Mechanistic and therapeutic investigation of secondary metastatic seeding from breast cancer bone lesion

远处器官转移是乳腺癌相关死亡的主要原因。骨头是最常见的 转移的目的地。超过45%的第一部位转移发生在骨，相比之下，19%发生在肺，5%发生在肝 2%的大脑。以骨骼为首发转移部位的患者预后较好， 以内脏器官为首发部位。然而，在超过三分之二的情况下，骨转移不会受到限制 骨骼，而是随后发生在其他器官，并最终杀死病人。这就提出了一个 从最初的骨病变到其他部位的继发性转移扩散的可能性。其实有些 首先在非骨器官中发现的转移瘤也可以从亚临床骨微转移瘤中播种， 这一发现表明，到达骨骼的癌细胞可以获得更具侵略性的表型， 才能发现明显的转移最近的基因组分析确实得出结论， 转移是由其他转移瘤而不是原发性肿瘤的播种引起的。因此，当务之急是 重要的是进一步研究骨病变的转移性种植，因为它可能导致预防 终末期，多器官转移，最终导致绝大多数死亡。尽管潜在的 相关性，我们对转移到转移的播种知之甚少。目前的临床前模型集中在 从原发性肿瘤的种植，但不能区分进一步的传播。利用最近一次 我们开发了一种选择性地将癌细胞输送到后肢骨骼的方法，我们发现了频繁的 从已建立的骨病变转移到多个其他器官。这种播种是假设性的 通过骨微环境诱导的效应，通过以下组合赋予更多的干样特性： 克隆选择和表观基因组适应。在本申请中，我们将阐明潜在的机制， 这一进程的时间进程，以提供有史以来第一次深入了解时间窗口和战略， 潜在的治疗干预。我们假设，克隆选择和表观遗传适应驱动的 骨微环境产生了播散性乳腺癌细胞进一步转移的能力， 阻断微环境诱导的改变可以限制骨转移，并防止进一步的骨转移。 扩散到其他胎儿器官。我们的具体目标是：1）表征转移性播种的动力学 从骨病变，并确定相应的潜在治疗窗口，和2）确定关键药物 靶点和设计针对骨病变继发转移性播种的治疗策略。这个项目 是创新和有影响力的，因为它是该领域的第一个专注于继发性转移和肿瘤转移的研究。 骨微环境对转移性种植的深刻重编程作用。结果很可能 对我们理解转移性演变产生重大影响，并为新疗法提供见解 限制转移以最终治愈。

Metastasis to distant organs is the major cause of breast cancer-related death. Bone is the most frequent destination of metastasis. Over 45% first-site metastases occur to bone, as compared to 19% to lung, 5% to liver and 2% to brain. Patients with skeleton as the first site of metastasis usually have better prognosis than those with visceral organs as first site. However, in more than two third of cases, bone metastases will not be confined to the skeleton, but rather subsequently occur to other organs and eventually kill patients. This raises the possibility of secondary metastatic dissemination from the initial bone lesions to other sites. In fact, some metastases first found in non-bone organs may be seeded from subclinical bone micrometastases as well, as suggested by the finding that cancer cells arrived in the bone can acquire more aggressive phenotypes even before establishing overt metastases. Recent genomic analyses indeed concluded that the majority of metastases result from seeding from other metastases, rather than primary tumors. Thus, it is of imperative importance to investigate further metastatic seeding from bone lesions, as it might lead to prevention of the terminal stage, multi-organ metastases that ultimately cause the vast majority of deaths. Despite the potential relevance, we know very little about metastasis-to-metastasis seeding. Current pre-clinical models focus on seeding from primary tumors, but cannot distinguish further dissemination. Taking advantage of a recently developed approach that selectively deliver cancer cells to hind limb bones, we have uncovered frequent metastatic seeding from established bone lesions to multiple other organs. This seeding is hypothetically enabled by the bone microenvironment-induced effects that confer more stem-like properties through a combination of clonal selection and epigenomic adaptation. In this application, we will elucidate the underlying mechanisms and temporal course of this process in order to provide the first ever insights into time window and strategies of potential therapeutic interventions. We hypothesize that clonal selection and epigenetic adaptation driven by the bone microenvironment engender the ability of disseminated breast cancer cells to further metastasize and blockade of the microenvironment-induced alterations may confine bone metastases and prevent further dissemination to other fetal organs. Our specific aims are 1) to characterize the kinetics of metastatic seeding from bone lesions and determine potential therapeutic windows accordingly, and 2) to identify key druggable targets and design therapeutic strategies against secondary metastatic seeding from bone lesions. This project is innovative and impactful because it is the first in the field that focuses on secondary metastasis and the profound reprogramming effects of bone microenvironment on metastatic seeding. The outcome will likely generate significant impact on our understanding of metastatic evolution and provide insights into novel therapies confining metastases for ultimate cure.