Deciphering Tumor-Host Biology

Tumor cells interact intimately with cells in their immediate surroundings' microenvironment, which can either counteract or favor cancer development. Similarly, tumors can dramatically affect distant organs and physiology. More than half of all advanced cancer patients suffer from cancer cachexia, a syndrome characterized by fatigue, inflammation, metabolic reprogramming, anorexia, insulin resistance, and body mass wasting. Using the fruit fly, Drosophila melanogaster - a powerful animal model for medical research- this project seeks to answer two broad questions. What are the mechanisms of communication and metabolic changes between tumors and cells of the immediate neighborhood and somatic organs? And what are the functional dependences of tumor cell growth and survival on these mechanisms? With a highly multidisciplinary team of national and international collaborators, we will pursue these questions using a range of advanced methods. Through our research, we expect to reveal fundamental new mechanistic insights into the interactions between tumor and host that may form a basis for future cancer management. We recently utilized micro-computed tomography (micro CT) to survey the sizes of all organs during cancer cachexia in flies and find atrophy of fat, muscle, and gut tissues, parallelling changes in patients. We developed a novel metabolic tracing technique using stable natural carbon isotopes to decipher whether organic building blocks for tumor mass increase derive from food or recycled nutrients derived from degrading organs. Using this approach we recently published that tumors induce muscle wasting through the cellular process of autophagy. We further demonstrate that the released nutrients are used by the tumor for its growth independent of feeding. Since the alimentary canal is strongly altered at the organ level during cachexia, we are studying how this affects nutrient utilization and weight loss. By leveraging genetic screens, we study the molecular genetic mechanisms in target tissues that underly cachexia and tumor-microenvironment interactions which supports tumor growth.

Tumor cells interact intimately with cells in their immediate microenvironment, which can either counteract or favour cancer development. Similarly, tumors can dramatically affect distant organs and physiology. In fact, 80% of advanced cancer patients suffer from devastating loss of muscle and fat tissue, despite sufficient food intake. 30% of patients are thought to die from this devastating syndrome, called Cancer Cachexia. There is a tremendous focused interest in mechanistically deciphering these tumor-host interactions since interfering with them holds a hope of mitigating symptoms, halting cancer progression, or even be curative. Untangling how these interactions work must be done in experimental animal models animals. In this project we use cancer models in the fruit fly, Drosophila melanogaster to decipher: 1) how host cells of the tumor microenvironment support tumor growth, and 2) how tumors cause cancer cachexia. To do this, we use novel and sophisticated tricks that allow us to experimentally change specifically tumor or host cells of the microenvironment, or even systemic organs using genetics. With a select multidisciplinary team of national and international collaborations we will pursue these questions using a range of advanced methods. Through our research we expect to reveal fundamental new mechanistic insights into the interactions of tumor and host that may form a basis for future cancer management.