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