Cancer cachexia is a tumor-induced debilitating wasting condition that causes loss of white adipose tissue and muscle degradation, exacerbated, paradoxically, by the loss of appetite by unclear mechanisms. Preventing cancer cachexia is profoundly important as it can prevent deterioration of patient health allowing sustained treatment and improved outcome. Cancer cachexia likely results from a systemic metabolic imbalance where tumors outcompete host tissues for essential nutrients that drive a catabolic process within normal tissues. Defining the cause of the systemic metabolic imbalance that favors the tumor at the expense of the patient and reversing it will improve cancer treatment and patient health.
A major goal of the Ludwig Princeton Branch is to determine how tumors cause the metabolic imbalance that drives cancer cachexia. With an understanding of the metabolic deregulation responsible for cancer cachexia, we can then reverse the condition by targeting the signaling mechanisms of the tumor and by supplying nutrients to correct the metabolic imbalance. We specifically aim to determine if dietary, pharmacologic, or genetic intervention can prevent or reverse cancer cachexia to improve the health, well-being and survival of cancer patients.
A recent Cancer Grand Challenges award assembles a multinational consortium supported by the National Cancer Institute and Cancer Research UK to build upon and expand cachexia work at the Ludwig Princeton Branch.
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Swanton C, Bernard E, Abbosh C, André F, Auwerx J, Balmain A, Bar-Sagi D, Bernards R, Bullman S, DeGregori J, Elliott C, Erez A, Evan G, Febbraio MA, Hidalgo A, Jamal-Hanjani M, Joyce JA, Kaiser M, Lamia K, Locasale JW, Loi S, Malanchi I, Merad M, Musgrave K, Patel KJ, Quezada S, Wargo JA, Weeraratna A, White E, Winkler F, Wood JN, Vousden KH, Hanahan D. Cell. 2024 Mar 28;187(7):1589-1616. doi: 10.1016/j.cell.2024.02.009. PMID: 38552609.
The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.
Yang X, Wang J, Chang CY, Zhou F, Liu J, Xu H, Ibrahim M, Gomez M, Guo GL, Liu H, Zong WX, Wondisford FE, Su X, White E, Feng Z, Hu W. Nat Commun. 2024 Jan 20;15(1):627. doi: 10.1038/s41467-024-44924-w. PMID: 38245529; PMCID: PMC10799847.
Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.
Ferrer M, Mourikis N, Davidson E, O Kleeman S, Zaccaria M, Habel J, Rubino R, Gao Q, Flint TR, Young L, Connell CM, Lukey MJ, Goncalves MD, White EP, Venkitaraman AR, Janowitz T. Cell Metab. 2023 Jul 11;35(7):1147-1162.e7. doi: 10.1016/j.cmet.2023.05.008. PMID: 37311455
Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis.