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Integrative multi-omics profiling reveals distinct evolutionary and immunogenic features of brain oligometastasis in
Rongxin Liao1,2, Qian Yu1,2, Yusheng Huang1
1Department of Cancer Center, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
Background:
Emerging evidence has demonstrated that lung cancer patients with brain oligometastases (oligo-BMs) could benefit from local radical therapies. Despite rapid advancements in the treatment of oligometastatic disease, the molecular determinants governing the oligometastatic phenotype in the central nervous system remain elusive.
Methods:
We performed 1021-panel sequencing, transcriptome profiling, DNA methylation mapping, and multiplex immunohistochemistry on 20 paired primary lung adenocarcinoma and oligo-BMs specimens to delineate their evolutionary dynamics and microenvironmental characteristics.
Results:
A pronounced intertumor heterogeneity was observed between primary tumors (PTs) and oligo-BMs, while intratumoral heterogeneity was conserved across lesions. Subclonal analysis and phylogenetic reconstruction demonstrated that oligo-BMs exhibited predominant polyclonal seeding patterns and parallel progression trajectories. Moreover, oligo-BMs displayed a more immunosuppressed microenvironment compared to PTs, characterized by attenuated immunogenic cell death signatures, downregulation of immune-activated pathways, and diminished infiltration of activated immune cells (including B cells, NK cells, and Th1 cells). The methylation levels at functional genomic regions were highly concordant between PTs and oligo-BMs. Notably, we identified NLGN1 as a potential regulator of oligo-BM, where the hypermethylation at its genebody regions was mechanistically associated with transcriptional upregulation. Clinical validation revealed that NLGN1 was specifically overexpressed in BMs compared to PTs and extracranial metastases, correlating with advanced pathological stages and poor prognosis. In vivo studies further confirmed NLGN1 promotes BM in mice.
Conclusions:
Our findings provide novel insights into the evolutionary trajectory, immune landscape and methylation pattern of oligo-BMs, potentially paving the way for the development of innovative therapeutic strategies for lung cancer patients with oligo-BMs.
Insights
Researchers identified NLGN1 as a key regulator in lung cancer brain metastases (oligo-BMs). This gene
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Lung cancer patients with brain oligometastases (oligo-BMs) may benefit from local radical therapies.
- Molecular drivers of CNS oligometastatic phenotype in lung cancer are not well understood.
Purpose of the Study:
- To investigate the evolutionary dynamics and microenvironmental characteristics of lung cancer brain oligometastases.
- To identify molecular determinants regulating the development of brain oligometastases.
Main Methods:
- Performed multi-omic analyses (1021-panel sequencing, transcriptome, methylation, IHC) on paired primary lung adenocarcinoma and oligo-BMs.
- Utilized subclonal analysis and phylogenetic reconstruction to understand tumor evolution.
- Conducted in vivo studies to validate findings.
Main Results:
- Oligo-BMs showed distinct intertumor heterogeneity but conserved intratumoral heterogeneity compared to primary tumors.
- Oligo-BMs exhibited polyclonal seeding and parallel progression, with a more immunosuppressed microenvironment.
- NLGN1 genebody hypermethylation correlated with transcriptional upregulation and was identified as a regulator of oligo-BMs, promoting metastasis in vivo.
Conclusions:
- Novel insights into the evolution, immune landscape, and methylation patterns of lung cancer brain metastases.
- NLGN1 overexpression is linked to advanced stages and poor prognosis in lung cancer brain metastases.
- Findings may guide development of novel therapeutic strategies for lung cancer patients with brain metastases.
