by Dr. Francisco Barriga, Memorial Sloan Kettering Cancer Center, New York
Cancers arise through genetic and epigenetic alterations that drive the transformation of single cells into malignant tumors. Among genetic changes, copy number alterations (CNAs) are recurrent chromosomal events that increase or decrease the dosage of specific regions of DNA and can affect up to 30% of a cancer cell genome. Despite their pervasiveness, the functional effects of specific CNAs on cancer phenotypes remain largely unknown. To dissect the biology of CNAs, we developed a new genome engineering approach termed Molecular Alteration of Chromosomes with Engineered Tandem Elements (MACHETE), which enables the rapid and flexible generation of megabase-sized chromosomal deletions. We initially focused on loss of chromosome 9p21.3, which are the most common homozygous deletions across cancer and portend dismal prognosis. The contributions of 9p21.3 loss to cancer have been broadly ascribed to the disruption of the cell cycle inhibitors CDKN2A/B, however these deletions frequently include a neighboring cluster of 16 type I interferon (IFN) genes with unknown roles in tumor initiation and progression. To determine the role of the IFN cluster co-deletion to the phenotypes associated with 9p21.3 loss, we applied MACHETE to an immunocompetent mouse model of pancreatic cancer and engineered Cdkn2a/b deletions with or without affecting the IFN cluster. Our data shows that concomitant loss of Cdkn2a/b and the IFN cluster exhibit enhanced metastatic initiating capacity through the disruption of immune surveillance. These differences in metastasis initiation were rescued in immune-deficient hosts, by inhibition of type I IFN signaling, or by depletion of CD8+ cells. Accordingly, deletion of the IFN cluster dictated significant changes in the tumor microenvironment, which were mirrored in human pancreatic cancer of the respective genotypes. Our results establish loss of tumor-intrinsic type I IFN genes as a pervasive genetic route for immune evasion and metastasis, revealing how a single genomic deletion promotes tumor progression by simultaneously disabling physically linked cell autonomous and non-autonomous mechanisms. Overall, our approach provides a framework for the systematic functional study of large genomic deletions in cancer and beyond.