Role of Cyr61/CCN1 in Pancreatic Cancer Progression and Therapy

 描述（由申请人提供）： 胰腺导管腺癌是胰腺最常见的恶性肿瘤。它是一种高度致命的疾病，是美国癌症死亡的第四大原因。只有不到5%的PC使用者寿命不超过5年。其具有如此差的预后的主要原因之一是大多数患者在诊断时已经具有转移，并且转移使得PC对包括吉西他滨（GEM）的许多化疗药物不敏感。因此，迫切需要新的方法来防治这种疾病。我们发现Cyr 61/CCN 1是一种细胞外蛋白，在PC细胞和标本中过表达，其表达与疾病进展和耐药性相关。此外，Cyr 61激活PC细胞和基质细胞中的音刺猬（SHh）信号传导、结缔组织生长因子（CTGF）、突变体K-Ras及其激活因子MAZ/SAF-1-转录因子，所有这些都有助于PC的发展以及耐药性。基于这些令人兴奋的初步发现，我们现在建议使用基因工程细胞系，基因工程小鼠模型（GEMM）沿着与最先进的技术，以解开如果阻断Cyr 61可以抑制PC的生长和药物致敏通过阻断促纤维增生反应在PC。 我们提出了三个目标来检验假设。在目的1中，我们将探索Cyr 61在K-Rasmut介导的PC的发展和进展中的作用，使用GEMM和基因工程PC细胞系的原位移植。在目标2中，我们将研究Cyr 61信号传导是否对维持PC起始细胞（PIC）/干细胞（PSC）的干细胞性和致瘤活性至关重要，并剖析执行这些事件所需的Cyr 61下游信号传导途径。最后，在目标3中，我们将确定Cyr 61在GEMM和原位模型中PC生长期间纤维组织生长（结缔组织增生）中的作用。为了测试目标，我们已经标准化了SCID小鼠模型中原位人胰腺癌异种移植物的使用，使用超声引导的PC细胞注射到胰腺和高分辨率成像技术。这些技术已经揭示了这种致命疾病进展的许多步骤，它们将与我们多学科合作团队的独特专业知识一起沿着使用，以探索Cyr 61在胰腺癌发生中的作用。 总的来说，这些发现将提供Cyr 61的基本功能的知识，不仅在PC的发展，而且在肿瘤间质相互作用的促纤维增生反应的发展的关键作用。这些知识将允许解剖这些重要事件背后的分子机制。此外，这些研究将直接表明，Cyr 61信号转导的中断将是一个新的治疗策略，对PC。

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PC) is the most common malignant disease in the human pancreas. It is a highly lethal disease and the fourth leading cause of cancer deaths in the US. Fewer than 5% of people with PC live no longer than five years. One of the main reasons it has such a poor prognosis is that the majority of patients already have metastasis at the time of diagnosis, and metastasis makes PC insensitive to many chemotherapeutic drugs including gemcitabine (GEM). Thus, new ways to combat this disease are urgently needed. We discovered that Cyr61/CCN1, an extracellular protein, is overexpressed in PC cells and specimens, and its expression is correlated with disease progression and drug resistance. Moreover, Cyr61 activates sonic hedgehog (SHh) signaling, connective tissue growth factor (CTGF), mutants K-Ras and its activator MAZ/SAF-1-transcription factor in PC cells and stromal cells, all of which contribute to the development of PC as well as drug resistance. Based on these exciting preliminary findings, we now propose to use genetically engineered cell lines, genetically engineered mouse models (GEMMs) along with state-of- the-art technology to unravel if blocking Cyr61 could inhibit PC growth and drug sensitization via blocking desmoplastic reaction in PC. We propose three aims to test the hypothesis. In Aim 1, we will explore the role of Cyr61 in K-Rasmut mediated PC development and progression using GEMMs and orthotopic transplants of genetically engineered PC cell lines. In Aim 2, we will examine whether Cyr61 signaling is crucial to maintain stemness and tumorigenic activity of PC-initiating cells (PICs)/stem cells (PSCs) and dissect the down-stream signaling pathway of Cyr61 required to perform these events. Lastly, in Aim 3 we will determine the role of Cyr61 in growth of fibrous tissue (desmoplasia) during PC growth in GEMMs and orthotopic models. To test the aims, we have already standardized the use of an orthotopic human pancreatic cancer xenograft in a SCID mouse model using ultrasound guided injection of PC cells into the pancreas and high resolution imaging techniques. These techniques have already revealed many steps of the progression of this deadly disease, and they will be used along with the unique expertise of our multi-disciplinary collaborative team to explore the role of Cyr61 in pancreatic carcinogenesis. Collectively, these findings will provide knowledge of the essential functions of Cyr61, not only in development of PC, but also the critical role in tumor-stromal interactions for the development of desmoplastic reaction. This knowledge will allow dissection of the molecular mechanisms behind these vital events. Moreover, these studies will directly indicate that disruption of Cyr61-signaling would be a new therapeutic strategy against PC.