MUC1 enhances Neuropilin-1 signaling in pancreatic ductal adenocarcinoma

描述（由申请人提供）：胰腺癌（PC）是一种高度转移的疾病，几乎没有有效的治疗选择。MUC1是一种糖蛋白，在超过60%的PC和100%的PC转移中过度表达和异常糖基化。肿瘤相关MUC1是侵袭性表型的标志，因为其表达与高转移和不良预后相关。我们最近发现，与没有或低MUC1的PDA相比，表达高MUC1的胰腺癌细胞和肿瘤的VEGFA共受体neuropilin-1 （nlp -1）水平升高。NRP-1增强VEGF受体信号传导和促血管生成活性。这可能表明肿瘤内血管生成和疾病进展增强。然而，许多靶向血管生成的药物产生了严重的副作用，包括高血压、血栓形成事件和过敏反应。此外，人们普遍认为药物递送到胰腺是困难的，因为PC具有高度的结缔组织可塑性和致密的间质。因此，我们假设MUC1通过增加NRP-1水平和随后的VEGFA信号传导诱导促血管生成肿瘤微环境。这可能是与MUC1相关的高转移性和侵袭性肿瘤表型的主要原因。其次，我们假设阻断肿瘤微环境中VEGF165与NRP-1之间的相互作用将带来治疗益处。因此，我们将首先研究MUC1+ PDA细胞在体外以依赖于nrp -1的方式对内皮细胞功能的影响。其次，我们将确定MUC1是否通过上调NRP-1和VEGF信号在体内产生促血管生成生态位。最后，我们将使用一种新型MUC1抗体将VEGF165-NRP-1抑制肽直接递送到表达MUC1的胰腺肿瘤微环境中，以传递肽阻断剂。我们建议使用合适的PDA小鼠模型来研究体内血管生成和药物传递。在这些小鼠中，胰腺肿瘤发生在胰腺内，再现了人类疾病，通过胰腺上皮内瘤变（PanINs）病变的全谱进展为浸润性腺癌并转移。这些小鼠要么表达人MUC1 (KCM)，要么表达MUC1 （KCKO）为零。通过使用这些小鼠模型，我们将能够在适当的环境下评估血管生成开关，其中包括胰腺的致密基质成分。此外，KCM小鼠的使用将使我们的结果具有高度可翻译性，因为我们能够测试我们针对人类MUC1的治疗方法。我们认识到，这种使用MUC1抗体的靶向递送从未尝试过，但如果成功，它将彻底改变小分子和肽递送到胰腺的方式，而不会产生不必要的副作用。如果获得资助，该地区的资助将保证PI实验室的强大研究环境，并将改善整体研究环境，有助于吸引最优质的学生，这对主要研究机构的成功发展至关重要。

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is a highly metastatic disease with few effective treatment options. MUC1 is a glycoprotein that is over-expressed and aberrantly glycosylated in over 60% of PC and 100% of PC metastases. Tumor-associated MUC1 is a marker of an aggressive phenotype, as its expression is correlated with high metastases and poor prognosis. We have recently found that pancreatic cancer cells and tumors expressing high MUC1 have increased levels of neuropilin-1 (NRP-1), a co-receptor of VEGFA as compared to PDA with no or low MUC1. NRP-1 potentiates VEGF receptor signaling and pro-angiogenic activities. This may be indicative of enhanced intra-tumoral angiogenesis and disease progression. However, many drugs targeting angiogenesis have produced serious side effects, including hypertension, thrombotic events, and allergic reactions. Additionally, it i well accepted that drug delivery into the pancreas is difficult, as PC is highly desmoplastic with dense stroma. Thus, we hypothesize that MUC1 induces a pro-angiogenic tumor microenvironment by increasing levels of NRP-1 and subsequent VEGFA signaling. This may be the leading cause for the highly metastatic and aggressive tumor phenotype associated with MUC1. Second, we hypothesize that blocking the interaction between VEGF165 and NRP-1 within the tumor microenvironment will lead to therapeutic benefit. We will therefore first aim to study the effects of MUC1+ PDA cells on endothelial cell function in an NRP-1-dependent fashion in vitro. Second, we will determine if MUC1 creates a pro-angiogenic niche in vivo by up-regulating NRP-1 and VEGF signaling. Finally, we will deliver a VEGF165-NRP-1 inhibitory peptide directly to the MUC1-expressing pancreatic tumor microenvironment using a novel MUC1 antibody to deliver the peptide blocker. We propose to use appropriate PDA mouse models to study in vivo angiogenesis and drug delivery. In these mice, pancreatic tumors occur within the pancreas and recapitulate the human disease, progressing through the full spectrum of pancreatic intraepithelial neoplasia (PanINs) lesions to invasive adenocarcinoma with metastases. These mice either express human MUC1 (KCM) or are null for Muc1 (KCKO). By using these mouse models, we will be able to evaluate angiogenesis switch in an appropriate setting which will include the dense stromal component of the pancreas. Further, the use of the KCM mice will render our results highly translatable, as we are able to test our therapy targeting human MUC1. We recognize that such targeted delivery using a MUC1 antibody has never been attempted but if this works, it will revolutionize the way small molecules and peptides are delivered to the pancreas without unwanted side effects. If funded, this AREA grant will guarantee a strong research environment in the PI's lab, and will enhance the overall research environment that will help draw in the highest quality students, which is critical to successful development of a major research institution.