Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions

Fuduan Peng¹, Ansam Sinjab², Yibo Dai³, Warapen Treekitkarnmongkol², Sujuan Yang², Lorena I Gomez Bolanos², Tieling Zhou², Minyue Chen⁴, Alejandra G Serrano², Avantika Krishna⁵, Nastaran Karimi⁶, Manvi Sharma², Akshay Basi⁷, Guangsheng Pei¹, Jianlong Liao¹, Yunhe Liu¹, Jiping Feng², Zahraa Rahal², Yang Liu¹, Jiahui Jiang³, Kai Yu¹, Tala Noun⁴, Yuejiang Liu⁴, Khaja Khan², Kyung Serk Cho¹, Jichao Chen⁸, Luisa M Solis², Sarah Mazzilli⁹, Steven Dubinett¹⁰, Tina Cascone¹¹, Avrum E Spira¹², Stephen Swisher¹³, Naoe Jimbo¹⁴, Takuo Hayashi¹⁵, Satsuki Kishikawa¹⁵, Kazuya Takamochi¹⁶, Tomoo Itoh¹⁴, Takashi Yao¹⁵, Kenji Suzuki¹⁶, Neda Kalhor¹⁷, Ignacio I Wistuba², Mingyao Li¹⁸, Seyed Javad Moghaddam⁵, Junya Fujimoto¹⁹, Jared Burks⁶, Jeffrey Myers²⁰, Kadir Akdemir²¹, Linghua Wang²², Humam Kadara²³

Affiliations

¹ Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
² Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
⁴ Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
⁵ The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Pediatrics, Perinatal Institute Division of Pulmonary Biology, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁹ Section of Computational Biomedicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.
¹⁰ Department of Medicine, The University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Thoracic Head & Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.
¹² Section of Computational Biomedicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA; Lung Cancer Initiative at Johnson & Johnson, Boston, MA, USA.
¹³ Department of Cardiovascular and Thoracic Surgery, UT MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan.
¹⁵ Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
¹⁶ Department of General Thoracic Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan.
¹⁷ Department of Anatomic Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
¹⁸ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁹ Clinical Research Center, Hiroshima University Hospital, Hiroshima, Japan.
²⁰ Department of Head and Neck Surgery, UT MD Anderson Cancer Center, Houston, TX, USA.
²¹ Department of Neurosurgery, UT MD Anderson Cancer Center, Houston, TX, USA.
²² Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; The James P. Allison Institute, UT MD Anderson Cancer Center, Houston, TX, USA; Institute for Data Science in Oncology, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: lwang22@mdanderson.org.
²³ Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Head and Neck Surgery, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: hkadara@mdanderson.org.

PMID: 41202811
DOI: 10.1016/j.ccell.2025.10.004

Free article

Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions

Fuduan Peng et al. Cancer Cell. 2025.

Free article

. 2025 Nov 6:S1535-6108(25)00445-3.

doi: 10.1016/j.ccell.2025.10.004. Online ahead of print.

Authors

Affiliations

¹ Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
² Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
⁴ Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
⁵ The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Pediatrics, Perinatal Institute Division of Pulmonary Biology, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁹ Section of Computational Biomedicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.
¹⁰ Department of Medicine, The University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Thoracic Head & Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.
¹² Section of Computational Biomedicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA; Lung Cancer Initiative at Johnson & Johnson, Boston, MA, USA.
¹³ Department of Cardiovascular and Thoracic Surgery, UT MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Diagnostic Pathology, Kobe University Hospital, Kobe, Japan.
¹⁵ Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
¹⁶ Department of General Thoracic Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan.
¹⁷ Department of Anatomic Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
¹⁸ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁹ Clinical Research Center, Hiroshima University Hospital, Hiroshima, Japan.
²⁰ Department of Head and Neck Surgery, UT MD Anderson Cancer Center, Houston, TX, USA.
²¹ Department of Neurosurgery, UT MD Anderson Cancer Center, Houston, TX, USA.
²² Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; The James P. Allison Institute, UT MD Anderson Cancer Center, Houston, TX, USA; Institute for Data Science in Oncology, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: lwang22@mdanderson.org.
²³ Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Head and Neck Surgery, UT MD Anderson Cancer Center, Houston, TX, USA. Electronic address: hkadara@mdanderson.org.

PMID: 41202811
DOI: 10.1016/j.ccell.2025.10.004

Abstract

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are prevalent in precursor lesions but become less frequent in LUADs. These niches are conserved in mice and promote alveolar progenitor growth. Targeting inflammation alone or in combination with immune checkpoint blockade in precancerous phase reduces alveolar progenitors. Epithelial-inflammatory niches are stage-specific, shape early LUAD development and represent promising targets for interception.

Keywords: IL-1β; LUAD interception; Xenium in situ; alveolar progenitors; epithelial-immune niche; lung adenocarcinoma; lung precursor lesions; proinflammatory pathways; reactive type II pneumocytes; spatial transcriptomics.

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Conflict of interest statement

Declaration of interests H.K. reports research funding from Johnson and Johnson. L.W. reports outside the scope of the submitted work honoraria for service on the Scientific Advisory Board of SELLAS Life Sciences. T.C. reports outside the scope of the submitted work speaker fees/honoraria (including travel/meeting expenses) from ASCO Post, AstraZeneca, Bio Ascend, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medicals, PeerView, Physicians' Education Resource, Targeted Oncology; advisory role/consulting fees (including travel/meeting expenses) from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Merck, oNKo-innate, Pfizer, and RAPT Therapeutics; institutional research funding from AstraZeneca and Bristol Myers Squibb. S.M.D. served on an advisory board and holds stock in Early Diagnostics and LungLife AI; and received research support from Johnson & Johnson. A.E.S. is an employee of Johnson and Johnson. I.I.W. reports grants and personal fees from Genentech/Roche, grants and personal fees from Bayer, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from AstraZeneca, grants and personal fees from Pfizer, grants and personal fees from HTG Molecular, personal fees from Asuragen, grants and personal fees from Merck, grants and personal fees from GlaxoSmithKline, grants and personal fees from Guardant Health, personal fees from Flame, grants and personal fees from Novartis, grants and personal fees from Sanofi, personal fees from Daiichi Sankyo, grants and personal fees from Amgen, personal fees from Oncocyte, personal fees from MSD, personal fees from Platform Health, grants from Adaptive, grants from Adaptimmune, grants from EMD Serono, grants from Takeda, grants from Karus, grants from Johnson & Johnson, grants from 4D, from Iovance and from Akoya, outside the submitted work.

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Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions

Affiliations

Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions

Authors

Affiliations

Abstract

Conflict of interest statement

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