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

尽管肿瘤微环境调控的过程在不断增加，但癌症研究主要集中在肿瘤细胞上。这在胰腺癌中尤其重要，因为间质室占肿瘤总质量的90%。在这种特殊的肿瘤中，大多数基质细胞是成纤维细胞。在伤口愈合过程中，成纤维细胞可被可逆地激活为肌成纤维细胞。因此，它们采用收缩、迁移和分泌型表型。在癌症中，成纤维细胞的激活更加稳定，并且与更强的分泌表型、免疫调节特性和增殖有关。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、细胞因子和其他促肿瘤因子来促进肿瘤的进展。胰腺癌的死亡率与发病率几乎相等，主要是由于这些肿瘤对化疗具有很高的耐药性。在过去的几年中，大量基质成分被确定为胰腺癌进展和耐药的主要原因。成纤维细胞的聚集和活化，导致ECM沉积，称为结缔组织增生。除了通过分泌促肿瘤因子促进癌症进展外，CAF还通过增加间质液压力来保护肿瘤免受化疗的影响，从而减少药物对肿瘤的浸润，从而导致耐药性。靶向ECM有助于恢复肿瘤内血管稳态，改善化疗的分布，从而提高其治疗效果。我们认为SEMA3C是信号蛋白家族的一员，可以用来干扰粘连形成。最近有研究表明，在胰导管癌（pancreatic ductal carcinoma， PDAC）中，SEMA3C表达的增加与肿瘤生长和转移的增强有关。我们的初步数据显示，SEMA3C在纤维化期间表达增加，而切割SEMA3C的Furin蛋白酶的表达消失。furin裂解的SEMA3C-p60亚型抑制TGF-β介导的肌成纤维细胞转分化和纤维化。SEMA3C通过PARP1抑制TGF-β受体II的表达。该项目旨在更好地了解Semaphorin-3C如何促进胰腺癌成纤维细胞的激活，并制定干预这一过程的临床前策略。我们将破译SEMA3C异构体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。我们开发了几种工具来将SEMA3C-p60传递到PDAC小鼠模型中。这将有助于分析其对肿瘤进展、肿瘤相关结缔组织形成、免疫抑制、化疗传递和转移的影响。总之，我们将获得关于SEMA3C亚型如何控制肿瘤相关的结缔组织形成的有价值的信息，从而为开发干扰肿瘤基质的新策略铺平道路。

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.