MUC1 in Therapy Resistance

MUC1 治疗耐药

• 批准号: 10707543
• 负责人: Michael A. Hollingsworth
• 金额: $ 26.1万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707543
• 关键词: Affect; Apoptosis; Biological; Biological Products; Breast; Cells; Cisplatin; Collaborations; Colorectal; Data; Distant; Drug resistance; Estrogen Receptors; Etoposide; Fibroblasts; Future; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Genomics; Head and neck structure; Immune; Immunofluorescence Immunologic; Immunotherapy; Induction of Apoptosis; Inhibition of Apoptosis; Invaded; Laboratories; Location; Longevity; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator; Metabolic; Molecular; Molecular Target; Mucin 1 protein; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; Paclitaxel; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Primary Neoplasm; Process; Property; Radiation; Resistance; Role; Sampling; Signal Transduction; Site; Stomach; Tamoxifen; Techniques; Tissues; Trastuzumab; Up-Regulation; cancer stem cell; cancer type; cell motility; chemotherapy; exosome; gemcitabine; glucose metabolism; glucose uptake; insight; kidney cell; knock-down; lenalidomide; neoplastic cell; novel; pancreatic cancer cells; pancreatic cancer patients; programs; refractory cancer; single-cell RNA sequencing; therapy resistant; transcription factor; transcriptomics; translational study; tumor; tumor growth; tumor microenvironment; virtual

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.

抽象的。胰腺癌是一种天生具有治疗耐药性的癌症，能够迅速获得 治疗后对治疗产生额外的抵抗力。我们和其他人已经证明，高水平的表达 MUC1 有助于胰腺癌（和其他致命癌症）的固有和获得性耐药性 疗法。 MUC1 在治疗耐药性中发挥关键作用的证据来自对以下项目的公正分析： 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， 揭示高水平的 MUC1 与对辐射、顺铂、雌激素受体靶标的抵抗力相关， 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 多种癌症的药物，包括胰腺癌、乳腺癌、结直肠癌、胃癌、头颈癌、肝细胞癌、非 小细胞肺癌、肾细胞和多种癌症干细胞。已知 MUC1 会影响致癌性 通过与信号传导效应器和转录的相互作用和作用来实现信号传导和转录程序 因素。我们与 Pankaj Singh 团队的合作表明，MUC1 可以稳定并激活 HIF-1a， 增加葡萄糖摄取和代谢，并且吉西他滨耐药细胞中 MUC1 的上调和 HIF 的同时稳定会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，提供了具有争议性的数据 表明：MUC1 在肿瘤细胞来源的外泌体上表达；表达外泌体的MUC1 肿瘤含有与不表达 MUC1 的外泌体不同的货物； MUC1 衍生的外泌体是 被癌症相关的成纤维细胞、免疫细胞、其他肿瘤细胞和包含以下成分的细胞选择性吸收 胰腺癌的转移前生态位。额外的数据表明，含有外泌体的 MUC1 改变了 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 位点，并增加在这些位点生长的肿瘤的耐药性。这引导我们走向总体 本申请研究的假设：胰腺癌细胞的外泌体诱导耐药性 通过重新编程肿瘤的代谢和功能特征来进行化疗和免疫治疗 原发肿瘤和远处转移中的细胞、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 MUC1阳性外泌体通过肿瘤细胞、癌症的重编程导致治疗抵抗 局部或转移部位的相关成纤维细胞和免疫细胞。具体目标 2. 评估表达 匹配的原发性肿瘤和转移性病变组中的治疗耐药性特征和途径 利用空间转录组学（单细胞 RNAseq）对未经治疗和已治疗的患者（来自我们的组织核心）进行分析 通过进行多重免疫荧光。