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Despite the fact that we have several billion blood and lymph vessel cells, malignant tumors very rarely arise in our vascular tree. Many of the genetic changes (mutations) that would cause cancer in other cell types instead give rise to so-called vascular malformations when they occur in the cells of the vessel wall (endothelial cells). Why the endothelial cells are so disinclined to form cancer is unclear, but knowledge about this is of interest even for more common forms of cancer. Sometimes, however, angiosarcoma forms - a difficult-to-treat, aggressive and metastatic form of vascular cancer that is usually linked to previous high radiation doses in cancer treatment or long-term lymphedema. How and why a benign vascular malformation or vascular tumor changes into the metastatic cancer form angiosarcoma is basically unknown. To study this process, we have created mouse models in which specific genes that drive cancer can be "turned on" or "turned off" in the cells of the vessel walls (endothelial cells) at the desired time. After this, we can follow the development from "local" malformation to cancer. We can then study exactly what happens to all the cells' genes and how this affects the cells' behavior, for example how they break away and metastasize. This unique information provides clues about how these aggressive tumors can be treated. With our research, we hope to find which subsets of endothelial cells (from blood or lymphatic vessels) form cancer, but also which critical cell changes drive them towards uncontrolled growth and spread. This information can lead us to which drugs can most effectively attack the signaling systems that are overactivated precisely in these processes. The goal is to reduce side effects in treatment and to understand if there are key factors that govern several different types of vascular-related cancers.

We study central signalling components and shear forces in the rearrangement of the heterogenous endothelial cell population into arteries, capillaries, and veins with a focus on genes causing vascular malformation in familial and sporadic human genetic disease.The overall aim is to develop, identify, and deliver drugs with high precision to manipulate blood vessel expansion, regression, and malformation to treat vascular-related diseases such as cancer, stroke, diabetes, heart failure and vascular anomalies.Analysis of our unique ScRNAseq data from malforming retinal vessels in mosaic genetic mouse models of human disease, exposes novel vessel-subtype specific genes of interest that will be validated in patient material and explored for therapeutic manipulation in mouse and fish models. We dissect the relative impact of downstream components PI3K and AKT, under the influence of flow, on arteriovenous malformation. We apply and develop advanced Cre-Lox/AAV genetic mouse models of human vascular disease in combination with in vivo 2P confocal live microscopy, microfluidics, in vivo phage display (AstraZeneca), scRNAseq and classical biochemistry.Project is driven by my lab with national and international collaboration over 5 years.The combinations of state-of-the-art technologies and unique data with direct relevance to human genetic disease, will drive therapies in modulation of vascular function and patterning for patients suffering from above mentioned diseases.

The blood vessels play an important role in the growth, spread and treatment of tumors. The walls of the blood vessels are made up of endothelial cells and support cells that together produce a common "scaffold", called the basement membrane. In cancer, the basement membrane is often altered, which affects surrounding cells, but we do not know how this contributes to inflammation and fibrosis - and thus increased cancer risk. In fatty liver, a rapidly increasing disease linked to obesity and diabetes that can turn into cancer, it is known that basement membrane changes, inflammation and fibrosis precede tumor development. This cancer today lacks effective treatment. The role of vessels in the development of fibrosis and on to liver cancer is unclear. We now map how the vessels and their basement membranes change during this process and which signals are driving this. Blocking of specific signals has been used with some success in the treatment of liver cancer but with noticeable vascular-related side effects. This will be studied in detail in models of liver cancer. We will also genetically prevent certain vascular changes that are linked to tumor development. Through unique animal models and new technologies, we gain knowledge about both cancer development and how we can reduce the side effects of new forms of treatment. We hope to identify genes that affect the vessels' production of basement membrane proteins and to map the role these play in fibrosis and tumor development. The goal is to find specific substances that can be directed at signals related to these genes. After evaluation in model systems, these can hopefully act as drugs to prevent fibrosis and thereby reduce the risk of tumor formation in liver disease. We also want to find ways to reduce the vascular malformations that occur in connection with new promising treatment for liver cancer and thereby enable further evaluation of this strategy.