez: University of California San Francisco Helen Diller Family Comprehensive Cancer Center
Tyiesha Brown: University of California San Francisco Helen Diller Family Comprehensive Cancer Center
Laura Moliner: L’Hospitalet de Llobregat
Miguel Mosteiro: L’Hospitalet de Llobregat
Pedro Rocha: Vall d’Hebron University Hospital
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: Penn State University
Hossein Borghaei: Fox Chase Cancer Center
Matthew Lee: Montefiore Medical Center/Albert Einstein College of Medicine
Lauren Young: Montefiore Medical Center/Albert Einstein College of Medicine
Raid Aljumaily: University of Oklahoma Health Sciences Center
Haris Mirza: Yale School of Medicine
David J. Kwiatkowski: Brigham and Women’s Hospital
Roy S. Herbst: Yale School of Medicine and Yale Cancer Center
Richard A. Flavell: Yale University
Abdul Rafeh Naqash: University of Oklahoma Health Sciences Center
Anne C. Chiang: Yale School of Medicine and Yale Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 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.

Date: 2025
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DOI: 10.1038/s41467-025-63091-0

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