Distinct contributions of mesenchymal cell niches in the therapeutic potential of the hedgehog pathway in triple negative breast cancer

间充质细胞生态位对三阴性乳腺癌刺猬通路治疗潜力的独特贡献

• 批准号: 10641327
• 负责人: Maribella Domenech
• 金额: $ 15.21万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641327
• 关键词: Biocompatible Materials; Cause of Death; Cells; Clinical; Complex Mixtures; Data; Development; Drug Modelings; Drug usage; Erinaceidae; Extracellular Matrix; Faculty; Grant; Hydrogels; Institution; Malignant Neoplasms; Mentors; Mesenchymal; Modeling; Neoplasm Metastasis; Oncogenic; Pathway interactions; Process; Prognosis; Public Health; Publications; Relapse; Research; Research Personnel; Route; Sampling; Secure; Seeds; Therapeutic; Tissues; Work; cancer subtypes; cancer type; cell behavior; clinical application; clinically relevant; drug testing; extracellular vesicles; malignant breast neoplasm; mimetics; nanovesicle; precision medicine; rapid growth; tool; triple-negative invasive breast carcinoma; tumor; tumorigenic

PROJECT SUMMARY Breast cancer remains a leading cause of death in the US. Among the breast cancer types, triple-negative breast cancer (TNBC) is considered to have a poorer prognosis due to its rapid growth, invasiveness, and rate of metastasis. Also, the TNBC subtype is more likely to relapse than other types of breast cancer. Recent studies support the tumor-associated extracellular matrix (ECM) as a critical factor in cancer development and relapse mechanisms. The ECM of normal or tumorigenic tissue comprises a complex mixture of biomolecules, such as the extracellular vesicles within the ECM known as the matrix-bound nanovesicles (MBVs). However, tumor- ECM, MBVs and their impact on the mechanism of breast cancer and TNBC remain poorly understood. ECMs, if appropriately processed, can be used as naturally derived biomaterials that promote a relevant microenvironment for cell and mechanistic research with a safe record of clinical use. Tissue-specific ECM hydrogels are ideal for clinical application, particularly given the emerging need to develop tools for precision medicine. We hypothesize that extracellular vesicles within the ECM (tumor or normal) work as an oncogenic seed that will modulate cellular behavior impacting drug test models. This proposal aims to define how tumor and stromal ECM and associated MBV components impact the Hedgehog pathway in TNBC as a potential route to develop relevant models for drug-testing treatments in breast cancer. Also, the diversity proposal looks to strengthen the clinical relevancy of the candidate's work, paving the way to become an independent investigator in the biomedical field while securing tenure in the institution. At the end of this supplemental diversity proposal and under the PI's mentoring plan, the candidate (faculty) will obtain publications in the field of cancer, build strategic networking, and gather preliminary data to support R-level grant submission.

项目摘要 在美国，乳腺癌仍然是死亡的主要原因。在乳腺癌类型中，三阴性 乳腺癌（TNBC）由于其快速生长，侵入性和速度而被认为预后较差 转移。同样，TNBC亚型比其他类型的乳腺癌更可能复发。最近的研究 支持与肿瘤相关的细胞外基质（ECM）作为癌症发展和复发的关键因素 机制。正常或肿瘤组织的ECM包括生物分子的复杂混合物，例如 ECM中的细胞外囊泡被称为基质结合的纳米植物（MBV）。但是，肿瘤 - ECM，MBV及其对乳腺癌和TNBC机制的影响仍然鲜为人知。 ECMS，如果经过适当处理，可以用作自然衍生的生物材料，以促进相关性 用于临床使用的安全记录的细胞和机械研究的微环境。组织特异性ECM 水凝胶是临床应用的理想选择，尤其是考虑到新兴需要开发精确的工具 药品。我们假设ECM内的细胞外囊泡（肿瘤或正常）充当致癌 将调节细胞行为影响药物测试模型的种子。该建议旨在定义肿瘤如何 以及基质ECM和相关的MBV组件影响TNBC中的刺猬途径 开发用于乳腺癌药物治疗的相关模型。另外，多样性提案看起来 加强候选人工作的临床相关性，为成为独立研究者的方式铺平了道路 在生物医学领域确保该机构的任期。在此补充多样性提案的结尾 根据PI的指导计划，候选人（教职员工）将在癌症领域获得出版物，建造 战略网络，并收集初步数据以支持R级赠款提交。