Cancer Core Europe Lecture: Dissecting the function of copy number alterations in cancer (Francisco Barriga)

Abstract:
Chromosomal deletions are prevalent in cancer, yet their function remains ill-defined. One of the most frequent losses affects chromosome 9p21.3, which disables the CDKN2A/B tumor suppressor genes. Intriguingly, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletions have not been functionally characterized. To dissect this biology we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy to create megabase-sized deletions. 9p21.3-syntenic deletions in a mouse model of pancreatic cancer revealed that concomitant loss of Cdkn2a/b and IFNs led to immune evasion and metastasis. Mechanistically, IFN co-deletion disrupted antigen-presenting cells and facilitated escape from CD8+ T cell surveillance in a cell extrinsic manner. Our results establish co-deletions of the IFN cluster as a pervasive route to tumor immune evasion and metastasis. This study establishes a framework to dissect the functions of genomic deletions in cancer and beyond.

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