Hepatic metabolic reprogramming drives pancreatic cancer cachexia

肝脏代谢重编程导致胰腺癌恶病质

• 批准号: 10668391
• 负责人: Aaron Grossberg
• 金额: $ 24.79万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668391
• 关键词: Adaptor Signaling Protein; Adipose tissue; Biochemical; Blood Glucose; Cachexia; Cancer Patient; Carbohydrates; Caring; Catabolism; Cells; Circadian Dysregulation; Circadian gene expression; Complication; Critical Pathways; Darkness; Data; Disease; Dissociation; Distant; Excision; FRAP1 gene; Fasting; Feeding behaviors; Gastrointestinal tract structure; Gene Expression; Genes; Goals; Hepatic; Hepatocyte; Homeostasis; Human; Immune; Intervention; K-Series Research Career Programs; Ketones; Link; Lipids; Liver; Longevity; Macronutrients Nutrition; Malignant Neoplasms; Malignant neoplasm of pancreas; Malnutrition; Measures; Mediating; Mentors; Mentorship; Metabolic; Modification; Monitor; Mortality Determinants; Mus; Muscle; Nutrient availability; Nutritional; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Periodicals; Peripheral; Phenotype; Phosphotransferases; Physicians; Physiology; Quality of life; Regulation; Research Personnel; Resistance; Role; Sampling; Scientist; Signal Transduction; Sirolimus; Site; Skeletal Muscle; TSC1 gene; Testing; Thinness; Time-restricted feeding; Tissues; Training; Tumor Biology; Venous; Wasting Syndrome; cancer cachexia; carbohydrate metabolism; circadian; circadian biology; circadian regulation; design; detection of nutrient; effective therapy; energy balance; feeding; functional disability; improved; inhibitor; insight; ketogenesis; ketogentic; lipid biosynthesis; lipid metabolism; liver metabolism; metabolic phenotype; molecular marker; mortality; muscle form; new therapeutic target; nutritional supplementation; pancreatic neoplasm; prevent; programs; response; targeted treatment; therapeutically effective; transcriptome sequencing; translational approach; tumor; tumor growth; tumor metabolism; wasting

PROJECT SUMMARY Cachexia is a devastating complication of pancreatic ductal adenocarcinoma (PDAC) defined by loss of lean mass out of proportion to the caloric deficit. Cachexia is a major determinant of both lifespan and quality of life in patients with PDAC. The mechanisms underlying this catabolic state are poorly understood, and there remain no effective treatments. We have recently found that PDAC alters the regulation of metabolic genes in the liver, the organ that controls whole-body physiology in response to nutrient availability. The metabolic program reflects high energy availability in the livers of cachectic mice, suggesting a mismatch between hepatic nutrient sensing and availability. In this proposal we will investigate the role of this hepatic metabolic reprogramming on PDAC-associated cachexia. In Aim 1 we will modulate the hepatic activity of mTOR, a nutrient-sensing kinase that controls liver metabolism, to demonstrate that modification of hepatic nutrient sensing impacts tissue wasting. In Aim 2 we will investigate the effect of PDAC on nutritive and circadian regulation of liver metabolism and explore human samples for coherent effects. These Aims will provide fundamental insight into the deregulation of hepatic metabolism by PDAC, its role in cancer cachexia, and the circulating signals that mediate these changes. My goal is to become a successful independent physician-scientist investigator and a leader in the field of cancer metabolism, with the long-term goals of identifying new therapeutic targets to improve lifespan and quality of life in cancer patients. During this mentored career development award, I will receive excellent mentorship from Dr. Rosalie Sears, a leader in pancreatic tumor biology and Director of the Brenden-Colson Center for Pancreatic Care. I will undertake additional training in the field of hepatic metabolism, with guidance from Dr. Markus Grompe, and cachexia physiology, under the tutelage of Dr. Daniel Marks.

