Periodic Reporting for period 2 - CancerAneuploidy (Understanding and targeting the functional consequences of aneuploidy in cancer)
Reporting period: 2023-04-01 to 2024-09-30
Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is a distinct feature of cancer. Recent years have seen conceptual, methodological and technical advances in the field of cancer aneuploidy research, but we are just beginning to scratch the surface of the underlying biology, and the potential vulnerabilities of aneuploid cancer cells remain under-explored. Cancer aneuploidy is therefore a biological enigma and a missed opportunity for cancer therapy.
Identifying the “Achilles heels” of aneuploidy remains a holy grail of cancer research. However, current models of aneuploidy fail to fully recapitulate the cellular consequences of aneuploidy in cancer, thus compromising the identification of aneuploidy-induced cellular vulnerabilities. The time is ripe to tackle cancer aneuploidy with state-of-the-art genomic and functional approaches.
In this project, we apply innovative genomic and functional approaches to overcome current barriers, and develop much-needed novel methodologies to study aneuploidy in relevant cellular contexts throughout tumorigenesis. We explore the evolution of aneuploidy in tumorigenesis, and uncover the functional consequences of cancer aneuploidy, with an emphasis on aneuploidy-associated cellular vulnerabilities. We envision that the results of this project will significantly improve our understanding of how aneuploidy evolves and how it can be targeted. Our vision is to ultimately bring aneuploidy into the focus of precision cancer medicine.
Our specific objectives are:
(1) To dissect the forces that shape the evoultion of aneuploidy in cancer.
(2) To identify synthetic lethalities of aneuploid cancer cells.
Identifying the “Achilles heels” of aneuploidy remains a holy grail of cancer research. However, current models of aneuploidy fail to fully recapitulate the cellular consequences of aneuploidy in cancer, thus compromising the identification of aneuploidy-induced cellular vulnerabilities. The time is ripe to tackle cancer aneuploidy with state-of-the-art genomic and functional approaches.
In this project, we apply innovative genomic and functional approaches to overcome current barriers, and develop much-needed novel methodologies to study aneuploidy in relevant cellular contexts throughout tumorigenesis. We explore the evolution of aneuploidy in tumorigenesis, and uncover the functional consequences of cancer aneuploidy, with an emphasis on aneuploidy-associated cellular vulnerabilities. We envision that the results of this project will significantly improve our understanding of how aneuploidy evolves and how it can be targeted. Our vision is to ultimately bring aneuploidy into the focus of precision cancer medicine.
Our specific objectives are:
(1) To dissect the forces that shape the evoultion of aneuploidy in cancer.
(2) To identify synthetic lethalities of aneuploid cancer cells.
We compared the environmental selection pressures of human tumors and patient-derived xenografts (PDXs), and found that the aneuploidy landscapes of PDXs diverges from that of human tumors. This work was published in Hoge & Getz et al. npj Precision Oncology 2021.
We found that whole-genome duplication (WGD) can alter the adaptive value of aneuploidies and consequently alter the genetic landscape of human tumors. This work was published in Prasad et al. Cancer Research 2022.
We found that CRISPR-Cas9 editing can lead to the acquisition of aneuploidy in primary human T cells. This work was published in Nahmad, Reuveni & Goldschmidt et al. Nature Biotechnology 2022.
We applied a machine-learning approach to reveal the tissue-specific genomic features that determine the aneuploidy landscapes of human cancer. This work was published in Jubran & Slutsky Genome Biology 2024.
We found that highly-aneuploid cells are more dependent on the proper function of the spindle assembly checkpoint, and are more sensitive to the depletion of KIF18A. This work was published in Cohen-Sharir et al. Nature 2021.
We also generated a platform for identifying synthetic lethalities associated with a high degree of aneuploidy, and found that highly-aneuploid cells are more dependent on the RAF/MEK/ERK pathway and on mechanisms of RNA and protein degradation. This work was published in two research articles: Zerbib & Ippolito et al. Nature Communications 2024, and Ippolito & Zerbib Cancer Discovery 2024.
Lastly, we found that loss of chromosome-arm 17p is associated with breast cancer brain metastasis through the inactivation of p53. This work was submitted to publication and was uploaded as a preprint in Lau & Pozzi et al. bioRxiv 2023.
We found that whole-genome duplication (WGD) can alter the adaptive value of aneuploidies and consequently alter the genetic landscape of human tumors. This work was published in Prasad et al. Cancer Research 2022.
We found that CRISPR-Cas9 editing can lead to the acquisition of aneuploidy in primary human T cells. This work was published in Nahmad, Reuveni & Goldschmidt et al. Nature Biotechnology 2022.
We applied a machine-learning approach to reveal the tissue-specific genomic features that determine the aneuploidy landscapes of human cancer. This work was published in Jubran & Slutsky Genome Biology 2024.
We found that highly-aneuploid cells are more dependent on the proper function of the spindle assembly checkpoint, and are more sensitive to the depletion of KIF18A. This work was published in Cohen-Sharir et al. Nature 2021.
We also generated a platform for identifying synthetic lethalities associated with a high degree of aneuploidy, and found that highly-aneuploid cells are more dependent on the RAF/MEK/ERK pathway and on mechanisms of RNA and protein degradation. This work was published in two research articles: Zerbib & Ippolito et al. Nature Communications 2024, and Ippolito & Zerbib Cancer Discovery 2024.
Lastly, we found that loss of chromosome-arm 17p is associated with breast cancer brain metastasis through the inactivation of p53. This work was submitted to publication and was uploaded as a preprint in Lau & Pozzi et al. bioRxiv 2023.
Identifying the “Achilles heel” of aneuploidy remains a holy grail of cancer research. Recent years have seen conceptual, methodological, and technical advances in the field of cancer aneuploidy research, but we are just beginning to scratch the surface of understanding the underlying biology and the resultant therapeutic opportunities. In this project, we are tackling this age-old fundamental issue with state-of-the-art genomic and functional approaches. At the conclusion of this project, we will have improved understanding of: a) the forces that shape the evolution of aneuploidy in tumors; b) the cellular consequences of aneuploidy in cancer cells; and c) the therapeutically-exploitable vulnerabilities of aneuploid cells. The results of the study will also provide improved tools to study cancer aneuploidy in appropriate cellular contexts in vitro and in vivo. Ultimately, a successful completion of this project will be a major step towards targeting cancer aneuploidy in the clinic.