MUC1 in Therapy Resistance

MUC1 治疗耐药

• 批准号: 10518248
• 负责人: Michael A. Hollingsworth
• 金额: $ 33.23万
• 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/10518248
• 关键词: Affect; Biological; Breast; Cells; Cisplatin; Collaborations; Colorectal; Data; Distant; Drug resistance; Estrogen Receptors; Etoposide; Fibroblasts; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Head and neck structure; Immune; Immunofluorescence Immunologic; Immunotherapy; Laboratories; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Molecular; Mucin 1 protein; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; Paclitaxel; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Primary Neoplasm; Property; Radiation; Resistance; Role; Signal Transduction; Site; Stomach; Tamoxifen; Tissues; Tooth Cervix; Trastuzumab; Up-Regulation; cancer stem cell; cancer type; chemotherapy; exosome; gemcitabine; glucose metabolism; glucose uptake; kidney cell; knock-down; lenalidomide; neoplastic cell; pancreatic cancer cells; programs; refractory cancer; single-cell RNA sequencing; therapy resistant; transcription factor; transcriptomics; tumor; tumor growth

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.

摘要。胰腺癌是一种能够迅速获得的先天性治疗耐药癌症