Role of the different Semaphorin-3C isoforms in cancer-associated desmoplasia.

不同 Semaphorin-3C 亚型在癌症相关结缔组织增生中的作用。

• 批准号: 419966437
• 负责人: Dr. Juan Rodriguez Vita
• 金额: --
• 依托单位: Abteilung Vaskuläre Signaltransduktion und Krebs
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419966437?language=en
• 关键词: Role; different; Semaphorin; 3C; isoforms

Cancer research is mainly focused in neoplastic cells despite the fact that the number of processes regulated by the tumor microenvironment is constantly increasing. This is of particular importance in pancreatic cancer where the stromal compartment accounts for up to 90% of the total tumor mass. In this specific tumor the majority of stromal cells are fibroblasts. Fibroblasts can be reversibly activated to myofibroblasts during wound healing. Thereby they adopt a contractile, migratory and secretory phenotype. In cancer, the activation of fibroblasts is more stable and associated with an even stronger secretory phenotype, immunomodulatory properties and proliferation. These so-called cancer-associated fibroblasts (CAF) contribute to tumor progression by secreting extracellular matrix (ECM) molecules, cytokines and other tumor-promoting factors. The mortality of pancreatic cancer is nearly equal to its incidence mainly due to high resistance of these tumors against chemotherapy. In the last years, the massive stromal component was identified as a main cause of progression and resistance in pancreatic cancer. The accumulation and activation of fibroblasts, resulting in ECM deposition, is called desmoplasia. Additional to their contribution to cancer progression by secreting pro-tumorigenic factors, CAF shield the tumor from chemotherapeutics by increasing the interstitial fluid pressure, thereby decreasing the infiltration of drugs into the tumor resulting in resistance. Targeting the ECM could help to regain vascular homeostasis within tumors to improve the distribution of chemotherapy and in turn increase its therapeutic effect. We propose that SEMA3C, a member of the Semaphorin protein family, could be employed to interfere with desmoplasia. It has recently been described that increased SEMA3C expression correlates with enhanced tumor growth and metastasis in pancreatic ductal carcinoma (PDAC). Our preliminary data show that SEMA3C expression increases during fibrosis while expression of Furin proteases, which cleave SEMA3C, disappears. The Furin-cleaved SEMA3C-p60 isoform inhibits TGF-β-mediated myofibroblast transdifferentiation and fibrosis. SEMA3C represses TGF-β receptor II expression through PARP1.This project is aimed at better understanding how Semaphorin-3C contributes to fibroblast activation in pancreatic cancer and to develop preclinical strategies interfering with this. We will decipher how SEMA3C isoforms transmit signals in fibroblasts and how this affects their behavior. We have developed several tools to deliver SEMA3C-p60 into PDAC mouse models. This will allow analyzing its effects on tumor progression, tumor-associated desmoplasia, immunosuppression, delivery of chemotherapy and metastasis. In summary, we will obtain valuable information on how SEMA3C isoforms control tumor-associated desmoplasia to pave the way towards novel strategies interfering with the tumor stroma.

癌症研究主要集中在肿瘤细胞中，尽管肿瘤微环境调节的过程数量不断增加。这在胰腺癌中特别重要，其中间质区室占总肿瘤质量的高达90%。在这种特定的肿瘤中，大多数基质细胞是成纤维细胞。成纤维细胞在伤口愈合过程中可以可逆地活化成肌成纤维细胞。因此，它们采用收缩、迁移和分泌表型。在癌症中，成纤维细胞的活化更稳定，并且与甚至更强的分泌表型、免疫调节特性和增殖相关。这些所谓的癌症相关成纤维细胞（CAF）通过分泌细胞外基质（ECM）分子、细胞因子和其他肿瘤促进因子而促进肿瘤进展。胰腺癌的死亡率几乎等于其发病率，主要是由于这些肿瘤对化疗的高抗性。在过去的几年中，大量的基质成分被确定为胰腺癌进展和耐药的主要原因。成纤维细胞的积累和活化，导致ECM沉积，称为结缔组织增生。除了通过分泌促肿瘤发生因子对癌症进展的贡献外，CAF通过增加间质液压力来保护肿瘤免受化疗药物的影响，从而减少药物渗入肿瘤中导致耐药性。靶向ECM可以帮助恢复肿瘤内的血管稳态，以改善化疗的分布，从而提高其治疗效果。我们建议，SEMA 3C，Semaphorin蛋白家族的成员，可以用来干扰结缔组织增生。最近已经描述了增加的SEMA 3C表达与胰腺导管癌（PDAC）中增强的肿瘤生长和转移相关。我们的初步数据表明，SEMA 3C表达增加纤维化过程中，而弗林蛋白酶，裂解SEMA 3C的表达，消失。弗林蛋白酶切割的SEMA 3C-p60同种型抑制TGF-β介导的肌成纤维细胞转分化和纤维化。SEMA 3C通过PARP 1抑制TGF-β受体II的表达。本研究旨在更好地了解Semaphorin-3C在胰腺癌成纤维细胞活化中的作用，并开发临床前干预策略。我们将破译SEMA 3C亚型如何在成纤维细胞中传递信号，以及这如何影响它们的行为。我们已经开发了几种工具来将SEMA 3C-p60递送到PDAC小鼠模型中。这将允许分析其对肿瘤进展、肿瘤相关结缔组织增生、免疫抑制、化疗递送和转移的影响。总之，我们将获得关于SEMA 3C亚型如何控制肿瘤相关结缔组织增生的有价值的信息，为干扰肿瘤间质的新策略铺平道路。