Using CRISPR technology, we first targeted regulatory regions in the genome linked to estrogen receptor-driven breast cancer cells. Our data, published in NAR Oct 2019, showed that such regions are required for hormone-driven breast cancer cell proliferation.
Second, we performed a comprehensive CRISPR screen for regulatory regions in our genome that are targets of the important oncogene. In a publication in Genome Biology Journal 2021, we elucidated how YAP induces cancer aggressiveness (progression and metastasis) through specific regions and chromatin structure, assisting in diagnosing cancer metastasis.
Third, the results obtained from this project and the tools made here were used to connect gene expression to the emergence of new mRNA isoforms. We uncovered a novel form of mRNA with translation potential and showed that these novel mRNA isoforms are important for cell survival and communication with the immune system.
Finally, this resource was used to initiate a new and completely novel research line examining the quality of proteins produced in cancer cells under nutrient shortage induced by immune cell attack. In a set of 3 published papers (2x Nature and 1x Molecular Cell, 1x Science, and 2x review papers in Molecular Cell and Oncogene) we uncovered the process of aberrant production of proteins in cancer cells in times of nutrient shortage. This novel phenomenon enriches the neo-epitope landscape of cancer cells and can help improve cancer immunotherapy. This line of research is absolutely novel, extremely interesting from a biological perspective, and important for advancing cancer immunotherapy further.
One aspect of exploitation of our finding is the identification of T cell receptors (TCRs) that target aberrant neoepitopes in a cancer-specific manner. We already have an in-press follow-up manuscript demonstrating that such an adoptive T-cell therapy approach might be feasible. A second exploitation aspect of this work is investigating whether and how such mechanisms are regulated at the molecular level. We already have secured an ERC advanced grant to follow this route in the next 5 years. Mainly, we would like to know if other types of shortages induce aberrant protein production in cancer and how aberrant protein production is regulated. Can aberrant protein production assist cancer cell survival? And can we find ways to modulate it to kill cancer cells?
