Targeting cancer cells through synthetic lethality

A collaborative study drawing from two IMP labs and led by IMP-alumnus Mark Petronczki, now at Boehringer Ingelheim RCV, demonstrates a unique Achilles heel of tumors carrying a frequent mutation in the cohesin-molecule. Targeting this vulnerability by inducing synthetic lethality opens a promising way for future therapies. The study was published in the online-journal eLife on 10 July 2017.

In 1997, IMP Postdoc Christine Michaelis in the lab of Kim Nasmyth discovered cohesin, a molecular complex essential for the successful execution of cell division, in yeast. Three years later, Izabela Sumara in Jan Peters’ lab identified two isoforms of cohesin - STAG1 and STAG2 - in human cells. The function of the two versions seems to be mostly redundant and cell division can proceed normally with only one of the two isoforms in place. However, if either STAG1 or STAG2 are mutated, disabling the other one has catastrophic consequences and will lead to cell death.

Recent cancer genome sequencing efforts have identified frequent mutations in STAG2, particularly in bladder cancer and Ewing sarcoma, a dangerous childhood bone cancer. Although it is not yet clear why mutations in the cohesin ring promote cancer development, researchers at the IMP and at Boehringer Ingelheim Regional Center Vienna (BI RCV) suspected that altered cohesin function could lead to unique vulnerabilities of these cancer-types. Finding genes whose inactivation would kill only STAG2 mutated cells would therefore lead to new therapeutic concepts to attack these cancer cells and leave healthy cells intact.

Building on basic research: possible clinical application

In a joint project led by BI RCV group leader Mark Petronczki – once a PhD student and Postdoc at the IMP - and involving Boehringer Ingelheim RCV, the Zuber and Peters labs at the IMP, CNIO in Madrid, the Children's Cancer Research Institute in Vienna and the Georgetown University School of Medicine, the team set out to use genetic screening to identify such genes.

In the resulting paper, published in eLife on 10 July 2017, first authors Petra van der Lelij and Simone Lieb together with their colleagues demonstrate that inactivation of STAG1 induces cell death only in STAG2 mutated but not in healthy cells. In STAG2 mutated cells, the additional loss of STAG1 function prevents the cohesin ring from holding sister genomes together. As a consequence, the characteristic X-shape of chromosomes is lost and cells undergo a lethal cell division.

STAG1 inactivation also killed bladder cancer and Ewing sarcoma cell lines with STAG2 mutations, but not without. This concept, which could provide a promising way to target cancer, is known as synthetic lethality.

The study suggests that developing inhibitors of STAG1 function has the potential to lead to safe and effective new therapies for patients affected by tumors harboring STAG2 mutations - an estimated half a million-cancer patients worldwide. The next step in moving towards this goal will involve defining suitable points of attack for therapeutic molecules on STAG1.

“Working on this project was deeply satisfying for me”, says Petra van der Lelij, a joint postdoc of the IMP and Boehringer Ingelheim. “I feel that I can finally contribute to helping patients in the future. The combined basic research-expertise at the IMP and the resources of Boehringer Ingelheim led to a perfect collaboration.”

Link to publication: https://elifesciences.org/articles/26980

Image Caption: Chromosome spreads prepared from human cancer cells that were stained with a DNA binding dye. The image depicts cells at different stages in the process of chromosome formation. X-shaped chromosomes are formed during cell division. X-shaped structures contain two replicated sister chromatids that are held together at the centromere by the cohesin complex. (c) Mark Petronczki