Report on the Multi-Omics Study of Lung Cancer Brain Metastases (LC-BMs)

Academic Background

Lung cancer is one of the most prevalent and deadly cancers worldwide. Lung cancer brain metastases (LC-BMs) are a common complication in patients with lung cancer and are associated with poor prognosis. Despite advances in lung cancer therapies, the standard treatment options for brain metastases remain limited and less effective. Understanding the molecular mechanisms and tumor microenvironment of LC-BMs is therefore essential for developing novel therapeutic strategies.

LC-BM progression involves complex mechanisms influenced by genomic, transcriptomic, proteomic, and metabolomic changes. The advent of multi-omics approaches has enabled researchers to comprehensively decipher the molecular characteristics of tumors, thus opening pathways toward precision medicine. However, there is still a paucity of multi-omics studies on LC-BMs, particularly those involving paired analyses of primary lung tumors and brain metastases. The current study aims to use an integrative multi-omics approach to characterize LC-BMs and explore potential therapeutic targets.

Source of the Paper

This paper, authored by Hao Duan, Jianlan Ren, Shiyou Wei, and others from multiple research institutions, including Sun Yat-sen University Cancer Center and West China Hospital, was published in 2024 in the journal Genome Medicine. The title of the study is “Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target.”

Research Workflow and Key Findings

1. Research Workflow

The study investigated multi-omics data from 154 patients with paired primary lung cancer and LC-BMs, including genomics, transcriptomics, proteomics, metabolomics, and single-cell RNA sequencing (scRNA-seq). The overall workflow comprised the following steps:

a) Patient Sample Collection and Data Processing

The study included samples from three previously published datasets and two newly generated cohorts, representing 119 patients for whole exome sequencing (WES), 56 for RNA sequencing (RNA-seq), 16 for proteomics data (4 patients for proteomics and 12 for reverse phase protein array [RPPA]), and 4 for metabolomics data. An independent scRNA-seq dataset was used for validation, containing 45,149 single cells derived from 15 primary lung tumors and 29,060 single cells from 10 brain metastases.

b) Genomic Analysis

Using WES data, the researchers analyzed somatic mutations, copy number variations (CNVs), and tumor mutational burden (TMB) between primary tumors and brain metastases. They discovered higher intra-tumor heterogeneity (ITH) in metastases and found that certain genes (e.g., TTN, TP53, MUC16) showed consistent mutation in both primary and metastasized tumors. Specific chromosomal regions (e.g., 5p15.33 and 20q13.33) were significantly amplified in brain metastases.

c) Transcriptomics and Proteomics Analysis

Transcriptomic and proteomics integrative analyses revealed that mitochondrial-specific metabolic pathways were significantly activated in brain metastases, whereas the tumor immune microenvironment was suppressed. These results were further validated via real-time PCR, immunohistochemistry (IHC), and multiplex immunofluorescence (MIF).

d) Metabolomics Analysis

Metabolites related to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathways were highly abundant in LC-BMs, while glycolytic pathways were more pronounced in primary lung tumors.

e) Therapeutic Strategy Validation

The researchers validated the efficacy of targeting OXPHOS using patient-derived organoids (PDOs) and mouse models. They found that Gamitrinib, a mitochondrial inhibitor, induced apoptosis and inhibited proliferation in LC-BM organoids. Combining Gamitrinib with anti-PD-1 immunotherapy significantly improved survival in mice with LC-BMs.

2. Key Findings

a) Genomic Features

Brain metastases exhibited greater intra-tumor heterogeneity (ITH) than primary lung tumors. Specific gene mutations (e.g., TTN, TP53, MUC16) were shared between primary and metastatic sites, while chromosomal amplifications (5p15.33 and 20q13.33) were more frequent in metastases.

b) Transcriptomic and Proteomic Features

Integrated transcriptomics and proteomics analyses showed that mitochondrial-specific metabolic pathways, particularly OXPHOS, were hyperactivated in brain metastases, while the tumor immune microenvironment was suppressed. These findings were confirmed through experimental methods like IHC and MIF.

c) Metabolomics Features

Metabolomics analysis revealed elevated activity in the TCA cycle and OXPHOS pathways in metastases, while glycolytic pathways were enhanced in primary tumors.

d) Therapeutic Validation

Gamitrinib successfully induced apoptosis and suppressed cell proliferation in LC-BM patient-derived organoids. Furthermore, combining it with anti-PD-1 therapies significantly prolonged survival in mouse models, highlighting the therapeutic potential for targeting metabolic vulnerabilities in LC-BMs.

3. Conclusions

This study provides a comprehensive multi-omics perspective on the molecular mechanisms underlying LC-BMs. It highlights mitochondrial-specific metabolic adaptations as key features of LC-BMs and identifies the tumor immune microenvironment as a suppressed state in the brain metastatic sites. The study also demonstrates the therapeutic potential of combining OXPHOS inhibition with immunotherapy, setting a framework for translating these findings into clinical trials.

Research Highlights

1. Multi-omics Integration: This is the first study to comprehensively integrate genomics, transcriptomics, proteomics, metabolomics, and scRNA-seq data to uncover the molecular features of LC-BMs.
2. Activation of Mitochondrial Metabolism: Mitochondrial-specific metabolic pathways, particularly OXPHOS, were significantly upregulated in brain metastases, providing a potential metabolic target for therapeutic intervention.
3. Suppressed Immune Microenvironment: The immunosuppressive tumor microenvironment in brain metastases suggests potential for immune-based therapies in treating LC-BMs.
4. Therapeutic Validation: This study demonstrated the efficacy of Gamitrinib, an OXPHOS-targeting drug, in PDOs and mice, and explored its combination with anti-PD-1 therapy, showing promising preclinical results.

Significance and Implications

This study offers new insights into the molecular mechanisms underlying LC-BMs and paves the way for developing novel, metabolically targeted therapies. The discovery of key genomic, proteomic, transcriptomic, and metabolic changes in LC-BMs provides a foundation for precision medicine approaches. Furthermore, the successful preclinical validation of targeting OXPHOS combined with immunotherapy offers a promising therapeutic strategy that could be advanced to clinical trials. This work represents a significant step forward in improving outcomes for LC-BM patients.