Adaptations of breast cancer metastasis to the aging lung

乳腺癌转移对衰老肺部的适应

• 批准号: 10726328
• 负责人: Ana da silva Gomes
• 金额: $ 21.06万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726328
• 关键词: Adolescent; Affect; Age; Aging; Basic Science; Bile Acids; Biogenesis; Biology; Biology of Aging; Blood flow; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; Cell Extracts; Cells; Chronic Obstructive Pulmonary Disease; Circulation; Clinical; Clinical Trials; Connective Tissue; DNA; Data; Databases; Diagnosis; Disease; Distal; Enrollment; Environment; FDA approved; FGF19 gene; Family; Fibroblast Growth Factor Receptors; Gene Expression Profile; Genetic; Goals; Growth; Home; Hormone secretion; Implant; Knowledge; Lipids; Longevity; Lung; Lung diseases; Malignant neoplasm of lung; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Mitochondria; Mus; Neoplasm Metastasis; Organ; Organism; Outcome; Oxygen; Patients; Process; Production; Prognosis; Proteins; Quality of life; Receptor Activation; Reporting; Research; Role; Signal Transduction; Testing; Therapeutic; Time; Tissues; Toxicity due to chemotherapy; Vulnerable Populations; Woman; Work; active method; age effect; age related; breast cancer progression; cancer cell; cancer diagnosis; cancer therapy; cancer type; cell age; chemotherapy; comorbidity; defined contribution; empowerment; feeding; fitness; human old age (65+); improved; inhibitor; lung colonization; malignant breast neoplasm; mitochondrial fitness; mitochondrial metabolism; mortality; neglect; new therapeutic target; older women; precision oncology; receptor; receptor for advanced glycation endproducts; response; side effect; success; therapeutic target; trait; transcription factor; triple-negative invasive breast carcinoma; tumor; tumorigenesis; wasting; young woman

Treatment options for older women with breast cancer are often limited due to co-morbidities as well as the tolerability of chemotherapies, often the only therapeutic option for advanced stage metastatic breast cancers. The clinical manifestation of metastasis in a vital organ is the final stage of breast cancer progression and the main culprit of breast cancer related mortality. Thus, there is a pressing need to better understand fundamental mechanisms that enable breast cancer cells to thrive in distal organs. As an organism ages cells throughout the body lose their ability to function or do so abnormally; byproducts and waste molecules build up in circulation and within tissues, and connective tissues become stiffer restricting blood flow and oxygen, collectively leading to damage to DNA, proteins, and lipids. The interaction of disseminated cancer cells with the secondary organ is essential for metastases to thrive and largely dependent on the biology of the specific organs. Despite this, research to date has largely neglected the role of aging in breast cancer as well as breast cancer metastasis, and no therapeutic targets have been identified specifically to aid in the treatment of older breast cancer patients. Thus, there is a pressing need to understand how the age of the patient affects tumorigenesis and metastasis with the goal of developing better treatment options for older women, a particularly vulnerable population. Motivated to bridge this gap in knowledge we took a similar approach to what has been used to define traits that empower metastasis in young hosts to evaluate if there are age-specific traits that enable breast cancer metastasis. Our preliminary data showed that the age of the host significantly affects the traits that enable metastatic colonization and revealed mitochondrial metabolism as a key trait in breast cancer cells extracted from metastases specifically in old hosts. Here, we will test if increased mitochondrial fitness is an essential feature for breast cancer metastasis in old hosts and define the mechanism by which the aging process results in this adaptation. Successful completion of these studies will unveil for the first time an adaptation of age- induced breast cancer metastasis, thus offering a therapeutic target with less toxicity than chemotherapies which in turn has the potential to increase the proportion of older women being able to receive active treatment and improve their quality of life.

老年乳腺癌患者的治疗选择往往是有限的，由于合并症以及 化疗的耐受性，通常是晚期转移性乳腺癌的唯一治疗选择。 重要器官转移的临床表现是乳腺癌进展的最后阶段， 乳腺癌相关死亡率的罪魁祸首。因此，迫切需要更好地了解基本的 乳腺癌细胞在远端器官中生长的机制。当一个有机体在整个生命周期中使细胞老化时， 身体失去功能或功能异常;副产品和废物分子在循环中积聚 和组织内，结缔组织变得僵硬，限制血液流动和氧气，共同导致 DNA蛋白质和脂质的损伤播散性癌细胞与次级器官的相互作用 对于转移瘤的生长至关重要，并且在很大程度上取决于特定器官的生物学特性。尽管如此， 迄今为止的研究在很大程度上忽略了衰老在乳腺癌以及乳腺癌转移中的作用， 并且还没有特别确定治疗靶点来帮助治疗老年乳腺癌患者。 因此，迫切需要了解患者的年龄如何影响肿瘤发生和转移 其目标是为老年妇女这一特别脆弱的群体制定更好的治疗方案。 为了弥合这一知识差距，我们采取了与用于定义特征的方法类似的方法， 使年轻宿主的转移能够评估是否有年龄特异性特征使乳腺癌 转移我们的初步数据显示，宿主的年龄显著影响了使 转移性定植，并揭示线粒体代谢作为乳腺癌细胞中提取的关键特征 特别是老年宿主的转移在这里，我们将测试是否增加线粒体健康是必不可少的， 乳腺癌在老年宿主中转移的特征，并确定衰老过程导致的机制， 在这个适应中。这些研究的成功完成将首次揭示年龄的适应- 诱导乳腺癌转移，从而提供比化疗更低毒性的治疗靶点， 反过来又有可能增加能够接受积极治疗的老年妇女的比例， 提高他们的生活质量。