Periodic Reporting for period 3 - NoMePaCa (Novel Metabolic Pathways in Cancer)
Période du rapport: 2021-05-01 au 2022-10-31
What is the problem being addressed? What are the overall objectives?
Life depends on a multitude of chemical reactions that we collectively call metabolism. Many of these reactions occur in defined sequences called metabolic pathways and are facilitated by a special type of proteins that are called enzymes. In most known metabolic pathways, we know which enzyme facilitates which reaction. However, our picture is still incomplete. First, cells contain hundreds of metabolites, which have not yet been identified and for which we don't know how they are synthesized. Second, there are still many proteins that look like enzymes, but for which we don't know the function. Third, some enzymes have been described to have functions that are likely not their primary functions.
In this project, we are trying to understand the function of one particular enzyme that seems to play a role in cancer biology. Cancer cells need to survive and proliferate in situations where normal cells would die or stop growing. To account for these requirements, cancer cells undergo metabolic adaptations. Our enzyme of interest likely plays a role in the metabolic adaptation of a specific subset of cancers but seems to be dispensable for most normal cells. Hence, we want to explore whether inhibition of this enzyme might represent a novel therapeutic approach.
Why is it important for society?
Many molecular changes have been identified in cancer. Some of these changes can be modulated by small molecules that can eventually be developed into treatments for patients. This is a long and arduous path. However, the first step on this path is to understand what the molecular targets of these therapies do in normal and in cancer cells. Our research aims to do this and open new avenues for future therapies.
Life depends on a multitude of chemical reactions that we collectively call metabolism. Many of these reactions occur in defined sequences called metabolic pathways and are facilitated by a special type of proteins that are called enzymes. In most known metabolic pathways, we know which enzyme facilitates which reaction. However, our picture is still incomplete. First, cells contain hundreds of metabolites, which have not yet been identified and for which we don't know how they are synthesized. Second, there are still many proteins that look like enzymes, but for which we don't know the function. Third, some enzymes have been described to have functions that are likely not their primary functions.
In this project, we are trying to understand the function of one particular enzyme that seems to play a role in cancer biology. Cancer cells need to survive and proliferate in situations where normal cells would die or stop growing. To account for these requirements, cancer cells undergo metabolic adaptations. Our enzyme of interest likely plays a role in the metabolic adaptation of a specific subset of cancers but seems to be dispensable for most normal cells. Hence, we want to explore whether inhibition of this enzyme might represent a novel therapeutic approach.
Why is it important for society?
Many molecular changes have been identified in cancer. Some of these changes can be modulated by small molecules that can eventually be developed into treatments for patients. This is a long and arduous path. However, the first step on this path is to understand what the molecular targets of these therapies do in normal and in cancer cells. Our research aims to do this and open new avenues for future therapies.
Finding 1: Identification of physiological substrates and their biogenesis.
One of the major metabolic pathways is called glycolysis. It serves to break down a specific type of sugar, called glucose. Using a combination of genetic, biochemical and analytical approachs, we have found that a metabolite from this pathway is sometimes erroneously used by an enzyme to damage at least three other metabolites. We are investigating the function of an enzyme that makes sure that the damaged metabolites do not accumulate.
Finding 2: Effect of substrates
When we inactivate our enzyme of interest in cancer cell lines, the damaged metabolites accumulate. One of these metabolites completely shuts down the synthesis of an abundant metabolite that might be required for the progression of a subset of cancers.
Finding 3: Novel pathomechanism in Parkinson's disease
We had anticipated that the novel pathway might be relevant in settings outside of cancer. While investigating this, we found evidence that an overlapping pathway might play a role in hereditary Parkinson's disease.
One of the major metabolic pathways is called glycolysis. It serves to break down a specific type of sugar, called glucose. Using a combination of genetic, biochemical and analytical approachs, we have found that a metabolite from this pathway is sometimes erroneously used by an enzyme to damage at least three other metabolites. We are investigating the function of an enzyme that makes sure that the damaged metabolites do not accumulate.
Finding 2: Effect of substrates
When we inactivate our enzyme of interest in cancer cell lines, the damaged metabolites accumulate. One of these metabolites completely shuts down the synthesis of an abundant metabolite that might be required for the progression of a subset of cancers.
Finding 3: Novel pathomechanism in Parkinson's disease
We had anticipated that the novel pathway might be relevant in settings outside of cancer. While investigating this, we found evidence that an overlapping pathway might play a role in hereditary Parkinson's disease.
We have identified how the substrates of our enzyme of interest are formed in cells, and how they modulate cellular metabolism. We are currently exploring the relevance of these findings in several model system for cancer development. We expect to be able to develop small molecular inhibitors of our enzyme of interest.