MICROENVIRONMENTAL CONTROLS OF TUMOR DORMANCY

骨转移是乳腺癌患者长期生存和生活质量的关键决定因素。 尽管大多数乳腺癌病例都是早期诊断的，但约有10%-20%的乳腺癌复发 患者以前被“治愈”，表明原发播散性肿瘤细胞(DTC)转移较早且 在遥远的地方休眠，几年后才苏醒过来。事实上，大约50%的患者有 在他们的骨髓和转移部位中，骨转移是最常见的部位和 与存活率和生活质量下降有关。考虑到有很大比例的患者会回到 在他们最初的“治愈”之后的几年里，以及治疗选择有限或只是姑息治疗的可悲事实， 发现保护休眠的DTC并允许它们最终生长的机制将有一个 对新疗法的开发和患者结果产生深远影响。我们开发了一部小说 遗传性小鼠模型(FASST)在空间和时间上控制小鼠衰老的激活 间质细胞，包括骨中的成骨细胞。使用FASST模型，我们发现激活 衰老导致与促肿瘤衰老相关的分泌表型表达增加 (SASP)在骨间充质细胞中促进局部骨转换和促进肿瘤DTC增殖 骨头。有趣的是，我们发现DCs定位在衰老细胞附近，这增加了小生境的可能性 由这些细胞产生的细胞驱动树突状细胞增殖。因为从最初的 诊断和复发，人体组织中衰老细胞在这段时间内增加的事实，我们 发现衰老细胞驱动DTC增殖，我们假设骨骼中衰老的激活 间质刺激从休眠中萌发并生长到明显的骨转移灶中。为了测试这一点 假设，我们建议建立骨转换和SASP对潜伏期DTC的功能影响 并确定衰老成骨细胞的枯竭如何影响骨内的DTC休眠。我们 也会询问休眠的DTC如何与骨骼相互作用，以及在激活时这一点如何改变 衰老。我们还会问，老化的免疫系统是否有助于DTCs从休眠中苏醒。 最后，我们将对从骨骼+/-激活中分离的DCs进行单细胞RNA测序。 衰老，以确定来自骨骼的外部信号如何影响DTC的内在途径。把这些放在一起 方法将使我们有能力开发针对骨基质间隔室的新疗法，同时 同时攻击根深蒂固的DTC。

Bone metastasis is a key determinant of long-term survival and quality of life for breast cancer patients. Despite the fact that the majority of breast cancer cases are diagnosed early, approximately 10-20% recur in patients previously “cured”, demonstrating that primary disseminated tumor cells (DTCs) metastasize early and remain dormant in distant sites only to awaken years later. Indeed, approximately 50% of patients harbor DTCs in their bone marrow and among metastatic sites, bone metastasis is the most common site and correlates with reduced survival and quality of life. Given the large percentage of patients who return to the clinic years after their initial “cure”, and the sad fact that treatment options are limited or only palliative, uncovering the mechanisms that protect dormant DTCs and allow their eventual outgrowth will have a profound impact on the development of novel therapies and patient outcome. We have developed a novel genetic mouse model (FASST) to spatially and temporally control the activation of senescence in mesenchymal cells including osteoblasts in the bone. Using the FASST model, we found that the activation of senescence led to increased expression of the protumorigenic senescence associated secretory phenotype (SASP) in bone mesenchymal cells that drove local bone turnover and facilitated tumor DTC proliferation in the bone. Intriguingly, we found that DTCs localized near senescent cells, raising the possibility that the niche created by these cells drove DTCs to proliferate. Because months to years can pass between an initial diagnosis and relapse, the fact that senescent cells increase in human tissue over this time frame and we that find that senescent cells drive DTC proliferation, we hypothesize that activation of senescence in the bone mesenchyme instigates emergence from dormancy and growth into overt metastatic bone lesions. To test this hypothesis, we propose to establish the functional impact of bone turnover and SASP on dormant DTC dynamics and determine how depletion of senescent osteoblasts impact DTC dormancy within the bone. We will also ask how dormant DTCs interact with the bone and how this is altered upon the activation of senescence. We will also ask if an aging immune system contributes to emergence of DTCs from dormancy. Finally, we will carry out single cell RNA sequencing of DTCs isolated from the bone +/- activation of senescence to determine how extrinsic signals from the bone impact DTC intrinsic pathways. Together these approaches will poise us to develop novel therapies that target the bone stromal compartment while simultaneously attacking entrenched DTCs.