项目摘要 缓存是胰腺导管腺癌（PDAC）的毁灭性并发症 与卡路里不足成比例的质量。卡希克西亚是寿命和生活质量的主要决定因素 PDAC患者。这种分解代谢状态的机制知之甚少，那里 仍然没有有效的治疗。我们最近发现，PDAC改变了代谢基因在中的调节 肝脏，可控制全身生理的器官，以响应营养的供应性。代谢 程序反映了缓存小鼠肝脏的高能量可利用性，这表明 肝营养感和可用性。在此提案中，我们将研究这种肝代谢的作用 对PDAC相关的恶病质进行重新编程。在AIM 1中，我们将调节MTOR的肝活动 控制肝脏代谢的营养感应激酶，以证明肝营养素的修饰 感知会影响组织浪费。在AIM 2中，我们将研究PDAC对营养和昼夜节律的影响 调节肝脏代谢并探索人类样品以产生连贯作用。这些目标将提供 PDAC对肝脏代谢放松的基本洞察力，其在癌症cachexia中的作用和 介导这些变化的循环信号。 我的目标是成为成功的独立医师科学家调查员和该领域的领导者 癌症代谢，其长期目标是确定新的治疗靶标，以改善寿命和 癌症患者的生活质量。在这个指导的职业发展奖中，我将获得出色的 胰腺肿瘤生物学领导者和布伦登·科尔森（Brenden-Colson）主任罗莎莉·西尔斯（Rosalie Sears）博士的指导 胰腺护理中心。我将在肝代谢领域接受其他培训，并在指导下 在Daniel Marks博士的指导下，来自Markus Grompe博士和Cachexia生理学。

项目成果

Use of a Therapeutic Trial of Graduated Neoadjuvant Radiation Therapy for Locally Advanced Esophageal Cancer in a Patient With Fanconi Anemia.

• DOI: 10.1016/j.adro.2021.100810
• 发表时间: 2022-01
• 期刊: Advances in radiation oncology
• 影响因子: 2.3
• 作者: Gardner UG Jr;Wood SG;Chen EY;Greenberger JS;Grossberg AJ
• 通讯作者: Grossberg AJ

Bioelectrical impedance analysis as a quantitative measure of sarcopenia in head and neck cancer patients treated with radiotherapy.

• DOI: 10.1016/j.radonc.2021.03.005
• 发表时间: 2021-06
• 期刊: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
• 作者: Grossberg AJ;Rock CD;Edwards J;Mohamed ASR;Ruzensky D;Currie A;Rosemond P;Phan J;Gunn GB;Frank SJ;Morrison WH;Garden AS;Fuller CD;Rosenthal DI
• 通讯作者: Rosenthal DI

Establishment and Validation of Pre-Therapy Cervical Vertebrae Muscle Quantification as a Prognostic Marker of Sarcopenia in Patients With Head and Neck Cancer.

• DOI: 10.3389/fonc.2022.812159
• 发表时间: 2022
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Olson B;Edwards J;Degnin C;Santucci N;Buncke M;Hu J;Chen Y;Fuller CD;Geltzeiler M;Grossberg AJ;Clayburgh D
• 通讯作者: Clayburgh D

Toll-like receptor 4 mediates the development of fatigue in the murine Lewis Lung Carcinoma model independently of activation of macrophages and microglia.

• DOI: 10.1016/j.psyneuen.2020.104874
• 发表时间: 2020-12
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Vichaya EG;Ford BG;Quave CB;Rishi MR;Grossberg AJ;Dantzer R
• 通讯作者: Dantzer R

Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia.

• DOI: 10.1038/s41467-021-22361-3
• 发表时间: 2021-04-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Olson B;Zhu X;Norgard MA;Levasseur PR;Butler JT;Buenafe A;Burfeind KG;Michaelis KA;Pelz KR;Mendez H;Edwards J;Krasnow SM;Grossberg AJ;Marks DL
• 通讯作者: Marks DL