A tumor-mesenchymal in vitro model of Hedgehog signaling in triple negative breas

三阴性乳腺癌中 Hedgehog 信号传导的肿瘤间质体外模型

• 批准号: 8766873
• 负责人: Maribella Domenech
• 金额: $ 10.79万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-17 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766873
• 关键词: Address; Adipose tissue; Adjuvant Chemotherapy; Area; Biology; Biomedical Engineering; Biomedical Research; Bone Marrow Stem Cell; Breast Cancer Cell; Cancer Biology; Cancer Patient; Cancer cell line; Cells; Clinic; Clinical; Clinical Engineering; Collaborations; Companions; Complement; Comprehensive Cancer Center; Data; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease; Disease remission; Educational workshop; Engineering; Environment; Epidermal Growth Factor Receptor; Epithelial; Equipment; Erinaceidae; Estrogen Receptors; Evaluation; Faculty; Fibroblasts; Fingerprint; Gene Bank; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Growth; Human; In Vitro; Institution; Knowledge; Laboratory Research; Lead; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Medical; Mentors; Mesenchymal; Mesenchymal Cell Neoplasm; Mesenchymal Stem Cells; Mesenchyme; Microfluidic Microchips; Microfluidics; Minority; Modeling; Molecular; Molecular Profiling; Outcome Study; Patients; Physiology; Positioning Attribute; Predisposition; Process; Progesterone; Prognostic Marker; Puerto Rico; Regression Analysis; Relapse; Research; Research Activity; Research Personnel; Resistance; Role; Science; Signal Transduction; Source; Staging; Survival Rate; Technology; Therapeutic; Therapeutic Agents; Time; Tissue Sample; Tissues; Training; Tumor Tissue; Universities; Validation; Visit; Work; anticancer research; base; cancer risk; cancer therapy; career; cell growth; cell type; cellular targeting; conventional therapy; gene panel; graduate student; in vitro Model; inhibitor/antagonist; innovation; intercellular communication; laboratory facility; malignant breast neoplasm; meetings; member; mouse model; nanoparticle; neoplastic cell; novel; novel therapeutic intervention; outcome forecast; paracrine; predictive modeling; professor; progenitor; public health relevance; research study; response; smoothened signaling pathway; stem; symposium; translational medicine; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): The PI holds a tenure track faculty position at the University of Puerto Rico in Mayaguez (UPRM) since January 2013 and is a member (adjunct assistant investigator) of the University of Puerto Rico Comprehensive Cancer Center (UPRCCC). Through her research career in the biomedical engineering field, she gained expertise in developing microfluidic devices and nanoparticle technologies for the study of cell signaling networks and therapies relevant to the progression of cancer. The PI's long term goal is to become an independent investigator in the cancer research field and a leader in the development of in vitro tumor microenvironment models that advance the study of processes that lead to cancer progression and therapy resistance. As a young investigator in the biomedical engineering field, the PI wants to fill critical knowledge gaps in the area of the tumor microenvironment and clinical therapeutic approaches to contribute to the broader cancer research field as an independent research professor. To continue progress towards becoming an independent cancer researcher, the PI, mentor and co-mentor developed a comprehensive career training plan to expand the PI's knowledge in breast tissue physiology, tumor microenvironment and therapeutic strategies. The career training plan involves research studies of tumor microenvironment, development of collaborations among clinical and engineering researchers at the UPRCCC, guided visits to the cancer clinic and the establishment of an on-campus cancer niche composed by clinicians, biology and engineering researchers. Environment: The UPR is a minority research institution composed by 11 campuses including Medical Sciences campus and UPRCCC. As a full-time faculty member of the UPRM, the PI has the opportunity to participate in multi-disciplinary professional development opportunities, biomedical research seminars and interact with a pool of biomedical researchers supported through various research centers at UPRM and other campuses. As part of the PI's recruitment package, the UPRM provides academic release time, stipend for graduate students, a private office space, a research laboratory, materials and access to shared biomedical laboratory facilities. As member of the UPRCCC, the PI has access to research activities (conferences/symposiums, meeting) and use of facilities/equipment in the UPRCCC. The UPRCCC hosts seminars, research meetings and workshops which are focused on advances in cancer research and therapeutic approaches. Researchers at the UPRCCC have the opportunity to interact with a professional network composed by researchers and clinicians at local and partner clinical centers in the cancer field. Research: Triple negative breast cancer (TNBC) is a clinical therapeutic challenge due the lack of responsiveness to standard adjuvant chemotherapy. Hedgehog (Hh) Recent studies show that signaling correlates with reduced survival rates in TNBC patients and pharmacological inhibition significantly reduces growth and invasion suggesting a potential therapeutic value for Hh inhibitors. The main cellular target of Hh inhibitors is the adjacent mesenchyme which has shown to promote tumor growth via a paracrine interaction. The source of mesenchymal cells in breast cancer tissues is unknown, with myo-differentiated fibroblasts, mesenchymal stem cells, and tumor cells that undergo epithelial-mesenchymal transition as main alternatives. There is a gap in knowledge regarding the role of mesenchymal cells derived from various sources in the development, progression and response to therapy of TNBC and other cancers. The objective in this project is to develop a tumor-mesenchymal in vitro model to evaluate the role of active Hh signaling in mesenchymal cells from different sources on the progression of TNBC. We hypothesized that active Hh signaling in the mesenchyme promotes tumor growth and that this effect is dependent on the source of mesenchymal cells. This research is based upon our preliminary data and work of others showing co- expression of Hh signaling target genes and mesenchymal markers in TNBC and increase in tumor cell growth through active Hh signaling in the adjacent mesenchyme. To address our hypothesis the following specific aims are proposed: Specific Aim 1. Determine the influence of Hh signaling in mesenchymal cells derived from different sources in the expansion TNBC cells and Specific Aim 2. Establish a gene signature composed by mesenchymal and Hh signaling markers to identify disease stage and potential patient candidates for Hh inhibitors. In aim 1, we will develop a tumor-mesenchymal in vitro model combining up to 3 mesenchymal cell types with active Hh signaling in a multi-compartment microplatform. In aim 2, we will develop a preliminary Hh-mesenchymal gene signature using public gene banks of TNBC to establish correlation among breast cancer stage for validation in tumor tissue samples. The outcome of the studies proposed here will influence the development of novel therapeutic approaches directed at the tumor microenvironment as a complement to conventional therapies targeting the tumor cells. Overall, the proposed approach will significantly impact both the cancer biology and translational medicine field.

