Osteoclast-independent mechanisms of early-stage bone colonization of breast canc

乳腺癌早期骨定植的不依赖破骨细胞的机制

• 批准号: 9118111
• 负责人: Xiang Zhang
• 金额: $ 32.47万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118111
• 关键词: Accounting; Adherence; Adhesions; Affect; Biological; Biology; Blood Circulation; Bone Marrow; Bone Resorption; Breast; Breast Cancer Patient; Cancer Model; Cell membrane; Cells; Cessation of life; Clinical; Coculture Techniques; Competence; Complex; Data; Diagnosis; Disease Progression; Dissection; Excision; FRAP1 gene; Genetic; Genetic screening method; Goals; Growth; Health; Human; Incidence; Indolent; Isogenic transplantation; Knowledge; Lesion; Lytic Metastatic Lesion; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Messenger RNA; Metastatic Neoplasm to the Bone; Micrometastasis; Microscopic; Molecular; Mus; Neoplasm Metastasis; Organ; Osteoblasts; Osteoclasts; Osteolytic; Outcome; Pathway interactions; Patients; Play; Prevention; Primary Neoplasm; Process; Proteins; Publications; Recruitment Activity; Recurrence; Research; Residual Cancers; Resolution; Role; Signal Transduction; Signaling Molecule; Staging; Symptoms; System; Techniques; Testing; Therapeutic; Time; Translations; Work; Xenograft procedure; base; bone; bone cell; cancer cell; clinically significant; design; human disease; innovation; insight; limb bone; malignant breast neoplasm; mortality; mouse model; neoplastic cell; new therapeutic target; novel; outcome forecast; precursor cell; progenitor; targeted treatment; therapeutic target

DESCRIPTION (provided by applicant): Metastasis accounts for nearly all breast cancer-related deaths. Bone is the organ most frequently affected by breast cancer. In the clinically significant stage, bone metastasis is driven by a vicious cycle between cancer cells and osteoclasts (bone-resorbing cells). Our knowledge of this vicious cycle has vastly increased in recent years, and therapies targeting osteoclasts can often significantly delay the progression of disease. However, bone metastases still remain incurable. On the other hand, there is often a latency of years to decades before bone metastases become clinically detectable, suggesting that residual cancer cells can exist in bone or bone marrow for a protracted period of time without activating osteoclasts. We set out to discover osteoclast-independent mechanisms in early-stage bone colonization before the onset of the vicious cycle. Our preliminary data demonstrated that osteoblasts (bone-making cells) and their precursor cells constitute the microenvironment niche of microscopic bone metastases. The direct cell-cell contact between cancer cells and the "osteoblastic niche" is crucial for their proliferation. Further studies indicated that the re-activation of the mTOR pathway is a hallmark of bone metastasis initiation. We also obtained preliminary evidence suggesting that the activation of mTOR is mediated by the formation of adhesion junctions (AJs) between cancer cells and niche cells. Based on these findings, we hypothesize that the osteoblastic niche facilitates bone metastasis progression of breast cancer from single cells to multi-cell micrometastases by augmenting the activity of the mTOR pathway, possibly through signaling downstream of AJ complexes. To test this hypothesis, we will pursue two specific aims: 1) to determine the mechanism mediating the crosstalk between cancer cells and the osteo-blastic niche, which entails direct cell-cell contact and leads to the activation of mTOR signaling, and 2) to identify the downstream effectors of mTOR that drive metastasis initiation. Our work is innovative and feasible because it employs a novel technique that selectively delivers cancer cells into hind limb bones via the circulation. This approach enables swift inspection and robust quantification of bone micrometastases at a single-cell resolution, yet avoids caveats of other conventional approaches. Application of this technique to several cancer models resulted in indolent or dormant bone metastases that mimic human diseases. We will use this approach for xenograft and syngeneic transplantation of human and mouse cancer cells, respectively, and investigate the roles of AJs, the mTOR complexes, and their related signaling molecules in bone metastasis initiation. In addition, we also invented a 3D co-culture system that faithfully recapitulates many features of cancer-niche interaction, which will facilitate the dissection of molecular mechanisms and accelerate our examination of candidate mediators. The fulfillment of these aims will enable the design of targeted therapies to suppress or eradicate latent tumor cells, and reduce the incidence of overt bone metastasis-related symptoms and mortality.

描述（由申请人提供）：转移几乎解释了与乳腺癌相关的所有死亡。骨骼是受乳腺癌影响最常的器官。在临床意义的阶段，骨转移是由癌细胞和破骨细胞（骨变形细胞）之间的恶性循环驱动的。近年来，我们对这个恶性循环的了解大大增加了，针对破骨细胞的疗法通常会显着延迟疾病的进展。但是，骨转移仍然无法治愈。另一方面，几十年来通常有几年的潜伏期才能在临床上检测到，这表明残留的癌细胞可以在骨髓或骨髓中持久存在，而无需激活破骨细胞。我们着手在恶性循环发作之前发现早期骨定殖的破骨细胞独立的机制。我们的初步数据表明，成骨细胞（造骨细胞）及其前体细胞构成了微观环境的微观环境，是微观骨转移的。癌细胞与“成骨细胞生态位”之间的直接细胞 - 细胞接触对于它们的增殖至关重要。进一步的研究表明，MTOR途径的重新激活是骨转移开始的标志。我们还获得了初步证据，表明MTOR的激活是由癌细胞和小裂细胞之间的粘附连接（AJ）形成的。基于这些发现，我们假设成骨细胞的小裂促进了乳腺癌从单个细胞从单细胞到多细胞微晶的骨转移进展，这可能会通过AJ复合物下游的信号传导来增加MTOR途径的活性。为了检验这一假设，我们将追求两个具体的目的：1）确定介导癌细胞与骨叶片之间的串扰的机制，这需要直接的细胞接触，并导致MTOR信号传导激活2），以识别驱动Metastasis启动的下游效应器。我们的工作具有创新性和可行性，因为它采用了一种新颖的技术，该技术通过循环有选择地将癌细胞传递到后肢骨骼中。这种方法可以在单细胞分辨率下快速检查和稳健对骨微发生的定量，但避免了其他常规方法的警告。该技术在几种癌症模型中的应用导致模仿人类疾病的懒惰或休眠的骨转移。我们将分别使用这种方法来对人和小鼠癌细胞的异种移植，并研究AJS，MTOR复合物及其相关信号分子在骨转移开始中的作用。此外，我们还发明了一个3D共培养系统，该系统忠实地概括了许多癌症相互作用的特征，这将促进分子机制的解剖并加速我们对候选介体的检查。这些目标的实现将使靶向疗法的设计抑制或消除潜在的肿瘤细胞，并减少与明显的骨转移相关症状和死亡率的发生率。