Adipose tissue as a novel facilitator of tumor growth and cachexia - PROJECT SUMMARY A majority of patients with lung cancer experience cancer cachexia (CC), a complex syndrome where the tumor dysregulates host tissue metabolism, leading to adipose tissue (AT) and skeletal muscle wasting. Despite known associations of CC with increased fatigue, treatment toxicity, and poor prognosis, little is known about the early mechanisms leading to tissue wasting. Reflecting this lack of understanding, no effective therapies are currently available to treat CC, which is in part due to the rapid development of currently available preclinical models of CC. These current models hinder our ability to understand how early pathological changes initiate CC, and how substrates released from wasting tissues impact tumor development and growth, knowledge that is essential for developing effective treatments for CC. To address this, we established a Kras-driven model of lung CC that progresses more slowly. Unlike other preclinical models of lung CC, this model develops tumors in the lungs, shares genetic characteristics with tumors in patients that predispose to lung CC, and better represents the metabolic properties of human lung tumors. Our preliminary data implicates adipose tissue wasting as an effector of tumor growth and tissue wasting in this model, as AT loss predates muscle wasting and is inversely associated with tumor growth. Furthermore, pharmacological inhibition of lipolysis reduces tumor growth in vivo but does not directly prevent tumor cell growth in vitro, suggesting substrates released from AT support tumor growth. Dietary fats are known to increase cancer incidence and are stored in AT for use as energy substrates. Based on our preliminary data we hypothesize that endogenous fat substrates from wasting AT and exogenous fat substrates from the diet have a dual pathological importance in supporting rapidly growing, treatment-resistant tumors and CC. To test our hypotheses, we will employ pharmacological inhibition of lipolysis, our novel, genetically engineered mouse model, and a combination of ex vivo and in vitro modeling of tumor, adipose, and muscle to dissect the contributions of substrates released from AT in supporting tumor growth and promoting muscle loss during CC progression. Results from these studies will address critical knowledge gaps about how tumor characteristics relate to CC, providing a foundation for clinical translation. This proposal upends the perspective that AT wasting during CC is a unidirectional product of tumor-derived factors to affect the host, and instead shifts the role of AT from a passive partner of muscle wasting to an effector of pathological consequence for not only CC, but also for tumor growth. Knowledge from these studies could broaden the range of potential therapeutic targets to treat CC and the inciting cancer.
