(PQD-3) Spatiotemporal Molecular Interrogation of Early Metastatic Evolution In Situ

(PQD-3) 早期原位转移演化的时空分子研究

• 批准号: 9067260
• 负责人: Siyuan Zhang
• 金额: $ 34.77万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067260
• 关键词: 4D Imaging; Address; Adjuvant Therapy; Aftercare; Algorithms; Behavior; Behavioral; Biological Models; Brain; Cancer Survivor; Categories; Cells; Cellular Structures; Characteristics; Chronic Disease; Clinic; Clinical; Clinical Treatment; Data; Data Analyses; Development; Diagnosis; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Environment; Event; Evolution; Exhibits; Extravasation; Failure; Fright; Future; Genetic Transcription; Health; Image Analysis; In Situ; Machine Learning; Malignant Neoplasms; Mammary Neoplasms; Metastatic malignant neoplasm to brain; Methods; Modeling; Molecular; Nature; Neoplasm Metastasis; Oncologist; Organ; Patients; Phenotype; Plant Roots; Primary Neoplasm; Process; Relapse; Research; Secondary to; Signal Transduction; Site; Staging; Statistical Models; Time; Tissue imaging; Tissues; Treatment Protocols; Validation; base; cancer cell; cancer therapy; checkup examination; clinical practice; data integration; design; glutamatergic signaling; imaging modality; in vivo; innovation; insight; intravital imaging; malignant breast neoplasm; metabolic abnormality assessment; mortality; multidisciplinary; neoplastic cell; new therapeutic target; novel; pre-clinical; pre-clinical research; pressure; screening; spatiotemporal; success; therapeutic target; therapy design; trait; transcriptome; transcriptome sequencing; tumor

 DESCRIPTION (provided by applicant): Every single cancer survivor fears relapse. While being free of the primary tumor after treatment is encouraging, it is emotionally devastating to step out of the clinic after a yearly checkup with a diagnosis of metastatic disease. Approximately 90% of cancer lethality is due to metastasis - the spreading of primary tumor cells to distant organs. Despite a dramatic increase in early screening methods and comprehensive treatment regimens for primary breast tumors, the overall mortality of patients who relapsed with metastatic cancer in the US has not changed in the past two decades. Clinical failure in treating metastatic tumors is largely due to the evolutionary nature of tumor metastasis. In order to survive and establish secondary tumors in a different tissue microenvironment at distant organs, disseminated tumor cells have to adapt (metastatic evolution) to the host environment. Clinically, metastatic tumors exhibit drastically different characteristics from their primary counterpart. Therefore, current cancer treatments, designed based on the features of primary tumors, are rarely effective. Optimal design of breakthrough anti-metastasis therapies relies on our in-depth understanding of the common and functionally important traits during the early metastatic evolution. In this proposed study, we will use breast cancer brain metastasis as model system and take state-of-the-art approaches to trace and analyze a single cancer cell within its precise metastatic microenvironment from the initial moment of metastatic colonization. This collaborative effort from a multidisciplinary team, including a cancer biologist, a computational biologist, a mathematician and a bioinformatician will allow us to: 1) depict the dynamics of gene transcription during the different stages of brain metastasis at single cell level; 2) visualize th behavior of a single colonized metastatic tumor cell and its interaction with the microenvironment through real-time intravital imaging and deep tissue imaging; 3) mathematically integrate molecular (RNA-seq), behavioral (intravital) and structural (deep tissue imaging) information to identify the common and functionally important early metastatic evolutionary traits during the breast cancer brain metastasis in its native tissue context. Shifting the current clinical treatment model relies on new in-depth mechanistic insight obtained through basic and pre-clinical innovative research. Utilizing cutting-edge sequencing and imaging modality in our proposed study, we will have the capacity to systematically dissect traits of early metastatic behavior and discover potential novel therapeutic targets for paradigm-shifting novel adjuvant therapy tailored to specific target metastatic evolution. The conceptual validation from our bold and pioneering attempt proposed in this study will serves as a blueprint for a new category of adjuvant therapies for effective anti-metastasis treatment.

 描述（由申请人提供）：虽然治疗后原发肿瘤消失是令人鼓舞的，但大约 90% 的癌症幸存者在每年一次检查后诊断出转移性疾病却会感到情绪激动。癌症致死率的主要原因是转移——原发性肿瘤细胞扩散到远处器官尽管原发性乳腺肿瘤的早期筛查方法和综合治疗方案大幅增加，但转移性癌症复发患者的总体死亡率仍然很高。在美国，治疗转移性肿瘤的临床失败很大程度上是由于肿瘤转移的进化性质，为了在远处器官的不同组织微环境中生存并形成继发性肿瘤，播散性肿瘤细胞已经发生了转移。适应（转移进化）宿主环境在临床上，转移性肿瘤表现出与其原发性肿瘤截然不同的特征，因此，目前根据原发性肿瘤的特征设计的癌症治疗很少有效。 突破性抗转移疗法的优化设计依赖于我们对早期转移演变过程中常见和功能上重要特征的深入了解。在这项拟议的研究中，我们将使用乳腺癌脑转移作为模型系统并采取最新状态。 -从转移定植的最初时刻起，通过艺术方法在其精确的转移微环境中追踪和分析单个癌细胞，这是一个多学科团队的共同努力，其中包括癌症生物学家、计算生物学家、数学家和科学家。生物信息学家将使我们能够：1）在单细胞水平上描述脑转移不同阶段的基因转录动态；2）通过实时活体成像可视化单个定植转移性肿瘤细胞的行为及其与微环境的相互作用。和深部组织成像；3）以数学方式整合分子（RNA-seq）、行为（活体）和结构（深部组织成像）信息，以确定乳腺癌脑转移过程中常见且功能重要的早期转移进化特征在其天然组织环境中。 改变当前的临床治疗模式依赖于通过基础和临床前创新研究获得的新的深入机制见解，在我们提出的研究中利用尖端测序和成像方式，我们将有能力系统地剖析早期转移行为的特征。并发现针对特定目标转移进化的范式转变新型辅助疗法的潜在新治疗靶标，我们在本研究中提出的大胆和开创性尝试的概念验证将作为有效辅助疗法的新类别的蓝图。抗转移治疗。