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

乳腺癌骨病灶继发转移种植的机制和治疗研究

• 批准号: 10204993
• 负责人: Xiang Zhang
• 金额: $ 48.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10204993
• 关键词: Adjuvant; Affect; Automobile Driving; Bar Codes; Blood Circulation; Brain; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; CRISPR/Cas technology; Cell Line; Cessation of life; Complement; Data; Destinations; Diagnosis; Distant; Epigenetic Process; Evolution; Genomics; Guide RNA; Investigation; Kinetics; Lead; Lesion; Liver; Lung; Malignant Bone Neoplasm; Mediating; Metastatic Neoplasm to the Bone; Micrometastasis; Modeling; Mutate; Neoplasm Metastasis; Organ; Outcome; Parabiosis; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Prevention; Primary Neoplasm; Process; Prognosis; Property; Recurrence; Research; Seeds; Site; Skeleton; System; Testing; Therapeutic; Therapeutic Intervention; Time; Visceral; Work; base; bone; bone cell; cancer cell; cancer stem cell; design; druggable target; epigenomics; fetal; genetic selection; genomic locus; high risk; inducible gene expression; innovation; insight; limb bone; malignant breast neoplasm; novel therapeutics; patient derived xenograft model; prevent; stem; stem-like cell; therapeutic target; tumor

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.

向远处器官转移是与乳腺癌相关死亡的主要原因。骨头是最常见的 转移目的地。骨出现超过45％的第一点转移，而肺部为19％，肝脏为5％ 和2％的大脑。骨骼作为转移的第一个部位的患者通常具有比那些的预后更好 以内脏器官作为第一个站点。但是，在超过三分之二的情况下，骨转移将不限制 到骨骼，但随后发生在其他器官，最终杀死患者。这提高了 从初始骨病变到其他部位的继发转移性传播的可能性。实际上，有些 在非骨器官中首先发现的转移酶也可能是从亚临床骨微发生酶种子的 通过发现癌细胞到达骨骼的发现，甚至可以获得更具侵略性的表型 在建立明显转移之前。最近的基因组分析确实得出结论，大多数 转移酶是由其他转移酶而不是原发性肿瘤的播种引起的。因此，这是当务之急 重要的是研究从骨骼病变中进一步转移播种，因为这可能导致预防 末端阶段，多器官转移，最终导致绝大多数死亡。尽管有潜力 相关性，我们对转移到矿物质的播种知之甚少。当前的临床前模型关注 从原发性肿瘤中播种，但无法区分进一步的传播。利用最近的 开发的方法有选择地输送癌细胞以阻碍肢体骨骼，我们发现了频繁的 从已建立的骨骼病变到其他多个器官的转移播。该播种是假设启用的 通过骨微环境引起的效应，通过结合结合了更类似茎状的特性 克隆选择和表观基因组适应。在此应用中，我们将阐明基本机制和 此过程的时间过程，以便提供有史以来的第一个见解，以了解时间窗口和策略 潜在的治疗干预措施。我们假设克隆选择和表观遗传适应 骨微环境使传播乳腺癌细胞进一步转移和 封锁微环境引起的改变可能会限制骨转移并进一步阻止 传播到其他胎儿器官。我们的具体目的是1）表征转移播的动力学 从骨骼病变中确定潜在的治疗窗口，以及2）确定可药物的关键 靶标和设计治疗策略，以抗骨病变的继发转移播。这个项目 具有创新性和影响力，因为它是该领域的第一个专注于次要转移和 骨微环境对转移播种的深刻重编程影响。结果可能会 对我们对转移进化的理解产生重大影响，并提供对新疗法的见解 限制转移以进行最终治疗。