1. Development of novel cancer therapies

We are particularly interested in developing novel treatment options for rare forms of cancer, as well as for cancers that do not respond to current forms of therapy. One example is mast cell leukemia, a rare but extremely aggressive form of leukemia with little treatment options and dismal prognosis. Another example is drug-resistant chronic myeloid leukemia (CML), which can also be difficult to treat. Using methods originally developed for yeast research, we have designed a powerful cell competition assay that we are using for high-throughput screening of large drug libraries. The goal of these screens is to identify compounds that specifically kill oncogene-expressing cells while leaving isogenic, untransformed cells unharmed. This project is sponsored by a persoanlized medicine grant from the Norwegian Cancer Society.

2. Personalized medicine for AML and CML patients

Acute myeloid leukemia (AML) is a common form of cancer. Unfortunately, AML has a relatively poor survival rate, especially for elderly patients who often do not tolerate the aggressive chemotherapy that is used to treat this disease. Further complicating effective treatment of patients is the fact that AML can be caused by a heterogeneous set of mutations, and it is believed that this heterogeneic nature of the disease is one of the underlying causes for chemotherapy failure. Sponsored by the personalized medicine grant from the Norwegian Cancer Society already mentioned above, we are collaborating with clinicians at Oslo University Hospital to develop a method for individualized treatment of AML patients. The ultimate goal is to provide treatment for patients that currently do not qualify for standard of care treatment, and for patients that have failed chemotherapy.

Goal of our yeast work

Cells are continuously exposed to changes in their environment. This is not only a challenge for single-celled organisms like budding yeast, but also for tumor cells, which can be exposed to various forms of stress including low oxygen levels, chemotherapy, radiation, and low nutrient levels. For optimal growth and survival, cells have developed mechanisms that sense environmental alterations and generate responses that maintain cellular homeostasis. We use the budding yeast Saccharomyces cerevisiae as a model organism to understand how cells cope with environmental changes, in particular nutrient stress.

Autophagy

A major response to environmental stimuli is activation of autophagy, which is a catabolic process that degrades cellular components into smaller molecules, thereby sustaining essential cellular processes. Whereas autophagy has been studied for decades, it remains unclear how cells control this process at the systems level. In particular, autophagy must be carefuly tuned, because excessive autophagy, or an inability to properly inactivate it, can be detrimental to cellular fitness.

Therefore, we performed a comprehensive study of autophagy dynamics, where we analyzed the effect of every gene in the genome both on activation and inactivation of autophagy over time at the single-cell level. This has resulted in a comprehensive dataset, AutoDRY (Autophagy Dynamics Repository in Yeast), which will be made publicly available shortly. A manuscript reporting this study has been posted on a the preprint server bioRxiv. Among other things, this study provides machine learning and bioinformatics tools for analyzing autophagic phenotypes; shows how each gene affects the kinetics of autophagy during starvation and during nutrient replenishment; visualizes how cell populations traverse the 'autophagic space' during activation/inactivation of autophagy; and provides a genome-wide map of the genetic network of autophagy-regulating genes.

Department of Molecular Cell Biology, Institute for Cancer Research
The Norwegian Radium Hospital, Montebello, N-0379 Oslo, Norway
Telephone +47 22 78 19 82 (Enserink), +47 22 78 12 69 (Dept. Secretary)
Email: j.m.enserink@ibv.uio.no