Our group studies the function of large-scale chromosomal changes known as copy number alterations (CNAs). We combine state of the art genome engineering strategies with in vivo models of cancer to uncover the mechanisms by which CNAs enable cancer cells to propagate and resist therapies. We are particularly interested in the role of these alterations in immune surveillance, tumor heterogeneity, and cancer genome evolution. Our long-term goal is to understand the complex biology of CNAs to identify new therapeutic strategies that target cells with these chromosomal aberrations.
Cancers arise through genetic and epigenetic alterations that drive the transformation of single cells into malignant tumors. Among the most frequent genetic changes observed in cancer we find copy number alterations (CNAs). As their name imply, CNAs change how many copies of specific regions of DNA a cancer cell has. Importantly, some CNAs are associated with poor clinical outcomes, yet we still do not know how they change the properties of cancer cells. In order to understand the function of CNAs, our lab combines in vivo models of cancer with MACHETE, a new approach that allows engineering CNAs.
Our previous work focused on studying the co-deletion of a cluster of 17 type I interferons linked to the tumor suppressor genes CDKN2A/B. By using MACHETE, we showed that combined loss of the interferon cluster and tumor suppressors led to immune evasion, metastasis, and reduced response to immunotherapy compared to CDKN2A/B-only deletions (Barriga, Tsanov, et al, Nature Cancer, 2022). This study illustrates the complex biology of CNAs, and the need of precise modeling to elucidate the biological consequences of these alterations. From a broader perspective, CNAs have a unique operational logic rooted on changes of gene dosage and DNA topology, which our group will explore in depth.
In the context of our ERC Starting Grant, our lab will explore CNA biology on the following research areas:
- Understanding the role of CNAs as mechanisms of immune evasion.
- Identifying the effect of CNAs in tumor heterogeneity.
- Dissecting the contribution of CNAs in shaping cancer genome evolution.
Francisco “Pancho” Barriga
ERC Starting Grant Acronym: MACHETE
- Edward P Evans Foundation