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

项目摘要 临床转移通常在切除原发乳腺肿瘤数年后被诊断出来，表明存在 全身播散的肿瘤细胞或微观转移。辅助疗法的设计是为了 消灭这些细胞。尽管取得了重大进展，但仍有相当一部分患者病情发展。 明显的转移，占乳腺癌相关死亡的90%以上。微转移是如何恢复的 侵袭性生长和成为无法治愈的显性转移仍然知之甚少。我们的长期目标 是为了阐明微小转移瘤存活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。该项目的总体目标是调查如何 转移性乳腺癌最常影响的器官--骨骼的组织动态平衡决定了命运 骨微转移瘤(BMM)。骨骼和骨髓由几个非常独特的 微环境利基。休眠的播散性肿瘤细胞(DTC)可能驻留在血管周围的壁龛中， 而增殖性BMM发现于表现出活跃成骨特征的成骨骨龛中( 骨制作过程)。癌细胞如何从一个利基转移到另一个利基，以及如何转移仍然是个谜。 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“迁徙-- “旁系”现象：癌细胞可与间充质干细胞等成骨细胞黏附。 通过高度柔韧和弹性的树枝状棘状结构(DSLS)。就像休眠的DTC一样，休眠 MSCs也定位于血管周围的壁龛。骨组织的周转释放信号以动员和化学- 将间充质干细胞吸引到需要成骨的部位，从而为癌细胞提供了一种可能的载体 从血管周围的壁龛转移到成骨的壁龛。随后MSCs的分化将 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，骨周转过程可能通过一种途径招募成骨细胞和DDC。 “系绳迁移”机制，促进成骨龛向促进骨的方向发展 殖民主义。我们将通过追求以下具体目标来检验这些假设。目的1.分子解剖 “系绳迁移”的机制，并确定其在成骨生态位和 DTC的早期骨定植。目的2.确定骨转换的扰动对 骨转移，并评估这种影响是如何通过新兵的“拴系迁移”机制来调节的 DDC向成骨的壁龛转移。拟议的研究将在多个层面产生影响。在细胞层面上，它 将阐明如何在微环境细胞的帮助下发生细胞迁移，而不需要获得 癌症固有的迁移特征。在生理和病理层面上，它将在 骨稳态和骨转移，揭示迟发性骨复发的病因，并提供治疗 洞察力。

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.