Multi-omic molecular profiling reveals potentially targetable abnormalities shared across multiple histologies of brain metastasis.

Multi-omic molecular profiling reveals potentially targetable abnormalities shared across multiple histologies of brain metastasis.

Publication date: Jan 04, 2021

The deadly complication of brain metastasis (BM) is largely confined to a relatively narrow cross-section of systemic malignancies, suggesting a fundamental role for biological mechanisms shared across commonly brain metastatic tumor types. To identify and characterize such mechanisms, we performed genomic, transcriptional, and proteomic profiling using whole-exome sequencing, mRNA-seq, and reverse-phase protein array analysis in a cohort of the lung, breast, and renal cell carcinomas consisting of BM and patient-matched primary or extracranial metastatic tissues. While no specific genomic alterations were associated with BM, correlations with impaired cellular immunity, upregulated oxidative phosphorylation (OXPHOS), and canonical oncogenic signaling pathways including phosphoinositide 3-kinase (PI3K) signaling, were apparent across multiple tumor histologies. Multiplexed immunofluorescence analysis confirmed significant T cell depletion in BM, indicative of a fundamentally altered immune microenvironment. Moreover, functional studies using in vitro and in vivo modeling demonstrated heightened oxidative metabolism in BM along with sensitivity to OXPHOS inhibition in murine BM models and brain metastatic derivatives relative to isogenic parentals. These findings demonstrate that pathophysiological rewiring of oncogenic signaling, cellular metabolism, and immune microenvironment broadly characterizes BM. Further clarification of this biology will likely reveal promising targets for therapeutic development against BM arising from a broad variety of systemic cancers.

Concepts Keywords
Brain Brain metastatic tumor
Breast Apparent multiple tumor
Carcinomas Immunosuppression
Cellular Immunity Branches of biology
Cohort Oncology
Cross C-Met
Exome Cancer
Immunofluorescence Metastasis
Indicative Cell signaling
Isogenic Tumor microenvironment
Kinase Phosphoinositide 3-kinase
Lung Carcinogenesis
Malignancies Metastatic breast cancer
Metabolism IRS1
Metastatic
Metastatic Tumor
Microenvironment
MRNA
Murine
Oncogenic
Oxidative Metabolism
Oxidative Phosphorylation
Pathophysiological
Phosphoinositide
PI3K
Proteomic
Renal
Sequencing
Tumor
Vivo

Semantics

Type Source Name
disease MESH abnormalities
disease MESH metastasis
disease MESH malignancies
disease MESH renal cell carcinomas
pathway KEGG Oxidative phosphorylation
disease MESH development

Original Article

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