Proliferating cells require an intricate machinery to split and pack their genetic material in a healthy way. One of the crucial molecules involved in the process is cohesin, a protein complex that holds duplicated DNA into loops to fit it into the cell nucleus.
The gene that encodes the cohesin subunit STAG2 is mutated in 25 percent of bladder cancers and Ewing sarcomas, and seven percent of acute myeloid leukaemia (AML). At present, these cancers are treated by cytotoxic therapies and surgery, which come with a host of undesirable side effects and have not eliminated high mortality. Developing selective and effective treatments is therefore of utmost importance for patients with STAG2 mutated cancer.
In the last call of the European Research Council’s (ERC) Proof of Concept Grants, Jan-Michael Peters secured 150,000 Euro of funding to explore the medical potential of his lab’s research on the subunits of the cohesin complex.
In a 2017 study, the Peters Lab and their collaborators have discovered that cancer cells with a mutated STAG2 gene were highly vulnerable to the inactivation of another gene, called STAG1, while healthy cells remained unaffected. This research effort included the labs of IMP Senior Scientist Johannes Zuber and IMP-alumnus Mark Petronczki at Boehringer Ingelheim.
“In 2020, we published another study in which we degraded STAG1 in STAG2-deficient cancer cells. The results were unequivocal: while STAG1 alone can keep cells alive, cancer cells die rapidly if both STAG1 and STAG2 are dysfunctional – a promising avenue for therapeutic strategies,” says Petra van der Lelij, who led both studies.
The researchers now want to use their new ERC grant to develop chemical approaches to inactivate STAG1. “This grant will help us identify and optimise a STAG1 inhibitor, a potential therapeutic,” says Renping Qiao Coudevylle, postdoc in the Peters Lab. “My work therefore aims at finding a molecule that will selectively bind to STAG1.”
“The sensitivity of cancer cells to STAG1 dysfunction is exceptional, and we hope our research can help exploit it,” says Jan-Michael Peters. “The ERC’s support has been instrumental in propelling our work to the forefront of our field – with this new grant, we will keep pushing the frontiers of cohesin research.”