Document text
Principal Investigator: Paige C Arneson-Wissink
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $118,041
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
80% of patients with Pancreatic Ductal Adenocarcinoma (PDAC) develop cachexia, which results in dispropor-
tionate skeletal muscle mass loss, relative to caloric deficits. Cachexia causes functional impairment and ineli-
gibility for anti-tumor therapeutic interventions, leading to drastically lower patient quality of life and increased
mortality. Supplemental nutrition is not sufficient to prevent tissue loss, and there is an abject lack of targeted
anti-cachectic therapeutics. This is largely due to an incomplete understanding of how effectors, such as inter-
leukin 6 (IL-6), drive cachexia, and mechanistic studies that poorly reflect the clinical scenarios of PDAC survi-
vorship. Improving the quality of life and survivorship of patients with PDAC requires that we address a funda-
mental knowledge gap in the mechanisms of cachexia persistence after cancer recovery. Our recent work shows
that systemic inflammation in PDAC prevents the liver from adapting to ketogenic metabolism during nutritional
scarcity, which leads to muscle loss. Loss of hepatic signal transducer and activator of transcription 3 (STAT3)
is sufficient to restore ketogenic potential and prevent muscle loss in PDAC mice. This work is the first to show
that improving hepatic fatty acid oxidation prevents cachexia progression. To improve the translation of these
findings we must address two unmet needs: 1) the mechanism of STAT3-driven down regulation of lipid oxidation
and 2) studies that address cachexia recovery in cancer survivors. Based on our prior work, we hypothesize that
STAT3 signaling acts on the liver to induce metabolic changes that persist after cancer recovery, at the detriment
of the muscle. This project is innovative because it uses advanced epigenetic techniques combined with a novel
mouse model of PDAC survivorship to clearly define the epigenetic reprogramming events that persist after
tumor clearance and increase vulnerability of muscle to nutritional stress. The significance of this project lies in
pre-clinical testing of metabolic interventions to protect muscle during PDAC recovery, defining a previously
undescribed action of STAT3 in hepatic metabolism control, and linking long-term metabolic dysfunction to epi-
genetic reprogramming during PDAC cachexia. The long-term goal of our research is to improve the quality of
life, from diagnosis through survivorship, of patients with cancer cachexia through a mechanistic understanding
of inter-organ metabolic events.
Terms: <APRF protein><ATAC sequencing><ATAC-seq><ATACseq><Acute-Phase Response Factor><Address><Affect><Anti-Cachexia Agents><Anti-cachectic><Anti-cachexia Drugs><Anticachectic><Anticachexia Agent><Anticachexia Drugs><Assay><Assay for Transposase-Accessible Chromatin using sequencing><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding><Bioassay><Biological Assay><Body Tissues><CUT&RUN><Cachectic><Cachexia><Cancer Cachexia><Cancer Survivor><Cancer Survivorship><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Circulation><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Clinical><Co-Immunoprecipitations><DNA><DNA Binding><DNA Binding Interaction><DNA Methylation><DNA Methyltransferase><DNA Modification Methylases><DNA Modification Methyltransferases><DNA bound><DNA-Methyltransferases><Data><Deoxyribonucleic Acid><Dependence><Detection><Diagnosis><Dnmt><Down-Regulation><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Esters><Event><Fasting><Fatty Acids><Foundations><Functional impairment><Gene Expression><Gene Inactivation><Gene Silencing><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genus Hippocampus><Goals><HPGF><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hepatocyte-Stimulating Factor><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><IL6-response factor><Impairment><Inflammation><Inflammatory><Interleukin-6><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ketones><Knock-out><Knockout><Knowledge><LIF-response factor><Link><Lipids><Liver><Liver Cells><MGI-2><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measures><Mediating><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolic dysfunction><Metabolism><Methylation><Mice><Mice Mammals><Mitochondria><Modeling><Modification><Modification Methylases><Molecular><Molecular Interaction><Murine><Mus><Muscle><Muscle Atrophy><Muscle Tissue><Muscular Atrophy><Mutation><Myeloid Differentiation-Inducing Protein><Nutrient availability><Nutritional><Organ><PDA model><PDAC Model><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Patients><Pattern><Plasmacytoma Growth Factor><Position><Positioning Attribute><Preclinical Testing><Production><Promoter Regions><Promotor Regions><QOL><Quality of life><Recovery><Regulation><Research><Role><STAT1 protein><Seahorse><Signal Transducer and Activator of Transcription 3><Signal Transduction><Signal Transduction Systems><Signaling><Site-Specific DNA-methyltransferase><Skeletal Muscle><Stat-1 protein><Stat-91 protein><Stat3 protein><Stat91 protein><Stimulus><Stress><Supplementation><Symptoms><Techniques><Testing><Therapeutic><Therapeutic Intervention><Tissues><Training><Transcription Regulation><Transcription Repressor><Transcriptional Control><Transcriptional Regulation><Transcriptional Repressor><Translations><Voluntary Muscle><Wasting Disease><Wasting Syndrome><Work><anti-cachexia><anticachexia><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological signal transduction><cancer associated cachexia><cancer induced cachexia><cancer-associated muscle wasting><cancer-induced muscle atrophy><cancer-induced muscle loss><cancer-induced muscle wasting><cancer-related cachexia><detection of nutrient><efficacious therapy><efficacious treatment><epigenetically><experience><fasted><fasts><fatty acid oxidation><gene locus><genetic locus><genetic promoter element><genetic promoter sequence><genetic repressor><genome mutation><genomic location><genomic locus><hepatic body system><hepatic metabolism><hepatic organ system><implantation><improved><inhibitor><innovate><innovation><innovative><interferon beta 2><intervention therapy><interventional strategy><ketogenesis><ketogenic><ketogentic><liver metabolism><malignancy><mitochondrial><mortality><mouse model><murine model><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle wasting><muscular><neoplasm/cancer><novel><nutrient sensing><nutrition><nutritious><overexpress><overexpression><oxidation><pancreatic cancer model><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic tumor model><perception of nutrients><pre-clinical><pre-clinical testing><preclinical><prevent><preventing><programs><promoter sequence><response><signal transducer and activator of transcription 1><social role><survivorship><systemic inflammation><systemic inflammatory response><timeline><transcription factor Stat91><transcriptional silencing><translation><tumor><tumor-induced cachexia><tumor-induced muscle wasting><wasting condition><wasting disorder>