Deconstructing cellular heterogeneity and subpopulation cooperation in non-small cell lung cancer metastasis

解构非小细胞肺癌转移中的细胞异质性和亚群合作

• 批准号: 10323872
• 负责人: Janna K Mouw
• 金额: $ 14.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10323872
• 关键词: Biological; Biomedical Engineering; Cancer Biology; Cancer Patient; Cells; Cellular biology; Cessation of life; Communication; Confocal Microscopy; Dedications; Distant Metastasis; Endothelium; Engineering; Fluorescence-Activated Cell Sorting; Funding; Genomics; Goals; Grant; Heterogeneity; In Vitro; Institutes; Institution; Journals; Laboratories; Lead; Legal patent; Malignant Neoplasms; Malignant neoplasm of lung; Mechanics; Medicine; Molecular; Nature; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Patients; Population; Prevention therapy; Publishing; Research; Role; Signal Transduction; Solid Neoplasm; Techniques; Testing; Training; Travel; Universities; Work; anticancer research; cancer cell; cancer therapy; cohesion; experience; in vivo; insight; migration; mimicry; multidisciplinary; new therapeutic target; programs; spatiotemporal; targeted treatment; translational impact; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Metastasis is responsible for 90% of cancer deaths, yet there is a severe lack of effective anti-metastatic targeted therapeutics. Collective invasion, where heterogeneous packs of cells travel together, is a major mode of metastasis observed in patients across many solid tumor types. The underlying biological mechanisms for how the collective invasion pack communicates to emerge, navigate, and persist as a single cohesive unit remain unclear. Using our patented SaGA technique (Spatiotemporal Genomic and Cellular Analysis), which leverages a combination of live-cell confocal microscopy and fluorescence-activated cell sorting, we found that cooperation between leader and follower subpopulations is crucial for successful collective invasion, with leaders promoting the invasion of followers, and followers promoting the survival and proliferation of leaders. The proposed work deconstructing how the collective invasion pack facilitates metastasis will be performed by Dr. Janna Mouw in the laboratory of Dr. Adam Marcus, the Unit Director, at the Winship Cancer Institute at Emory University. The overall objective of the proposed work is to dissect the molecular underpinnings of subpopulation cooperation in promoting collective invasion and metastasis as outlined in Dr. Marcus's funded R01 grants, R01CA236369 and R01CA250422. As such, the goals of Dr. Mouw's project are to: 1) define how heterogeneous lung cancer subpopulation cooperation and spatial coordination through Jag1 drive collective cancer cell invasion and tumor metastasis, and 2) establish whether atypical angiogenic mimicry and leader cell-driven Jag1 signaling destabilize the tumor endothelium to promote lung cancer transendothelial migration and metastasis. Dr. Mouw has more than 15 years of experience in cancer research at top-tier institutions. She has a multidisciplinary background in cancer biology, bioengineering, and mechanical engineering, bringing a unique expertise and perspective to her research on the roles for subpopulation communication and collective invasion in cancer progression and metastasis. Through these experiences, Dr. Mouw has extensive training using a vast variety of in vitro and in vivo approaches to comprehensively test her hypotheses. Dr. Mouw has made significant contributions to Dr. Marcus's research program, and has published multiple first-author articles in well-regarded journals, such as Nature Medicine and Nature Cell Biology. Overall, Dr. Mouw has the expertise and dedication to lead these studies, which will define the metastatic potential and translational impact of the rare, yet invasive leader population in lung cancer patients. Taken together, the work proposed here will be of impactful benefit to the research program, and provide critical mechanistic insight into the atypical angiogenic mimicry program and translational value towards targeting lung cancer patient leader cell biology.

项目总结/摘要 转移是造成90%癌症死亡的原因，但目前严重缺乏有效的抗转移靶向药物。 治疗学集体入侵，其中异质细胞包一起旅行，是一种主要的模式， 在许多实体瘤类型的患者中观察到转移。这些潜在的生物学机制 集体入侵包通信，以出现，导航，并坚持作为一个单一的凝聚力单位仍然存在 不清楚使用我们的专利佐贺技术（时空基因组和细胞分析）， 结合活细胞共聚焦显微镜和荧光激活细胞分选，我们发现， 领导者和追随者亚群之间的关系对于成功的集体入侵至关重要， 追随者的入侵，以及追随者促进领导者的生存和扩散。拟议工作 Janna Mouw博士将在 埃默里大学温希普癌症研究所主任亚当·马库斯博士的实验室。的 拟议工作的总体目标是剖析亚群合作的分子基础， 促进集体侵袭和转移，如Marcus博士资助的R 01赠款R 01 CA 236369所述， R01CA250422。因此，Mouw博士的项目的目标是：1）定义异质性肺癌是如何发生的， 通过Jag 1驱动集体癌细胞侵袭和肿瘤的亚群合作和空间协调 转移，和2）确定是否非典型血管生成拟态和前导细胞驱动的Jag 1信号传导 使肿瘤内皮不稳定，促进肺癌跨内皮迁移和转移。穆博士 在顶级机构从事癌症研究超过15年。她有一个多学科 在癌症生物学，生物工程和机械工程的背景，带来了独特的专业知识， 她对亚群交流和集体侵袭在癌症中的作用的研究 进展和转移。通过这些经验，Mouw博士接受了广泛的培训， 在体外和体内的方法来全面测试她的假设。穆博士已经取得了重大进展， 马库斯博士的研究计划，并发表了多篇第一作者的文章，在备受好评的 《自然医学》和《自然细胞生物学》等期刊。总体而言，Mouw博士拥有专业知识和奉献精神 领导这些研究，这将确定转移潜力和翻译的影响，罕见的，但侵入性 肺癌患者中的主要人群。总之，这里提出的工作将对以下方面产生重大影响： 研究计划，并提供关键的机制洞察到非典型血管生成拟态计划， 翻译价值对靶向肺癌患者领导细胞生物学。