Cancer is still one of the main causes of death, particularly in the Western world, and is a major topic of interest at CeMM. It has been over 40 years since Richard Nixon, then president of the U.S., declared a ‘war on cancer’, which highlighted the difficulties being faced and generated substantial funding for cancer research. But unfortunately the war is still raging today.
To help break the impasse, several of the groups at CeMM are working on cancer-related projects ranging from basic science, through to finding new and more effective anti-cancer drugs.
The role of epigenetics in cancer
Epigenetics is defined as heritable changes in gene activity that are not encoded in the DNA. Global epigenetic changes are one of the classic hallmarks of cancer. We are only now beginning to appreciate their significance and how they might provide a new angle for cancer therapeutics. The groups of Christoph Bock and Stefan Kubicek at CeMM are each studying different aspects of epigenetics and cancer.
- Christoph Bock’s group is modelling the dynamics of DNA methylation in leukemia using high-throughput sequencing and computational methods.
- Stefan Kubicek’s group is studying chromatin modifying enzymes, including DNA methyltransferases, to see which ones play a role in cancer and how they might be exploited for developing new drugs.
Understanding cancer biology
Cancer cells are derived from our own cells, and harness many capabilities to enable unrestricted proliferation and the ability to spread throughout the body (metastasize).
- Georg Busslinger's group uses human organoid cultures as a model system in combination with CRISPR-Cas9 and high-throughput sequencing approaches to investigate the mode-of-action of highly-specialised human cell types as well as the role of human-specific gut microbes in the development of gastrointestinal diseases. They are also characterising the cellular composition of disease-specific gene expression changes by single-cell RNA sequencing using human biopsies, with the overarching goal of better understanding the epithelial cell behaviour that contributes to disease development.
Tumor cells often express aberrant proteins or epitopes that can elicit endogenous immune responses. However, intricate suppressive mechanisms have evolved in tumors to avoid detection and eliminaiton by the immune system. We are now only beginning to understand how immune cells are reprogrammed in the tumor microenvironment, how they control anti-tumor immunity, and which therapeutic strategies successfully induce and enhance tumor-directed immune responses.
- Barbara Maier’s group uses a wide array of approaches, including high-dimensional profiling and mechanistic strategies in different model systems to study cellular interactions within the tumor microenvironment with the goal of identifying mechanisms of immune checkpoint blockade in cancer patients and exploring novel combinatorial immunotherapy options. A recent study by Barbara Maier, that is fundamental to her tumor immunology program at CeMM, shed light on the regulatory phentoypes of tumor-associated myeloid cells and uncovered targetable mechanisms of immunosuppression in the tumor microenvironment.
Now that most of the genetic abnormalities that cause cancer have likely been discovered, targeted therapies can be developed that exploit specific genetic mutations. A handful of these are now clinically available and some result in dramatic therapeutic responses. However, cancers are developing drug resistance, which has become the next big challenge.
- Giulio Superti-Furga’s group at CeMM is looking to boost the development of effective anti-cancer drugs. They use pathway mapping by interaction proteomics, chemical proteomics and genetic screens to identify new drug targets, understand the mechanism of action of drugs and figure out how cancer cells can become resistant to specific drugs, which has become a major problem in the clinic.
- The group of Georg Winter is interested in understanding the molecular basis of aberrant gene regulation in cancer. In order to identify, characterize and mechanistically dissect novel oncogenic transcriptional circuits, they are using and developing chemical biology centric approaches in a highly integrated fashion with the ultimate goal of advancing chemical modulation of oncogenic gene regulation as a therapeutic approach.