Mechanisms of tumor-induced wasting

Mechanisms of tumor-induced wastin80% of advanced cancer patients suffer from cancer cachexia with significant loss of muscle and fat mass. The condition is characterized by systemic inflammation, metabolic changes, and exhaustion. This reduces quality of life, prevents the use of chemotherapy, and worsens the prognosis. The mechanisms of tumor-induced wasting are poorly understood.The overall goal of the project is to understand the causes and underlying mechanisms of tumor-induced wasting. In the long term, the goal is to improve quality of life and slow cancer development and wasting in patients suffering from cancer cachexia. To understand this, we have established a model for cancer cachexia in the fruit fly, Drosophila melanogaster, which reflects all the main components of cachexia in cancer patients including insulin resistance, metabolic reprogramming, inflammation, exhaustion, catastrophic breakdown of muscle and fat tissue, and subsequent death. In collaboration with a team of experts in metabolism, gene expression, cell biology, cancer genetics, and clinical work with advanced cancer patients, we will address three main challenges: a) How does the tumor cause metabolic reprogramming and wasting in muscle and fat tissue? b) What are the cellular mechanisms that lead to wasting of muscle and fat? c) Does the breakdown of muscle and fat serve as building blocks for the growth of the tumor? Summary of results submitted for publication: Tumor cells require large amounts of nutrients as building blocks and energy sources to increase cell size and divide. To maintain energy levels and building blocks in the tumor cell, cells perform so-called self-eating, or autophagy. During autophagy, the cell eats up parts of its own content called cytoplasm with energy stores such as glycogen and fat and discards defective proteins and mitochondria that form the cell's energy in the form of ATP. This way, the tumor cell maintains its own energy level and metabolism. We have created a cancer cachexia model in the fruit fly. Using groundbreaking X-ray techniques (micro X-ray computed tomography) with high resolution, we have documented that while the tumor grows 10 times in volume, muscle ,fat tissue and other organs are partially broken down. Muscle breakdown is dependent on inflammation signaling through a transcription factor called Nuclear Factor kappa B (NFkB) and Upd2/IL6-type signaling. NFkB stimulates increased autophagy in muscles, which executes muscle wasting. Thus, we have found that organ wasting through autophagy releases amino acids and sugar into the blood. In addition to the release of amino acids and sugars, we have found that elevated lipid mobilization occurs and that maximal tumor growth depends on both mobilized circulating lipids and generating their own lipids for tumor growth (Submitted). Through the development of new groundbreaking methods for tracking natural carbon isotopes, we subsequently demonstrated that the tumor mainly uses nutrients secreted from emaciated organs and not food to grow. When wasting is prevented, tumor growth stops. Together, this supports the notion that systemic inflammation observed in patients with cancer cachexia can drive organ wasting through autophagy and that organ wasting, in turn, drives tumor growth by transferring nutrients through a form of cannibalism. We are now working to understand more about the process and how we can transfer this knowledge to drug use in patients in the future.