Multi-omic Profiling Provides Insights Into the Heterogeneity, Microenvironmental Features, and Biomarker Landscape of Small-Cell Lung Cancer

Authors

Mingchao Xie
Miljenka Vuko
Shashank Saran
Siyu Liu
Andrew G Chambers
Hana Baakza
Helen K Angell
Felicia Ng
Carl M Gay
Robert J Cardnell
Felix J Segerer
Alma Andoni
Jaime Rodriguez-Canales
Paul M Waring
Markus Schick
J Carl Barrett
Lauren A Byers
Giulia Fabbri

Language

English

Publication Date

12-2-2025

Journal

Molecular Cancer

DOI

10.1186/s12943-025-02514-4

PMID

41331472

PMCID

PMC12781381

PubMedCentral® Posted Date

12-2-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Greater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.

Methods: We explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.

Results: Multi-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest potential benefit from adding immunotherapy to chemotherapy; high DLL3 expression associated with neuroendocrine subtypes and an immune-cold tumor microenvironment. Multiplex immunofluorescence demonstrated associations of MHC-I with spatial arrangement and phenotypic features of immune cells in the tumor microenvironment of high-MHC-I-expressing SCLC, providing mechanistic rationale for MHC-I as a potential biomarker of immunotherapy response.

Conclusions: This multimodal profiling analysis provides further insights into the biologic complexity of SCLC and highlights potential therapeutic vulnerabilities of distinct disease subtypes.

Keywords

Humans, Small Cell Lung Carcinoma, Tumor Microenvironment, Biomarkers, Tumor, Lung Neoplasms, Proteomics, Prognosis, Gene Expression Profiling, Female, Male, Gene Expression Regulation, Neoplastic, Multiomics, Biomarkers, Immune profiling, Immunotherapies, Methylomics, MHC-I, Molecular subtyping, Proteomics, SCLC subtypes, Small-cell lung cancer

Published Open-Access

yes

Recommended Citation

Xie, Mingchao; Vuko, Miljenka; Saran, Shashank; et al., "Multi-omic Profiling Provides Insights Into the Heterogeneity, Microenvironmental Features, and Biomarker Landscape of Small-Cell Lung Cancer" (2025). Faculty, Staff and Student Publications. 5411.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5411