MUC1 in Therapy Resistance

抽象的。胰腺癌是一种先天性的治疗抗性癌症，能够迅速获得 治疗后对治疗的额外抵抗。我们和其他人已经证明了高水平的表达 MUC1的表达有助于胰腺癌（和其他致命癌症）对 治疗MUC1在对治疗的抵抗中起关键作用的证据来自对MUC1的无偏分析。 不同肿瘤中的基因表达谱，以及许多实验性敲除研究的结果， 揭示了高水平的MUC1与对放射、顺铂、雌激素受体靶点的抗性有关， 来那度胺、紫杉醇、他莫昔芬、曲妥珠单抗、吉西他滨、FOLFIRINOX、依托泊苷和其他实验性 在许多癌症中的药物，包括胰腺癌、乳腺癌、结肠直肠癌、胃癌、头颈部癌、肝细胞癌、非 小细胞肺癌、肾细胞癌和多种癌症干细胞。已知MUC1影响致癌基因 通过与信号传导效应子和转录的相互作用和效应的信号传导和转录程序 因素我们与Pankaj Singh小组的合作表明，MUC1稳定并激活HIF-1a， 增加葡萄糖摄取和代谢，以及吉西他滨抗性细胞中MUC1的上调， HIF的同时稳定诱导合成代谢葡萄糖代谢，从而赋予吉西他滨耐药性， 胰腺癌细胞我们实验室的最新结果，如下所示，提供了令人鼓舞的数据 显示：MUC1在肿瘤细胞来源的外泌体上表达;来自肿瘤细胞的表达MUC1的外泌体 肿瘤含有与不表达MUC1的外来体不同的货物; MUC1衍生的外来体是 选择性地被癌症相关的成纤维细胞、免疫细胞、其他肿瘤细胞和包含以下的细胞摄取： 胰腺癌的转移前小生境。额外的数据显示，含有MUC1的外来体改变了细胞的增殖。 细胞的生物学特性，以增强原发性和转移性肿瘤生长的方式吸收它们 在这些部位生长，并增加肿瘤的耐药性。这把我们带到了 本申请研究的假设：来自胰腺癌细胞的外泌体诱导耐药性 通过重编程肿瘤的代谢和功能特征， 原发性肿瘤和远处转移瘤中的细胞、癌症相关成纤维细胞和免疫细胞 网站.为了研究这一假设，我们提出了两个目标：具体目标1。阐明了 MUC1阳性外泌体通过肿瘤细胞的重编程引起治疗抗性，癌症 相关的成纤维细胞和局部或转移部位的免疫细胞。具体目标2。计算表达式的值 原发性肿瘤和转移性病变的匹配组中的治疗抗性的特征和途径， 未治疗和治疗的患者（来自我们的组织核心）通过利用空间转录组学（单细胞RNAseq）， 通过多重免疫荧光。

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.