Mechano-sensing stem cells to study, detect and treat cancer metastases

描述(申请人提供)：超过90%的乳腺癌死亡是由转移引起的，然而目前没有直接针对转移癌的治疗方法。转移性乳腺癌患者几十年的治疗结果一直很黯淡，研究表明存活率仅略有增加，这往往伴随着全身化疗的严重副作用。最近的研究表明，细胞微环境的力学特性(机械生态位)，特别是刚性，与乳腺癌的转移密切相关。具体地说，人们已经注意到，乳腺癌会将酶(赖氨酸氧化酶)分泌到循环系统中，使胶原蛋白交联，并增加在肺转移发生的区域积累的组织的硬度。此外，当间充质干细胞(MSCs)被注入血液中时，可以主动和选择性地定位于乳腺癌转移，它们的分化受到硬质干细胞的严格调控。 当地环境。鉴于组织硬度与乳腺癌转移和MSC分化的密切相关，我建议开发一种机械反应细胞系统(MRCS)，以直接针对乳腺癌转移的机械环境线索，以定位和特异性地递送诊断报告和抗肿瘤药物。该项目将涉及1)通过识别和克隆骨髓间充质干细胞中的僵硬特异性启动子来建立MRCS。这些启动子可用于驱动成像探针和治疗药物的表达，2)测试MRCS在体内检测癌症转移和测量转移生态位硬度的能力，以及3)通过治疗药物的特异性和局部激活，在体内使用MRCS治疗乳腺癌肺转移。在完成上述目标后，我们将创建第一个直接询问基质刚性的治疗系统，并将其应用于乳腺癌转移的局部给药。该系统对提高超过15万美国转移性乳腺癌患者的治疗效果，同时改善全身化疗的相关症状具有重要的临床意义。重要的是，拟议的MRCS将成为未来应用于针对潜在任何类型癌症转移的异常组织僵硬的治疗的平台技术。此外，我们的MRCS有可能成为诊断微转移和监测高危患者组治疗的常规做法。此外，用于原位测量基质机械性能的基于细胞的硬度传感器的产生将代表一种范式转换方法，动态询问原发肿瘤、转移瘤的机械环境，以及在疾病进展和体内细胞分辨率的治疗反应期间基质硬度的变化。

DESCRIPTION (provided by applicant): Metastasis is responsible for over 90% of breast cancer deaths, however no current treatments directly target metastatic cancer. Results from decades of treatment of metastatic breast cancer patients has been bleak, with studies indicating only slight increases in survival which is often accompanied by the severe side effects of systemic chemotherapy. Recent studies have revealed that the mechanical properties of cellular microenvironments (mechano-niche), specifically stiffness, have a close relation with breast cancer metastasis. Specifically, it has been noted that the breast tumor secretes enzymes (lysyl oxidase) into the circulatory system that crosslink collagens and increase the stiffness of tissues accumulate at areas in the lung where metastases occur. Additionally, mesenchymal stem cells (MSCs) can actively and selectively home to breast cancer metastases when injected into the blood and their differentiation is tightly regulated by the stiffness of the local environment. In light of the tight correlation between tissue stiffness with breast cancer metastasis and MSC differentiation, I propose to develop a mechanoresponsive cell system (MRCS) to directly target the mechano-environmental cues of breast cancer metastases for localized and specific delivery of diagnostic reporters and anti-tumor agents. The project will involve 1) establishing the MRCS by identifying and cloning stiffness-specific promoters in MSCs. These promoters can be used to drive expression of imaging probes and therapeutics, 2) testing the ability of MRCS to detect cancer metastases and measure stiffness in metastatic niche in vivo, and 3) treating breast cancer lung metastases in vivo using MRCS through specific and local activation of therapeutics. Upon accomplishing the above goals, we will have created the first therapeutic system to directly interrogate matrix stiffness and applied it to localized delivery of agents to breast cancer metastases. This system has major clinical implications in increasing the effectiveness of therapies for the over 150,000 Americans living with metastatic breast cancer while also ameliorating the symptoms associated with systemic chemotherapy. Importantly, the proposed MRCS will serve as a platform technology for future application to therapies targeting aberrant tissue stiffness in potentially any types of cancer metastasis. Additionally, our MRCS has the potential to become a routine practice for diagnosis of micrometastases and for monitoring treatment in high-risk patient groups. Furthermore, generation of a cell-based stiffness sensor for measurement of matrix mechanical properties in situ will represent a paradigm-shifting method of dynamically interrogating the mechano-environment of primary tumors, metastases, and changes in matrix stiffness during disease progression and response to therapies at a cellular resolution in vivo.