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.

项目总结 在美国，乳腺癌仍然是主要的死亡原因。在乳腺癌类型中，三阴性 乳腺癌(TNBC)因其生长迅速、侵袭性强、发生率高而被认为预后较差。 转移的可能性。此外，TNBC亚型比其他类型的乳腺癌更有可能复发。最新研究 支持肿瘤相关细胞外基质(ECM)作为癌症发生和复发的关键因素 机制。正常或致癌组织的细胞外基质由一种复杂的生物分子混合物组成，例如 ECM内的细胞外小泡称为基质结合纳米囊泡(MBV)。然而，肿瘤-- ECM、MBV及其在乳腺癌和TNBC发病机制中的作用仍知之甚少。 如果适当加工，细胞外基质可以用作天然衍生的生物材料，促进相关的 用于细胞和机制研究的微环境，具有安全的临床使用记录。组织特异性ECM 水凝胶是临床应用的理想选择，特别是考虑到开发精密工具的新需求。 医药。我们假设ECM(肿瘤或正常)内的细胞外小泡起致癌作用。 将调节细胞行为的种子将影响药物测试模型。这项提案旨在定义肿瘤是如何 基质ECM和相关的MBV组分影响TNBC中的Hedgehog途径，作为一种潜在的途径 为乳腺癌的药物测试治疗开发相关模型。此外，多样性提案还着眼于 加强候选人工作的临床相关性，为成为一名独立的研究人员铺平道路 在生物医学领域，同时确保在该机构的终身教职。在这个补充的多样性提案的结尾 根据PI的指导计划，候选人(教职员工)将获得癌症领域的出版物， 战略网络，并收集初步数据以支持R级赠款提交。