MUC1 in Therapy Resistance

抽象的。胰腺癌是一种先天耐药的癌症，能够迅速获得 治疗后对治疗的额外抵抗力。我们和其他人已经证明了高水平的表达 对胰腺癌(和其他致命性癌症)的固有和获得性耐药。 治疗。MUC1在抵抗治疗中起关键作用的证据来自于对 不同肿瘤中的基因表达谱，以及许多实验敲除研究的结果，这些研究具有 研究表明，高水平的MUC1与对辐射、顺铂、雌激素受体靶点的抵抗有关， 来那度胺、紫杉醇、三苯氧胺、曲妥珠单抗、吉西他滨、FOLFIRINOX、依托泊苷等实验性药物 治疗多种癌症的药物，包括胰腺癌、乳腺癌、结直肠癌、胃癌、头颈部、肝细胞癌、非 小细胞肺癌、肾细胞癌和多种类型的癌症干细胞。已知MUC1会影响致癌作用 通过与信号效应器和转录的相互作用和影响来实现信号和转录程序 各种因素。我们与Pankaj Singh研究小组的合作表明，MUC1稳定并激活HIF-1a和 增加葡萄糖的摄取和代谢，并上调吉西他滨耐药细胞的MUC1和 缺氧诱导因子的稳定化诱导合成糖代谢使吉西他滨耐药 胰腺癌细胞。我们实验室的最新结果，如下所示，提供了具有挑衅性的数据。 结果表明：MUC1表达在肿瘤细胞来源的外切体上；MUC1表达的外切体来自于 肿瘤含有不同于不表达MUC1的外体的货物；MUC1衍生的外体是 被癌症相关的成纤维细胞、免疫细胞、其他肿瘤细胞和包括 胰腺癌转移前的利基。更多的数据表明，含有外切体的MUC1改变了 以促进原发和转移肿瘤生长的方式摄取它们的细胞的生物学特性 并增加在这些部位生长的肿瘤的耐药性。这就把我们带到了最重要的 本应用研究假设：胰腺癌细胞外切体诱导耐药 通过对肿瘤的代谢和功能特征进行重新编程来进行化疗和免疫治疗 原发灶和远处转移灶中的细胞、癌相关成纤维细胞和免疫细胞 网站。为了研究这一假说，我们提出了两个目标：特定的目标1.阐明 MUC1阳性外切体通过肿瘤细胞、癌症的重新编程而导致治疗抵抗 局部或转移部位的相关成纤维细胞和免疫细胞；特定目的2.评估表达 在配对的原发灶和转移灶中耐药的特征和途径 未治疗和治疗的患者(来自我们的组织核心)利用空间转录(单细胞RNAseq)和 通过执行多路免疫荧光。

Abstract. Pancreatic cancer arises as an innately therapy-resistant cancer that is capable of rapidly acquiring additional resistance to therapy upon treatment. We and others have demonstrated that high levels of expression of MUC1 contribute to both inherent and acquired resistance of pancreatic cancer (and other lethal cancers) to therapies. Evidence that MUC1 plays a critical role in resistance to therapy comes from unbiased analysis of gene expression profiles in different tumors, and results of many experimental knockdown studies, which have revealed that high levels of MUC1 are associated with resistance to radiation, cisplatin, estrogen receptor targets, lenalidomide, paclitaxel, tamoxifen, trastuzumab, gemcitabine, FOLFIRINOX, etoposide, and other experimental drugs in numerous cancers including pancreatic, breast, colorectal, gastric, head and neck, hepatocellular, non- small cell lung cancer, renal cell and multiple types of cancer stem cells. MUC1 is known to affect oncogenic signaling and transcriptional programs through interactions and effects with signaling effectors and transcription factors. Our collaboration with Pankaj Singh's group has shown that MUC1 stabilizes and activates HIF-1a and increases glucose uptake and metabolism, and that upregulation of MUC1 in Gemcitabine resistant cells and concomitant stabilization of HIF induces anabolic glucose metabolism to impart Gemcitabine resistance to pancreatic cancer cells. Recent results from our laboratory, presented below, have provided provocative data showing that: MUC1 is expressed on tumor cell derived exosomes; that MUC1 expressing exosomes from tumors contain cargoes distinct from exosomes that do not express MUC1; that MUC1 derived exosomes are selectively taken up by cancer associated fibroblasts, immune cells, other tumor cells and cells that comprise the premetastatic niche of pancreatic cancer. Additional data show that MUC1 containing exosomes alter the biological properties of cells that take them up in ways that enhance tumor growth at primary and metastatic sites, and increase drug resistance of tumors growing at those sites. This leads us to the Overarching Hypothesis for the studies in this application: Exosomes from pancreatic cancer cells induce resistance to chemotherapy and immunotherapy by reprogramming metabolic and functional features of tumor cells, cancer associated fibroblasts and immune cells in the primary tumor and at distant metastatic sites. To investigate this hypothesis, we propose two aims: Specific Aim 1. Elucidate the molecular features of MUC1 positive exosomes that cause therapy resistance through reprogramming of tumor cells, cancer associated fibroblasts, and immune cells at local or metastatic sites.; Specific Aim 2. Evaluate expression signatures and pathways of therapy resistance in matched sets of primary tumors and metastatic lesions from untreated and treated patients (from our tissue core) by utilizing spatial transcriptomics (single cell RNAseq) and by performing multiplexed immunofluorescence.