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: 8670428
• 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/8670428
• 关键词: Accounting; Adherence; Adhesions; Affect; Biological; Biology; Blood Circulation; Bone Marrow; Bone Resorption; Breast; Cancer Model; Cancer Patient; Cell membrane; Cells; Cessation of life; Clinical; Coculture Techniques; Commit; Competence; Complex; Data; Diagnosis; Disease Progression; Dissection; Excision; Genetic; Genetic screening method; Goals; Growth; Growth Factor; 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 FRAP1 protein; human disease; innovation; insight; limb bone; malignant breast neoplasm; mortality; mouse model; neoplastic cell; new therapeutic target; novel; outcome forecast; precursor cell; progenitor; public health relevance; therapeutic target

Project Summary 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 prelimi- nary data demonstrated that osteoblasts (bone-making cells) and their precursor cells constitute the microenvi- ronment niche of microscopic bone metastases. The direct cell-cell contact between cancer cells and the "os- teoblastic 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 progres- sion 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 iden- tify the downstream effectors of mTOR that drive metastasis initiation. Our work is innovative and feasible be- cause 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 reso- lution, 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 ap- proach for xenograft and syngeneic transplantation of human and mouse cancer cells, respectively, and inves- tigate the roles of AJs, the mTOR complexes, and their related signaling molecules in bone metastasis initia- tion. 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.

项目摘要 转移几乎占与乳腺癌相关的所有死亡。骨骼是最常受到的器官 乳腺癌。在临床意义的阶段，骨转移是由癌症之间的恶性循环驱动的 细胞和破骨细胞（骨呈现细胞）。我们对这个恶性循环的了解已大大增加了 几年，靶向破骨细胞的疗法通常会显着延迟疾病的进展。然而， 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 骨转移在临床上可以检测到，这表明残留的癌细胞可以存在于骨头或骨骼中 骨髓在旷日持久的时间内，没有激活破骨细胞。我们着手发现破骨细胞 - 在恶性循环发作之前，早期骨定殖的独立机制。我们的预赛 NARY数据表明，成骨细胞（造骨细胞）及其前体细胞构成了微烯。 显微镜骨转移的ronment小境。癌细胞与“ OS-之间的直接细胞 - 细胞接触 teoblastic的利基”对于它们的增殖至关重要。进一步的研究表明，MTOR的重新激活 途径是骨转移开始的标志。我们还获得了初步证据，表明 MTOR的激活是由癌细胞与细分市场之间形成粘附连接（AJ）的介导的 细胞。基于这些发现，我们假设成骨细胞的利基促进了骨转移的前体 - 通过增强MTOR的活性，从单细胞到多细胞微转移的乳腺癌。 途径，可能通过AJ复合物下游的信号传导。为了检验这一假设，我们将追求两个 具体目的：1）确定介导癌细胞与骨之间串扰的机制 Blastic的利基市场需要直接的细胞接触并导致MTOR信号的激活，以及2） 介绍MTOR的下游效应器，以驱动转移开始。我们的工作是创新的，可行的 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离处快速检查和稳健地定量骨微转移 插入，但避免了其他常规方法的警告。将此技术应用于几种癌症 模型导致模仿人类疾病的懒惰或休眠骨转移。我们将使用此ap- 分别用于人类和小鼠癌细胞的异种移植和合成性移植，并入侵 探讨AJ，MTOR复合物及其相关信号分子在骨转移initia- tion。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癌症的许多特征 - 利基相互作用将促进分子机制的解剖并加速我们的检查 候选人。这些目标的实现将使目标疗法的设计能够抑制或 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。