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.

摘要/叙述 癌症恶病质（CCX），肌肉和/或脂肪的消耗，与20-30%的所有癌症相关 我们的临床研究表明，CCX的存在与中位死亡率下降50%相关。 生存期（14个月vs 28个月，p<0.001）独立于肿瘤定向治疗。2 -3没有FDA- 批准CCX方案，大多数试验集中在限制肌肉减少症。使用多个已建立 在小鼠CCX小鼠模型中，我们一致观察到与肌肉相比， 萎缩此外，使用全脂肪酶缺失小鼠阻断脂肪细胞脂解限制了脂肪消耗和脂肪代谢。 CCX小鼠模型中的肌肉减少症。了解癌症用于激发脂肪的上游机制 脂肪分解和消耗可以提供新的治疗靶点，以扭转CCX综合征。 脂肪组织内复杂的细胞内（基质、血管、免疫和脂肪细胞）相互作用 通过改变脂肪细胞甘油三酯脂解和合成的相关信号，最终调节CCX消耗。 为了了解这些相互作用的收敛性，我们开发了一种体外CCX脂肪细胞测定来筛选 来自CCX系的分泌因子，其通过诱导脂肪细胞脂解而增加脂肪炎症和消耗 并确定了细胞因子白血病抑制因子（LIF）。5通过JAK依赖性炎症反应， 重组LIF使小鼠脂肪组织重编程，导致脂肪量减少> 50%，瘦 质量和体重> 10%，概括CCX。LIF还改变了脂肪表达和全身性 其他细胞因子/脂肪因子的水平来放大这种炎症并改变食物摄入。JAK抑制剂在鼠中的用途 CCX模型导致脂肪炎症减少（STAT 3磷酸化减少），脂肪细胞脂解， 和脂肪/肌肉消耗，都增加了存活率。为了了解脂肪细胞内 在CCX脂肪炎症的调节中，我们选择性地沉默LIF受体（LIFR）或 脂肪细胞中的STAT 3。与同窝对照组相比，两种小鼠模型的脂肪量都增加了一倍。 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 证实了脂肪炎症与持续的STAT 3磷酸化，导致部分抑制， CCX和定义脂肪对CCX消耗的非脂肪细胞贡献。FACS分析验证 CCX进展期间免疫细胞的纵向富集，提供额外的肿瘤/细胞因子靶点 支持CCX脂肪炎症和消耗。我们假设CCX脂肪炎症通过以下途径发生： JAK依赖性肿瘤-细胞因子-脂肪轴，通过JAK/STAT信号转导重编程脂肪， 多种细胞亚型，以增加脂肪细胞脂解并改变细胞/脂肪因子的分泌，导致 浪费SA 1 -2将剖析该轴的多种细胞/分子信号传导组分，其促进脂肪代谢。 炎症支持这种CCX消耗。SA 3将验证JAK/STAT信号事件之间的关联 在人体脂肪中诱导CCX的患者。