描述（由申请人提供）：PI自2013年1月起在Mayaguez的波多黎各大学（UPRM）担任终身教职，并且是波多黎各大学综合癌症中心（UPRCCC）的成员（兼职助理研究员）。通过她在生物医学工程领域的研究生涯，她获得了开发微流体设备和纳米颗粒技术的专业知识，用于研究与癌症进展相关的细胞信号网络和疗法。PI的长期目标是成为癌症研究领域的独立研究者，并成为体外肿瘤微环境模型开发的领导者，以促进对导致癌症进展和治疗耐药性的过程的研究。作为生物医学工程领域的年轻研究者，PI希望填补肿瘤领域的关键知识空白 微环境和临床治疗方法，以促进更广泛的癌症研究领域作为独立的研究教授。为了继续成为独立的癌症研究人员，PI，导师和共同导师制定了全面的职业培训计划，以扩大PI在乳腺组织生理学，肿瘤微环境和治疗策略方面的知识。职业培训计划涉及肿瘤微环境的研究，UPRCCC临床和工程研究人员之间的合作发展，癌症诊所的指导访问以及由临床医生，生物学和工程研究人员组成的校园癌症利基的建立。环境：UPR是一个少数民族研究机构，由11个校区组成，包括医学科学校区和UPRCCC。作为UPRM的全职教师，PI有机会参与多学科专业发展机会，生物医学研究研讨会，并与通过UPRM和其他校区的各种研究中心支持的生物医学研究人员进行互动。作为PI招聘计划的一部分，UPRM提供学术释放时间，研究生津贴，私人办公空间，研究实验室，材料和共享生物医学实验室设施。作为UPRCCC的成员，PI可以参加研究活动（会议/研讨会，会议）并使用UPRCCC的设施/设备。UPRCCC举办研讨会，研究会议和讲习班，重点是癌症研究和治疗方法的进展。UPRCCC的研究人员有机会与癌症领域当地和合作伙伴临床中心的研究人员和临床医生组成的专业网络进行互动。研究：三阴性乳腺癌（TNBC）是一个临床治疗挑战，由于缺乏对标准辅助化疗的反应。最近的研究表明，信号传导与TNBC患者的存活率降低相关，并且药理学抑制显著降低了生长和侵袭，这表明Hh抑制剂具有潜在的治疗价值。Hh的主要细胞靶点 抑制剂是邻近的间充质，其已显示通过旁分泌相互作用促进肿瘤生长。乳腺癌组织中间充质细胞的来源尚不清楚，肌分化成纤维细胞、间充质干细胞和经历上皮-间充质转化的肿瘤细胞是主要的替代物。关于来源于各种来源的间充质细胞在TNBC和其他癌症的发展、进展和对治疗的反应中的作用的知识存在差距。本研究的目的是建立一种肿瘤-间充质细胞体外模型，以评估不同来源间充质细胞中活跃的Hh信号传导在TNBC进展中的作用。我们假设间充质中活跃的Hh信号促进肿瘤生长，并且这种作用依赖于间充质细胞的来源。本研究基于我们的初步数据和其他人的工作，显示了Hh信号传导靶基因和间充质标志物在TNBC中的共表达，以及通过邻近间充质中的活性Hh信号传导增加肿瘤细胞生长。为了解决我们的假设，提出了以下具体目标：具体目标1。确定在扩增TNBC细胞和特异性Aim 2中来源于不同来源的间充质细胞中Hh信号传导的影响。建立由间充质和Hh信号传导标志物组成的基因签名，以鉴定疾病阶段和Hh抑制剂的潜在患者候选人。在目标1中，我们将开发一种肿瘤-间充质体外模型，该模型在多室微平台中将多达3种间充质细胞类型与活性Hh信号转导相结合。在目标2中，我们将使用TNBC的公共基因库开发初步的Hh-间充质基因签名，以建立乳腺癌阶段之间的相关性，用于在肿瘤组织样品中进行验证。本文提出的研究结果将影响针对肿瘤微环境的新型治疗方法的发展，作为对靶向肿瘤细胞的传统疗法的补充。总的来说，所提出的方法将对癌症生物学和转化医学领域产生重大影响。