Temporal Clonal Tracing Reveals Tumor-Intrinsic IFNγ-Dependencies Driving Niche Adaptation and Early Metastatic...

Area of Science:

• Oncology
• Cancer Metastasis
• Immunology

Background:

• Metastasis involves complex interactions between disseminating tumor cells (DTCs) and organ-specific niches.
• The mechanisms enabling DTC survival and homing to distant sites are not fully understood.
• Ovarian cancer metastasis is a significant clinical challenge requiring deeper mechanistic insights.

Purpose of the Study:

• To map the temporal and clonal dynamics of DTCs and immune cells in ovarian cancer metastatic niches.
• To elucidate the intrinsic and niche-driven factors governing DTC survival and metastasis.
• To identify key molecular pathways driving ovarian cancer peritoneal metastasis.

Main Methods:

• MetTag: a single-cell barcoding and transcriptome profiling approach with time-stamped batch identifiers.
• Single-cell RNA sequencing (scRNA-seq) and velocity analyses of ascites and omental metastases.
• In vivo CRISPR/Cas9 screening to assess the functional importance of identified gene signatures.

Main Results:

• Early-disseminated clones showed preferred enrichment across metastatic niches.
• An interferon-gamma (IFNγ) centric transcriptional trajectory was identified in ascites and enriched in early seeding clones.
• Genes in the ascites IFNγ signature (e.g., Marco, Gbp2b, Slfn1) are functionally critical for peritoneal metastasis.
• Tumor cell intrinsic IFNγ signaling, via IFNGR1, significantly reduced metastatic burden and improved survival.
• Tumor-intrinsic IFNγ response and ascites-derived tumor-associated macrophages (TAMs) protect cancer cells from anoikis.

Conclusions:

• An ascites-driven, IFNγ program represents a necessary pro-metastatic adaptation in ovarian cancer.
• Tumor cell intrinsic IFNγ signaling is a critical driver of ovarian cancer metastasis.
• Understanding this IFNγ-mediated adaptation offers potential therapeutic targets for ovarian cancer.