Cararo Lopes, E. | Search bioRxiv

bioRxiv2025

JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake

Lung cancer is the leading cause of cancer-related death and is frequently accompanied by reduced food intake and cachexia, a debilitating syndrome characterized by weight loss and skeletal muscle wasting. We sought to identify contributors to cachexia using a murine model of lung cancer that reproduces key features of this syndrome. A multiplex cytokine screening approach, integrated with western blot and transcriptomic analyses, identified tumor-derived inflammatory mediators and downstream signaling pathways associated with cachexia. Notably, IL-6 superfamily members were elevated in the tumor and plasma of mice and patients with cachexia. The JAK-STAT3 signaling was upregulated in liver and skeletal muscle, driving the acute phase response and impairing lipid metabolism. Pharmacologic inhibition of JAK1/2 with ruxolitinib improved body weight, fat mass, and overall survival without altering tumor burden. These effects were driven primarily by blunted hypothalamic leptin receptor signaling, which increased food intake early in the disease course. In the liver, JAK inhibition reduced STAT3 activity, restored fatty acid oxidation, and decreased the production of acute-phase proteins. These findings support JAK inhibition as a therapeutic strategy for lung cancer-associated cachexia. Statement of SignificanceCancer cachexia is a lethal complication of lung cancer that lacks effective treatment. We show that JAK inhibition by ruxolitinib restores weight, fat mass, and prolongs survival in murine models of lung cancer. These effects were independent of tumor burden, underscoring the relevance of addressing cachexia to improve survival in cancer patients and supporting clinical testing of JAK inhibition for cancer cachexia

cancer biology↗

bioRxiv2024

RESPIRATION DEFECTS LIMIT SERINE SYNTHESIS REQUIRED FOR LUNG CANCER GROWTH AND SURVIVAL

Mitochondrial function is important for both energetic and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations directly impact these functions, resulting in the detrimental consequences seen in human mitochondrial diseases. The role of pathogenic mtDNA mutations in human cancers is less clear; while pathogenic mtDNA mutations are observed in some cancer types, they are almost absent in others. We report here that the proofreading mutant DNA polymerase gamma (PolGD256A) induced a high mtDNA mutation burden in non-small-cell lung cancer (NSCLC), and promoted the accumulation of defective mitochondria, which is responsible for decreased tumor cell proliferation and viability and increased cancer survival. In NSCLC cells, pathogenic mtDNA mutations increased glycolysis and caused dependence on glucose. The glucose dependency sustained mitochondrial energetics but at the cost of a decreased NAD+/NADH ratio that inhibited de novo serine synthesis. Insufficient serine synthesis, in turn, impaired the downstream synthesis of GSH and nucleotides, leading to impaired tumor growth that increased cancer survival. Unlike tumors with intact mitochondrial function, NSCLC with pathogenic mtDNA mutations were sensitive to dietary serine and glycine deprivation. Thus, mitochondrial function in NSCLC is required specifically to sustain sufficient serine synthesis for nucleotide production and redox homeostasis to support tumor growth, explaining why these cancers preserve functional mtDNA. In briefHigh mtDNA mutation burden in non-small-cell lung cancer (NSCLC) leads to the accumulation of respiration-defective mitochondria and dependency on glucose and glycolytic metabolism. Defective respiratory metabolism causes a massive accumulation of cytosolic nicotinamide adenine dinucleotide + hydrogen (NADH), which impedes serine synthesis and, thereby, glutathione (GSH) and nucleotide synthesis, leading to impaired tumor growth and increased survival. HighlightsO_LIProofreading mutations in Polymerase gamma led to a high burden of mitochondrial DNA mutations, promoting the accumulation of mitochondria with respiratory defects in NSCLC. C_LIO_LIDefective respiration led to reduced proliferation and viability of NSCLC cells increasing survival to cancer. C_LIO_LIDefective respiration caused glucose dependency to fuel elevated glycolysis. C_LIO_LIAltered glucose metabolism is associated with high NADH that limits serine synthesis, leading to impaired GSH and nucleotide production. C_LIO_LIMitochondrial respiration defects sensitize NSCLC to dietary serine/glycine starvation, further increasing survival. C_LI O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/596339v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@3dac07org.highwire.dtl.DTLVardef@e93401org.highwire.dtl.DTLVardef@555c48org.highwire.dtl.DTLVardef@1d7d31_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