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Abstract

For the majority of cancer patients, tumor-derived factors systemically induce metabolic and inflammatory changes which cause involuntary body weight loss, known as cancer cachexia (CC). The extensive changes in the body’s metabolism induce an imbalance in energy expenditure, reduced quality of life and heightened treatment toxicity resulting in increased morbidity and mortality. Endothelial cells (ECs) play a central role during chronic inflammation and cancer progression. In response to primary tumor-derived signals, quiescent ECs become activated and secrete paracrine, so called angiocrine, factors that serve as instructive signals to modulate the microenvironment. In a previous study, we could show that ECs act as amplifier of tumor-derived signals supporting the colonization of disseminated tumor cells in the lung. Yet, the role of angiocrine signals during CC progression remains largely elusive. This project focuses on the endothelial signaling during CC and the relevance of angiocrine signaling during CC progression. I propose that tumor-derived factors drive CC progression by systemically reprogramming angiocrine signaling mechanisms.

To study the role of angiocrine signaling in CC in a homogenous and clinically relevant setting, a resection model was established which enabled the establishment of lung metastasis independent of primary tumor growth. The resection of the primary tumor recapitulates the process performed in the clinics and creates the opportunity to study (1) primary tumor-induced cachexia, (2) recovery after tumor removal and (3) secondary cachexia during metastasis in one mouse model. Following the tumor resection, body composition normalized, and cachectic symptoms were re-established upon subsequent outgrowth of overt lung metastases. Longitudinal transcriptomic and plasma proteomic changes were determined at the distinct biological timepoints. By comparing the gene expression of ECs in wasted organs (heart, adipose tissue) with a metastatic organ (lung), I observed that CC initiated systemic EC reprogramming which was largely mitigated after surgical tumor removal. Interestingly, the transcription factor STAT3 was similarly regulated in ECs indicating endothelial involvement in inflammatory responses during cachexia. The endothelial-specific deletion of Stat3 diminished adipose tissue wasting and prolonged survival verifying that ECs are actively involved in CC progression. Additionally, STAT3-regulated acute phase proteins (APP) were increased in the plasma during cachexia. Notably, the most upregulated EC-derived APP group in cachectic mice was the serine protease inhibitor family, SERPINA3. Mechanistic in vitro studies confirmed that the reduction of EC-derived SERPINA3 diminished muscle wasting. The analysis of the recently published lung cancer dataset of the TRACERx study confirmed the correlation of SERPINA3 plasma concentration and the cachectic status of the patients.