The TGF-Beta/MUC4 Signaling Axis in Circulating Tumor Cells of Metastatic Breast Cancer

转移性乳腺癌循环肿瘤细胞中的 TGF-β/MUC4 信号轴

基本信息

批准号：
10751169
负责人：
Savannah R Free
金额：
$ 4.03万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751169
关键词：
Affect Anoikis Apical Apoptosis Automobile Driving Behavior Binding Biochemical Biological Assay Blood Circulation Blood Platelets Breast Breast Cancer Cell Breast Cancer Treatment Breast Cancer cell line Breast cancer metastasis Cell Communication Cell Survival Cells Cessation of life Chemicals Circulation Development Disease Distant Metastasis ERBB2 gene Epidermal Growth Factor Epithelial Cells Face Feedback Gene Expression Genes Genetic Transcription Glycoproteins Goals Immune In Vitro Intervention Link Lubricants Maintenance Mediating Mediator Membrane Glycoproteins Metastatic breast cancer Methods Modeling Molecular Morphology Mucins Neoplasm Circulating Cells Neoplasm Metastasis Outcome P-Selectin Patient-Focused Outcomes Patients Platelet Activation Platelet aggregation Play Prevention Primary Neoplasm Proteins Publishing Regulation Research Resistance Role Signal Transduction Surface Survival Rate Tail Techniques Testing Therapeutic Intervention Transcript Transforming Growth Factor beta Tumor Promotion Up-Regulation Veins cell behavior epithelial to mesenchymal transition glycosylation improved in vivo in vivo Model malignant breast neoplasm mouse model neoplastic cell new therapeutic target novel receptor recruit standard of care success tumor tumor xenograft

项目摘要

PROJECT SUMMARY Metastasis is responsible for the majority of breast cancer deaths, and standard-of-care treatments fail to effectively target metastasizing cells. Circulating tumor cells (CTCs) in the bloodstream rely on the physical protection and chemical signals of platelets to survive and seed metastatic lesions. One such chemical signal is transforming growth factor beta (TGF-β), which, after secretion by platelets, has been shown to modulate CTC gene expression and behavior. TGF-β has also been shown to upregulate expression of the cell-surface glycoprotein Mucin-4 (MUC4) in various cellular contexts. MUC4 has been implicated in tumor development and maintenance and was recently observed to contribute to platelet-CTC interactions. This raises the question of whether platelet-secreted TGF-β may be upregulating CTC-MUC4, enhancing platelet-CTC interaction and generating a positive feedback loop. The hypothesis driving the proposed studies is that platelet-TGF-β upregulates CTC-MUC4, reinforcing CTC-platelet binding and enhancing metastatic cell survival. Specific Aim 1 will determine the effects of platelet-derived TGF-β on tumor cell MUC4 expression using cellular, molecular, and biochemical techniques, and assess MUC4-dependent cellular aggressiveness in vitro. Specific Aim 2 will characterize the role of MUC4 in platelet-tumor cell interactions using in vitro binding assays. Specific Aim 3 will assess the effects of platelet-TGF-β and CTC-MUC4 crosstalk in vivo using tail vein and orthotopic xenograft tumor mouse models of metastasis. Successful completion of this research will reveal a novel form of platelet- CTC crosstalk, exposing an important means by which metastasizing cells survive and illuminating a potential new therapeutic target for breast cancer metastatic prevention.

项目摘要转移造成大多数乳腺癌死亡，并且护理标准治疗未能有效靶向转移细胞。血液中循环肿瘤细胞（CTC）依赖于物理血小板的保护和化学信号生存和种子转移性病变。一个这样的化学信号是转化生长因子β（TGF-β），血小板分泌后，已被证明调节CTC 基因表达和行为。 TGF-β也已显示出上调细胞表面的表达糖蛋白粘蛋白-4（MUC4）在各种细胞环境中。 MUC4已在肿瘤发育和维护，最近观察到有助于血小板-CTC相互作用。这提出了一个问题血小板分泌的TGF-β是否可以上调CTC-MUC4，增强了血小板-CTC相互作用和产生积极的反馈循环。推动拟议研究的假设是血小板-TGF-β 上调CTC-MUC4，增强CTC-Allet结合并增强转移性细胞存活。具体目标1 将确定血小板衍生的TGF-β对使用细胞，分子，和生化技术，并在体外评估MUC4依赖性细胞攻击性。具体目标2将使用体外结合测定法表征MUC4在血小板肿瘤细胞相互作用中的作用。具体的目标3将使用尾静脉和原位异种移植物在体内评估血小板-TGF-β和CTC-MUC4串扰的影响转移的肿瘤小鼠模型。这项研究的成功完成将揭示一种新型的血小板形式 CTC串扰，暴露了转移细胞生存并照亮电势的重要手段乳腺癌转移性预防的新治疗靶点。