Project 3 – Stromal derived IL-6/STAT3 signaling in the development and progression of PDAC

项目总结：项目3 PDAC是最致命的恶性实体肿瘤之一，大约92%的患者死于 在确诊后五年内患病，且除手术外没有有效的治疗方法。重要的是，它被广泛地 认识到患有PDAC的患者特别容易出现恶病质，这种综合征的特征是明显的 由于消耗骨骼肌和脂肪组织而导致的体重减轻。因此，患者往往很虚弱， 疲劳，这使他们对化疗和放射治疗的耐受性降低。动脉导管未闭的组织病理学特征 其独特的致密间质反应，包括激活的、与癌症相关的成纤维细胞，增加了额外的 细胞基质(ECM)、免疫细胞浸润和异常血管生成。这引起了人们对 选择性靶向肿瘤间质，以提高治疗效果。然而，与间质癌相关的 成纤维细胞也可以具有肿瘤抑制功能，挑战间质靶向治疗的疗效。在……里面 此外，人们越来越认识到间质间充质细胞在肌肉内稳态中的双重作用。 和再生，以及肌肉萎缩疾病，包括癌症恶病质。解决PDAC的进展 将需要对其宏观环境的新知识，包括肿瘤和外周之间的串扰 纸巾。在项目3中，我们假设IL6/STAT3通路是参与PDAC大环境的关键通路 相声。与此计划项目中的项目和核心的协同互动将使我们能够测试 假设肿瘤和肌肉中间质间充质细胞中的STAT3信号是一个组成部分 肿瘤大环境中的前馈环路有利于PDAC进展和癌症恶病质。

PROJECT SUMMARY: PROJECT 3 PDAC is among the most deadly malignant solid tumors, with approximately 92% of patients succumbing to the disease within five years of diagnosis, and with no effective therapies beyond surgery. Importantly, it is widely recognized that patients with PDAC are especially prone to cachexia, a syndrome characterized by pronounced weight loss due to depleting skeletal muscle and adipose tissues. As a result, patients are often weak and fatigued, which makes them less tolerant to chemo- and radiotherapy. The histopathological hallmark of PDAC is its uniquely dense stromal reaction, comprised of activated, cancer associated fibroblasts, increased extra- cellular matrix (ECM), immune cell infiltrates, and abnormal angiogenesis. This has engendered attention for selectively targeting the tumor stroma to increase therapeutic efficacy. However, stromal cancer-associated fibroblasts can also have tumor suppressive functions, challenging the efficacy of stromal-targeting therapies. In addition, there is increasing appreciation for the dual role of stromal mesenchymal cells in muscle homeostasis and regeneration, as well as in muscle wasting diseases, including cancer cachexia. Progress in tackling PDAC will require new knowledge of its macroenvironment encompassing crosstalk between the tumor and peripheral tissues. In Project 3, we posit the IL6/STAT3 pathway is a key pathway involved in PDAC macroenvironment cross-talk. Synergistic interactions with the Projects and Cores in this Program Project will allow us to test the hypothesis that STAT3 signaling in stromal mesenchymal cells present in the tumor and muscle is a component of a feed-forward loop in the tumor macroenvironment that favors PDAC progression and cancer cachexia.