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

• 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
• 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

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.

项目总结 转移是导致大多数乳腺癌死亡的原因，而标准护理治疗未能 有效靶向转移细胞。血液中的循环肿瘤细胞(CTCs)依赖于 保护和化学信号的血小板存活和种子转移病变。一种这样的化学信号是 转化生长因子-β(转化生长因子-β)，经血小板分泌后，已被证明能调节CTC 基因表达和行为。转化生长因子-β也被证明可以上调细胞表面的表达。 糖蛋白粘蛋白-4(MUC4)在不同的细胞环境中。MUC4与肿瘤的发生和发展有关 维持，最近被观察到促进了血小板-CTC的相互作用。这就提出了一个问题： 血小板分泌的转化生长因子-β是否上调CTC-MUC4，增强血小板与CTC的相互作用 产生正反馈循环。推动这项研究的假设是血小板-转化生长因子-β 上调CTC-MUC4，增强CTC-血小板结合，提高转移细胞存活率。具体目标1 将利用细胞、分子和分子水平确定血小板衍生的转化生长因子-β对肿瘤细胞MUC4表达的影响， 和生化技术，并在体外评估MUC4依赖的细胞侵袭力。特定目标2将 用体外结合实验研究MUC4在血小板-肿瘤细胞相互作用中的作用。具体目标3将 利用尾静脉和异种原位移植评价血小板转化生长因子-β和CTC-MUC4的体内串扰效应 小鼠肿瘤转移模型的建立。这项研究的成功完成将揭示一种新的血小板形式-- CTC串扰，揭示了转移细胞存活的重要手段，并照亮了潜在的 预防乳腺癌转移的新治疗靶点。