Identifying the Cellular and Molecular Targets of JAK/STAT-Driven Adipose Wasting to Reverse Cancer Cachexia

确定 JAK/STAT 驱动的脂肪消耗的细胞和分子靶点以逆转癌症恶病质

• 批准号: 10338639
• 负责人: Rodney E Infante
• 金额: $ 53.92万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338639
• 关键词: Adipocytes; Adipose tissue; Advanced Malignant Neoplasm; Atlases; Biological Assay; Biopsy; Blood; Blood Vessels; Body Weight; Body Weight decreased; Cancer Etiology; Cancer Patient; Cardiac; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Complex; Development; Eating; Event; FDA approved; Family; Fractionation; Genetic Models; Human; Immune; In Vitro; Inflammation; Inflammatory; Institutional Review Boards; Interleukin-6; Knockout Mice; LIF gene; Lipase; Lipids; Lipolysis; Malignant Neoplasms; Metabolic; Modeling; Molecular; Molecular Target; Mus; Muscular Atrophy; Pathway interactions; Patients; Peripheral; Phenotype; Phosphorylation; Play; Process; Protocols documentation; Quality of life; Recombinants; Regimen; Regulation; Resolution; Role; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Syndrome; TNF gene; Thinness; Triglycerides; adipokines; allotransplant; cancer cachexia; cancer survival; cellular targeting; cytokine; ghrelin; improved; inhibitor; leukemia inhibitory factor receptor; mouse model; new therapeutic target; sarcopenia; single molecule; transcriptome; tumor; wasting

ABSTRACT/NARRATIVE Cancer cachexia (CCX), wasting of muscle and/or adipose, is associated with 20-30% of all cancer related deaths.1 Our clinical studies have shown that the presence of CCX is associated with a 50% decrease in median survival (14 months vs 28 months, p<0.001) independent of tumor-directed therapies.2-3 There are no FDA- approved CCX regimens, with a majority of trials focused on limiting sarcopenia. Using multiple established murine CCX mouse models, we consistently observed significant adipose tissue loss compared to muscle atrophy. Furthermore, blocking adipocyte lipolysis using global lipase null mice limited both adipose wasting and sarcopenia in murine models of CCX. Understanding upstream mechanisms cancers use to provoke adipose lipolysis and wasting could offer novel therapeutic targets to reverse CCX syndrome. The complex intracellular (stromal, vascular, immune, and adipocyte) interactions within adipose tissue ultimately regulate CCX wasting by altering the relative signals of adipocyte triglyceride lipolysis and synthesis. To understand the convergence of these interactions, we developed an in vitro CCX adipocyte assay to screen secreted factors from CCX lines that increase adipose inflammation and wasting by inducing adipocyte lipolysis and identified the cytokine leukemia inhibitory factor (LIF).5 Through the JAK-dependent inflammatory reprogramming of adipose tissue in mice, recombinant LIF caused a decrease in adipose mass by >50%, lean mass, and body weight by >10%, recapitulating CCX. LIF also altered the adipose expression and systemic levels of other cyto/adipokines to amplify this inflammation and alter food intake. Use of JAK inhibitors in murine CCX models led to decreased adipose inflammation (decreased STAT3 phosphorylation), adipocyte lipolysis, and adipose/muscle wasting, all increasing survival. To understand the contributions of adipose intracellular signaling in the regulation of CCX adipose inflammation, we selectively silenced the LIF receptor (LIFR) or STAT3 in adipocytes. Both mouse models doubled their adipose mass compared to littermate controls during development highlighting an inverse CCX phenotype. When allotransplanted with CCX tumors, both models still demonstrated adipose inflammation with persistent STAT3 phosphorylation, resulting in a partial suppression of CCX and defining the non-adipocyte cellular contributions of adipose to CCX wasting. FACS analysis verified longitudinal enrichment of immune cells during CCX progression, offering additional tumor/cytokine targets supporting CCX adipose inflammation and wasting. We hypothesize that CCX adipose inflammation occurs via a JAK-dependent Tumor-Cytokine-Adipose Axis that reprograms adipose through JAK/STAT signaling of multiple cellular subtypes to increase adipocyte lipolysis and alter secretion of cyto/adipokines, resulting in wasting. SA1-2 will dissect the multiple cellular/molecular signaling components of this axis facilitating adipose inflammation in support of this CCX wasting. SA3 will validate associations between JAK/STAT signaling events in human adipose to CCX induction in patients.

抽象/叙事 癌症恶病质(CCX)，肌肉和/或脂肪的消耗，与所有癌症相关的20%-30%有关 死亡1我们的临床研究表明，CCX的存在与中位数下降50%有关 生存期(14个月与28个月，p&lt；0.001)独立于肿瘤导向治疗。2-3没有FDA- 批准的CCX方案，大多数试验侧重于限制石棺减少。使用多个已建立的 小鼠CCX小鼠模型，我们始终观察到与肌肉相比显著的脂肪组织丢失 萎缩。此外，使用全球脂肪酶缺失小鼠阻止脂肪细胞脂肪分解既限制了脂肪浪费，也限制了 CCX小鼠模型中的石棺减少。了解癌症刺激脂肪的上游机制 脂肪分解和消瘦可为逆转CCX综合征提供新的治疗靶点。 脂肪组织内复杂的细胞内(间质、血管、免疫和脂肪细胞)相互作用 最终通过改变脂肪细胞甘油三酯脂解和合成的相关信号来调节CCX的消耗。 为了了解这些相互作用的汇聚性，我们开发了一种体外CCX脂肪细胞试验来筛选 CCX株系分泌的通过诱导脂肪细胞脂解而增加脂肪炎症和消耗的因子 并鉴定出细胞因子白血病抑制因子(LIF)。5通过JAK依赖的炎症反应 小鼠脂肪组织的重新编程，重组LIF导致脂肪质量减少50%，瘦身 体重和体重增加了10%，这是对CCX的概括。LiF还改变了脂肪的表达和全身 其他细胞/脂肪因子的水平，以放大这种炎症和改变食物的摄入量。JAK抑制剂在小鼠体内的应用 CCX模型导致脂肪炎症减轻(STAT3磷酸化减少)，脂肪细胞脂解， 脂肪/肌肉萎缩，所有这些都提高了存活率。了解细胞内脂肪的贡献 在CCX脂肪炎症的调节中，我们选择性地沉默了LIF受体(LIFR)或 脂肪细胞中的STAT3。两个小鼠模型的脂肪质量都比产仔对照组增加了一倍 发展突出了反向CCX表型。当同种异体移植CCX肿瘤时，两种模型仍然 持续的STAT3磷酸化显示脂肪炎症，导致部分抑制 并确定脂肪对CCX消耗的非脂肪细胞贡献。FACS分析得到证实 CCX进展过程中免疫细胞的纵向浓缩，提供额外的肿瘤/细胞因子靶点 支持CCX脂肪炎症和消瘦。我们假设CCX脂肪炎症通过 JAK依赖的肿瘤细胞因子-脂肪轴通过JAK/STAT信号途径对脂肪进行再编程 多种细胞亚型增加脂肪细胞脂解并改变细胞/脂肪因子的分泌，导致 浪费。SA1-2将剖析这一轴的多个细胞/分子信号成分，以促进脂肪 炎症支持了这种CCX的浪费。SA3将验证JAK/STAT信令事件之间的关联 在人体脂肪中诱导CCX的患者。