Pan-Cancer Molecular Subtypes of Metastasis Reveal Distinct and Evolving Transcriptional Programs

Authors

Yiqun Zhang
Fengju Chen
Chad J Creighton

Publication Date

2-21-2023

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2023.100932

PMID

36731467

PMCID

PMC9975284

PubMedCentral® Posted Date

2-1-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Humans, Neoplasms, Antineoplastic Agents, Transcriptome, metastasis, transcriptomics, patient-derived xenografts, PDX, molecular subtypes, pan-cancer, MYC, prostaglandins, EZH2, immune checkpoint

Abstract

Molecular mechanisms underlying cancer metastasis span diverse tissues of origin. Here, we synthesize and collate the transcriptomes of patient-derived xenografts and patient tumor metastases, and these data collectively represent 38 studies and over 3,000 patients and 4,000 tumors. We identify four expression-based subtypes of metastasis transcending tumor lineage. The first subtype has extensive copy alterations, higher expression of MYC transcriptional targets and DNA repair genes, and bromodomain inhibitor response association. The second subtype has higher expression of genes involving metabolism and prostaglandin synthesis and regulation. The third subtype has evidence of neuronal differentiation, higher expression of DNA and histone methylation genes and EZH2 transcriptional targets, and BCL2 inhibitor response association. The fourth subtype has higher expression of immune checkpoint and Notch pathway genes. The metastasis subtypes reflect expression differences from paired primaries, with subtype switching being common. These subtypes facilitate understanding of the molecular underpinnings of metastases beyond tissue-oriented domains, with therapeutic implications.

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