Christian Riedel

Aging is the biggest risk factor for human morbidity and mortality, caused by damage accumulation and resulting functional decline of the organism over time. Fortunately, aging can be interfered with, and thus detailed mechanistic understanding of the underlying pathways could instruct powerful therapies to extend our healthspan and lifespan. Our research focuses on one of the most powerful aging regulators, the insulin/IGF signaling (IIS) pathway, relaying nutrient scarcity into a transcriptional program that improves stress resistance, slows damage accumulation, and ultimately defers aging. Much of this program is driven by the transcription factor (TF) DAF-16/FOXO, but it has long been thought that also the chromatin landscape could play an important role in its coordination. Indeed, by ATAC-seq we identified vast changes in chromatin accessibility under reduced IIS, and through different approaches we identified four chromatin-associated proteins that either confer or utilize these changes to contribute to the aging-preventive transcriptional outcomes. These include two chromatin-associated proteins that directly bind to DAF-16/FOXO, namely BAF-1 and PQN-51, and two TFs that bind enhancer regions which open up under reduced IIS, LIN-39 and LIN-32. Each of them are essential for reduced IIS to prevent aging but they function through distinct mechanisms of action, and we think that their full understanding will provide exciting new insights into aging prevention.

Despite many years of intensive research, there is currently a lack of effective treatment options for many types of cancer. It is clear that to be able to cure more forms of cancer, new therapeutic strategies are required. Treatment of cancer is today focused on the cancer cells themselves, but it is now clear that cancer requires interaction between the cancer cells and surrounding cells, which are in themselves healthy but which support the cancer cells. The molecular mechanisms that make up the interaction between cancer cells and surrounding tissue are currently incompletely mapped. A characteristic of most cancer cells is that they carry an abnormal number of chromosomes compared to normal cells, a condition known as aneuploidy. This chromosomal imbalance facilitates the cancer cells' ability to usurp extreme properties, such as uncontrolled growth through cell division. However, aneuploidy also involves a strain on basal cellular mechanisms. New data indicate that such cellular stress leads to the secretion of signaling molecules that can affect surrounding normal cells. In this project, we wish to validate the existence of this communication between cells and investigate whether it is important in tumor diseases. To begin with, we hope to confirm the existence of this new form of communication between cancer cells and their cellular neighbors in the local tissue. If this works, we will map the underlying molecular mechanisms and test whether they are required for cancer cell survival and the ability to form tumors. If so, manipulation of these communication mechanisms may represent a new strategy for treating cancer.

Despite many years of intensive research, there is currently a lack of effective treatment options for many types of cancer. It is clear that to be able to cure more forms of cancer, new therapeutic strategies are required. Treatment of cancer is today focused on the cancer cells themselves, but it is now clear that cancer requires interaction between the cancer cells and surrounding cells, which are in themselves healthy but which support the cancer cells. The molecular mechanisms that make up the interaction between cancer cells and surrounding tissue are currently incompletely mapped. A characteristic of most cancer cells is that they carry an abnormal number of chromosomes compared to normal cells, a condition known as aneuploidy. This chromosomal imbalance facilitates the cancer cells' ability to usurp extreme properties, such as uncontrolled growth through cell division. However, aneuploidy also involves a strain on basal cellular mechanisms. New data indicate that such cellular stress leads to the secretion of signaling molecules that can affect surrounding normal cells. In this project, we wish to validate the existence of this communication between cells and investigate whether it is important in tumor diseases. To begin with, we hope to confirm the existence of this new form of communication between cancer cells and their cellular neighbors in the local tissue. If this works, we will map the underlying molecular mechanisms and test whether they are required for cancer cell survival and the ability to form tumors. If so, manipulation of these communication mechanisms may represent a new strategy for treating cancer.