Pan-cancer molecular subtypes of metastasis reveal distinct and evolving transcriptional programs

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Cancer metastasis is a complex process involving molecular changes that vary by tissue of origin.
• Understanding these molecular mechanisms is crucial for developing effective cancer therapies.

Purpose of the Study:

• To identify and characterize molecular subtypes of cancer metastasis that are independent of tumor lineage.
• To explore the therapeutic implications of these newly identified metastasis subtypes.

Main Methods:

• Transcriptome data from patient-derived xenografts and patient tumor metastases were collated from 38 studies.
• Analysis included over 3,000 patients and 4,000 tumors to identify expression-based subtypes.
• Subtype characteristics were associated with genomic alterations, gene expression patterns, and drug response.

Main Results:

• Four distinct expression-based metastasis subtypes were identified, transcending tumor origin.
• Subtype 1: Associated with copy alterations, MYC targets, DNA repair genes, and bromodomain inhibitor response.
• Subtype 2: Characterized by metabolism and prostaglandin synthesis/regulation gene expression.
• Subtype 3: Linked to neuronal differentiation, methylation genes, EZH2 targets, and BCL2 inhibitor response.
• Subtype 4: Enriched for immune checkpoint and Notch pathway genes.
• Metastasis subtypes showed expression differences from paired primary tumors, with common subtype switching.

Conclusions:

• The identified metastasis subtypes provide a framework for understanding metastasis molecular underpinnings beyond tissue-specific domains.
• These subtypes have significant implications for developing targeted therapies for metastatic cancers.
• Further research into subtype switching and therapeutic vulnerabilities is warranted.