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上，相比之下，19%发生在肺，5%发生在肝脏。 对大脑的影响为2%。以骨骼为首发转移部位的患者预后通常好于那些 以内脏器官为第一部位。然而，在超过三分之二的病例中，骨转移不会受到限制。 而是随后发生在其他器官，最终导致患者死亡。这引发了 继发转移的可能性从最初的骨病变扩散到其他部位。事实上，有些人 首先在非骨器官发现的转移瘤也可能是亚临床骨微转移瘤的种子。 这一发现表明，进入骨骼的癌细胞甚至可以获得更具侵袭性的表型 在确定明显的转移之前。最近的基因组分析确实得出结论，大多数 转移瘤源于其他转移瘤，而不是原发肿瘤。因此，这是势在必行的。 研究骨病变的进一步转移种植的重要性，因为它可能导致预防 晚期，多器官转移，最终导致绝大多数死亡。尽管有潜在的 与此相关的是，我们对转移-转移播种知之甚少。目前的临床前模型主要集中在 播散于原发肿瘤，但不能区分进一步扩散。利用最近的一次 开发了一种选择性地将癌细胞输送到后肢骨骼的方法，我们经常发现 从已建立的骨骼病变转移到多个其他器官。此种子设定是假设启用的 通过骨微环境诱导的效应，通过结合 克隆选择和表观基因组适应。在这个应用中，我们将阐明潜在的机制和 这一过程的时间进程，以便提供对时间窗口和战略的首次洞察 潜在的治疗干预措施。我们假设克隆选择和表观遗传适应是由 骨骼微环境产生播散性乳腺癌细胞进一步转移和 阻断微环境诱导的改变可能会限制骨转移并防止进一步 扩散到其他胎儿器官。我们的具体目标是：1)描述转移播种的动力学 并据此确定潜在的治疗窗口，以及2)确定关键的可用药 针对骨肿瘤继发转移的靶点和治疗策略的设计。这个项目 是创新和有影响力的，因为它是该领域第一个专注于继发性转移和 骨微环境对转移性种植的深刻重编程效应。结果很可能是 对我们对转移进化的理解产生重大影响，并为新的治疗方法提供见解 限制转移以达到最终治愈。

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.