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

点击翻译按钮获取中文摘要

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.