Dear All,

On Thursday 06.03 in the CN lecture hall we will host Francisco M. Barriga, PhD, Group Leader - Cancer Genome Engineering Lab, Vall D´Hebron Institute of Oncology (VHIO). His lecture will be entitled: “Dissecting the function of copy number alterations in cancer”. The lecture will take place at 3 p.m. in the CN lecture hall and it will be followed by a get together.

Abstract:

Somatic chromosomal deletions are prevalent in cancer, yet their functional contributions remain ill-defined. Among the most prominent of these events are deletions of chromosome 9p21.3, which disable a cell intrinsic barrier to tumorigenesis by eliminating the CDKN2A/B tumor suppressor genes. However, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletions have not been functionally characterized. To dissect how 9p21.3 and other genomic deletions impact cancer, we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy that enables flexible modeling of megabase-sized deletions. Generation of 9p21.3-syntenic deletions in a mouse model of pancreatic cancer revealed that concomitant loss of Cdkn2a/b and the IFN cluster led to immune evasion and metastasis compared to Cdkn2a/b-only deletions. Mechanistically, IFN co-deletion disrupted type I IFN signaling, altered 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, revealing how deletions can disable physically linked cell intrinsic and extrinsic tumor suppression. This study establishes a framework to dissect the functions of genomic deletions in cancer and beyond, which we are currently exploring in depth in my group.

Tomasz Wypych