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: 10028080
• 负责人: Xiang Zhang
• 金额: $ 50.09万
• 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/10028080
• 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; Property; Recurrence; Research; Seeds; Site; Skeleton; System; Testing; Therapeutic; Therapeutic Intervention; Time; Visceral; Work; Xenograft procedure; 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; outcome forecast; 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.

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 转移目的地。超过 45% 的原发转移发生在骨，而 19% 发生在肺，5% 发生在肝 2% 进入大脑。以骨骼为第一转移部位的患者通常比那些以骨骼为转移部位的患者预后更好 以内脏器官为第一部位。然而，在超过三分之二的病例中，骨转移不会局限于 骨骼，但随后发生在其他器官并最终杀死患者。这提高了 从最初的骨病变到其他部位的继发性转移扩散的可能性。事实上，有些 首先在非骨器官中发现的转移也可能源自亚临床骨微转移，因为 研究结果表明，到达骨骼的癌细胞甚至可以获得更具侵袭性的表型 在建立明显的转移之前。最近的基因组分析确实得出结论，大多数 转移瘤是由其他转移瘤而不是原发肿瘤的播种引起的。因此，势在必行 进一步研究骨病变的转移播种很重要，因为它可能有助于预防 晚期，多器官转移，最终导致绝大多数死亡。尽管有潜力 相关性，我们对转移到转移播种知之甚少。目前的临床前模型侧重于 从原发性肿瘤播种，但无法区分进一步的传播。趁着最近 开发出选择性地将癌细胞传递至后肢骨的方法，我们发现经常 从已形成的骨病变转移到多个其他器官。假设已启用此播种 通过骨微环境诱导的效应，通过组合赋予更多类似干的特性 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 这个过程的时间过程，以便提供对时间窗口和策略的首次见解 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 骨微环境赋予播散性乳腺癌细胞进一步转移和转移的能力 阻断微环境引起的改变可能会限制骨转移并防止进一步 传播到其他胎儿器官。我们的具体目标是 1) 表征转移播种的动力学 从骨病变中分析并相应地确定潜在的治疗窗口，2) 确定关键的可药物治疗 针对骨病变继发性转移种植的目标并设计治疗策略。这个项目 具有创新性和影响力，因为它是该领域第一个专注于继发性转移和 骨微环境对转移播种的深刻重编程影响。结果很可能会 对我们对转移进化的理解产生重大影响，并为新疗法提供见解 限制转移以获得最终治愈。