Signatures of Plasticity, Metastasis, and Immunosuppression in an Atlas of Human Small Cell Lung Cancer

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2021 Oct 15

PMID 34653364

Citations 161

Authors

Joseph M Chan

Alvaro Quintanal-Villalonga

Vianne Ran Gao

Yubin Xie

Viola Allaj

Ojasvi Chaudhary

Ignas Masilionis

Jacklynn Egger

Andrew Chow

Thomas Walle

Marissa Mattar

Dig V K Yarlagadda

James L Wang

Fathema Uddin

Michael Offin

Metamia Ciampricotti

Besnik Qeriqi

Amber Bahr

Elisa de Stanchina

Umesh K Bhanot

W Victoria Lai

Matthew J Bott

David R Jones

Arvin Ruiz

Marina K Baine

Yanyun Li

Natasha Rekhtman

John T Poirier

Tal Nawy

Triparna Sen

Linas Mazutis

Travis J Hollmann

Dana Peer

Charles M Rudin

Affiliations

Soon will be listed here.

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.

Citing Articles

Lethal co-expression intolerance underlies the mutually exclusive expression of ASCL1 and NEUROD1 in SCLC cells.

Watanabe H, Inoue Y, Tsuchiya K, Asada K, Suzuki M, Ogawa H NPJ Precis Oncol. 2025; 9(1):74.

PMID: 40082639 PMC: 11906894. DOI: 10.1038/s41698-025-00860-6.

Analyze the Diversity and Function of Immune Cells in the Tumor Microenvironment From the Perspective of Single-Cell RNA Sequencing.

Ma L, Luan Y, Lu L Cancer Med. 2025; 14(5):e70622.

PMID: 40062730 PMC: 11891933. DOI: 10.1002/cam4.70622.

Exploring YAP1-related TIME in SCLC: implications for survival and treatment response to immuno-chemotherapy.

Chen Y, Tan J, Gao L, Yang J, Huang J, Yang J Cancer Drug Resist. 2025; 8:8.

PMID: 40051494 PMC: 11883233. DOI: 10.20517/cdr.2024.177.

ACT001 Suppresses the Malignant Progression of Small-Cell Lung Cancer by Inhibiting Lactate Production and Promoting Anti-Tumor Immunity.

Ding X, Mei T, Xi X, Wang J, Wang W, Chen Y Thorac Cancer. 2025; 16(5):e70028.

PMID: 40016971 PMC: 11868026. DOI: 10.1111/1759-7714.70028.

Differential expression of the MYC-Notch axis drives divergent responses to the front-line therapy in central and peripheral extensive-stage small-cell lung cancer.

Luo L, Xia R, Mao S, Liu Q, Du H, Jiang T MedComm (2020). 2025; 6(3):e70112.

PMID: 39974662 PMC: 11836348. DOI: 10.1002/mco2.70112.

References

Zimmerman K, Espeland M, Langefeld C . A practical solution to pseudoreplication bias in single-cell studies. Nat Commun. 2021; 12(1):738. PMC: 7854630. DOI: 10.1038/s41467-021-21038-1. View

Vallieres E, Shepherd F, Crowley J, Van Houtte P, Postmus P, Carney D . The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol. 2009; 4(9):1049-59. DOI: 10.1097/JTO.0b013e3181b27799. View

Byers L, Rudin C . Small cell lung cancer: where do we go from here?. Cancer. 2014; 121(5):664-72. PMC: 5497465. DOI: 10.1002/cncr.29098. View

Quintanal-Villalonga A, Molina-Pinelo S, Cirauqui C, Ojeda-Marquez L, Marrugal A, Suarez R . FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy. J Thorac Oncol. 2019; 14(4):641-655. DOI: 10.1016/j.jtho.2018.12.021. View

Aizarani N, Saviano A, Sagar , Mailly L, Durand S, Herman J . A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature. 2019; 572(7768):199-204. PMC: 6687507. DOI: 10.1038/s41586-019-1373-2. View

Travaglini K, Nabhan A, Penland L, Sinha R, Gillich A, Sit R . A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature. 2020; 587(7835):619-625. PMC: 7704697. DOI: 10.1038/s41586-020-2922-4. View

Pang X, Xie R, Zhang Z, Liu Q, Wu S, Cui Y . Identification of SPP1 as an Extracellular Matrix Signature for Metastatic Castration-Resistant Prostate Cancer. Front Oncol. 2019; 9:924. PMC: 6760472. DOI: 10.3389/fonc.2019.00924. View

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

Farabaugh S, Micalizzi D, Jedlicka P, Zhao R, Ford H . Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-β signaling, epithelial-mesenchymal transition, and cancer stem cell properties. Oncogene. 2011; 31(5):552-62. PMC: 3183358. DOI: 10.1038/onc.2011.259. View

10.

Gay C, Stewart C, Park E, Diao L, Groves S, Heeke S . Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021; 39(3):346-360.e7. PMC: 8143037. DOI: 10.1016/j.ccell.2020.12.014. View

11.

Chen T, Wu Q, Zhang Y, Lu T, Yue W, Zhang D . Tcf4 Controls Neuronal Migration of the Cerebral Cortex through Regulation of Bmp7. Front Mol Neurosci. 2016; 9:94. PMC: 5046712. DOI: 10.3389/fnmol.2016.00094. View

12.

Borromeo M, Savage T, Kollipara R, He M, Augustyn A, Osborne J . ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. Cell Rep. 2016; 16(5):1259-1272. PMC: 4972690. DOI: 10.1016/j.celrep.2016.06.081. View

13.

Mollaoglu G, Guthrie M, Bohm S, Bragelmann J, Can I, Ballieu P . MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell. 2017; 31(2):270-285. PMC: 5310991. DOI: 10.1016/j.ccell.2016.12.005. View

14.

Zhang M, Ergin V, Lin L, Stork C, Chen L, Zheng S . Axonogenesis Is Coordinated by Neuron-Specific Alternative Splicing Programming and Splicing Regulator PTBP2. Neuron. 2019; 101(4):690-706.e10. PMC: 6474845. DOI: 10.1016/j.neuron.2019.01.022. View

15.

Li J, Diao B, Guo S, Huang X, Yang C, Feng Z . VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism. Nat Commun. 2017; 8(1):1322. PMC: 5673889. DOI: 10.1038/s41467-017-01327-4. View

16.

Rudin C, Durinck S, Stawiski E, Poirier J, Modrusan Z, Shames D . Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012; 44(10):1111-6. PMC: 3557461. DOI: 10.1038/ng.2405. View

17.

Elakad O, Lois A, Schmitz K, Yao S, Hugo S, Lukat L . Fibroblast growth factor receptor 1 gene amplification and protein expression in human lung cancer. Cancer Med. 2020; 9(10):3574-3583. PMC: 7288860. DOI: 10.1002/cam4.2994. View

18.

Saunders L, Bankovich A, Anderson W, Aujay M, Bheddah S, Black K . A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015; 7(302):302ra136. PMC: 4934375. DOI: 10.1126/scitranslmed.aac9459. View

19.

Laughney A, Hu J, Campbell N, Bakhoum S, Setty M, Lavallee V . Regenerative lineages and immune-mediated pruning in lung cancer metastasis. Nat Med. 2020; 26(2):259-269. PMC: 7021003. DOI: 10.1038/s41591-019-0750-6. View

20.

Takahashi K, Koga K, Linge H, Zhang Y, Lin X, Metz C . Macrophage CD74 contributes to MIF-induced pulmonary inflammation. Respir Res. 2009; 10:33. PMC: 2681459. DOI: 10.1186/1465-9921-10-33. View