Osteoclast-Independent Mechanisms of Early-Stage Bone Colonization of Breast Cancer

项目摘要 明显的转移通常在原发性乳腺肿瘤切除后数年才被诊断出来，这表明乳腺癌的存在。 全身扩散的肿瘤细胞或微小转移。辅助治疗的目的是 消灭这些细胞。虽然取得了重大进展，但仍有相当一部分患者 明显的转移，占乳腺癌相关死亡的90%以上。微转移如何恢复 侵袭性生长并成为不可治愈的显性转移仍然知之甚少。我们的长期目标 是为了阐明微观转移的生存和进展的生物学基础，并设计 针对这些潜伏的肿瘤细胞的治疗策略。本项目的总体目标是研究如何 骨是最常受转移性乳腺癌影响的器官，其组织稳态决定了乳腺癌的命运。 骨微转移（BMM）骨骼和骨髓由几种高度独特的 微环境生态位背侧播散的肿瘤细胞（DTC）可能位于血管周围的小生境中， 而增生性BMM则位于成骨龛中，表现出活跃的成骨特征（ 骨制造过程）。癌细胞如何从一个小生境转移到另一个小生境， 它们的命运从休眠到生长在寻找这种机制的过程中，我们观察到一种有趣的“迁移”- “栓系”现象：癌细胞可以粘附到成骨细胞如间充质干细胞（MSC）上， 通过高度柔韧和弹性的树突状棘状结构（DSLS）。就像休眠的DTC， MSC还定位于血管周围的龛。骨组织的更新释放出动员和化疗的信号。 将MSC吸引到需要成骨的部位，从而为癌细胞提供了可能的载体“骑”， 从血管周围小生境重新定位到成骨小生境。MSC的后续分化将 促进成骨生态位的发展，并直接促进转移进展。这些发现 这使我们假设骨转换过程可能通过一种新的途径招募成骨细胞和DTC。 “栓系迁移”机制，促进成骨龛发育，促进骨形成 殖民化我们将通过追求以下具体目标来检验这些假设。目标1.从分子上剖析 “通过栓系迁移”机制，并确定其在成骨生态位发育中的作用， DTC的早期骨定植。目标2.确定骨转换扰动对 骨转移，并评估这种影响是如何介导的“迁移拴系”机制，招募 DTC到成骨龛。拟议的研究将在多个层面产生影响。在细胞水平上， 将阐明细胞迁移如何在微环境细胞的帮助下发生，但不需要获得 癌症固有的迁移特征。在生理和病理层面上，它将建立 骨稳态和骨转移，揭示晚发性骨复发的病因，并提供治疗 见解.

Project Summary Overt metastases are often diagnosed years after the removal of primary breast tumors, indicating the existence of systemically disseminated tumor cells or microscopic metastases. Adjuvant therapies have been designed to eliminate these cells. Although significant advances were made, a substantial proportion of patients still develop overt metastases, accounting for over 90% of breast cancer-related deaths. How micrometastases resume aggressive outgrowth and become incurable overt metastases remains poorly understood. Our long-term goals are to elucidate the biology underlying the survival and progression of microscopic metastases and to design therapeutic strategies against these latent tumor cells. The overall objective of this project is to investigate how tissue homeostasis of the bone, the organ most frequently affected by metastatic breast cancer, dictates the fate of bone micrometastases (BMM). Bone and bone marrow comprise of several highly distinctive microenvironment niches. Dormant disseminated tumor cells (DTCs) may reside in the perivascular niche, whereas proliferative BMM were found in the osteogenic niche that exhibit features of active osteogenesis (the bone-making process). It remains elusive how cancer cells are relocated from one niche to another, and switch their fates from dormancy to outgrowth. In search for such mechanism, we observed an interesting “migration- by-tethering” phenomenon: cancer cells can adhere to osteogenic cells such as mesenchymal stem cells (MSCs) through a dendritic spine-like structure (DSLS) that is highly pliable and elastic. Like dormant DTCs, resting MSCs also localize in perivascular niches. Turnover of bone tissues releases signals to mobilize and chemo- attracted MSCs to sites needing osteogenesis, thereby providing a possible vehicle for cancer cells to “ride” and relocate from the perivascular niche to the osteogenic niche. The subsequent differentiation of MSCs will then fuel the development of the osteogenic niche, and directly promoting metastasis progression. These findings lead us to hypothesize that the bone turnover process may recruit both osteogenic cells and DTCs via a “migration-by-tethering” mechanism, and foster the development of osteogenic niche to pro-mote bone colonization. We will test these hypotheses by pursuing the following specific aims. Aim 1. To molecularly dissect the “migration-by-tethering” mechanism and determine its role in the development of the osteogenic niche and early-stage bone colonization of DTCs. Aim 2. To determine the impact of perturbations of bone turnover on bone metastasis, and assess how this impact is mediated by the “migration-by-tethering” mechanism that recruits DTCs to the osteogenic niche. The proposed research will have impact at multiple levels. At a cellular level, it will elucidate how cell migration can occur with assistance of microenvironment cells but without acquisition of cancer-intrinsic migratory traits. At a physiological and pathological level, it will establish connections between bone homeostasis and bone metastasis, reveal etiology of late-onset bone recurrences, and provide therapeutic insights.