HER2 Cancer Protrusion Growth Signaling Regulated by Unhindered, Localized Filopodial Dynamics
HER2 Cancer Protrusion Growth Signaling Regulated by Unhindered, Localized Filopodial Dynamics
Abstract Protrusions are plasma membrane extensions that are found in almost every cell in the human body. Cancer cell filopodial and lamellipodial protrusions play key roles in the integral processes of cell motility and signaling underlying tumor invasion and metastasis. HER2 (ErbB-2) is overexpressed in diverse types of tumors and regulates PI3K-pathway-mediated protrusion growth. It is known that HER2 resides at breast cancer cell protrusions, but how protrusion-based HER2 spatiotemporal dynamics shape cancer signaling is unclear. Here, we study how HER2 location and motion regulate protrusion signaling and growth using quantitative spatio-temporal molecular imaging approaches. Our data highlight morphologically-segregated features of filopodial and lamellipodial protrusions, in in vitro 2D breast cancer cells and in vivo intact breast tumor. Functional-segregation parallels morphological-segregation, as HER2 and its activated downstream pAKT-PI3K signaling remain spatially-localized at protrusions, provoking new protrusion growth proximal to sites of HER2 activation. HER2 in SKBR3 breast cancer cell filopodia exhibits fast, linearly-directed motion that is distinct from lamellipodia and non-protrusion subcellular regions (～3-4 times greater diffusion constant, rapid speeds of 2-3 um2/s). Surprisingly, filopodial HER2 motion is passive, requiring no active energy sources. Moreover, while HER2 motion in lamellipodia and non-protrusion regions show hindered diffusion typical of membrane proteins, HER2 diffuses freely within filopodia. We conclude that HER2 activation, propagation, and functional protrusion growth is a local process in which filopodia have evolved to exploit Brownian thermal fluctuations within a barrier-free nanostructure to transduce rapid signaling. These results support the importance of developing filopodia and other protrusion-targeted strategies for cancer.
Mostofian Barmak、Jorgens Danielle、Kwon Sunjong、Chin Koei、Jacob Thomas、Heiser Katie、Agrawal Anurag、Gray Joe、Lidke Keith A.、Carpenter M. Alexandra、Vu Tania Q.、Nan Xiaolin、Bruchez Marcel、Wang Yi、Wang Jing、Chang Young Hwan、Zuckerman Daniel M.、Lam Wai Yan
Department of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science UniversityCenter for Spatial Systems Biomedicine, Oregon Health and Science UniversityDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science UniversityDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science UniversityDepartment of Biomedical Engineering, Oregon Health and Science UniversityDouble Helix LLCDouble Helix LLCDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science University||Knight Cancer Center, Oregon Health and Science UniversityDepartment of Physics and Astronomy, University of New MexicoMolecular Biosensor and Imaging Center, Carnegie Mellon University||Department of Chemistry, Carnegie Mellon UniversityDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science University||Knight Cancer Center, Oregon Health and Science UniversityDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science University||Knight Cancer Center, Oregon Health and Science UniversityMolecular Biosensor and Imaging Center, Carnegie Mellon University||Department of Chemistry, Carnegie Mellon UniversityMolecular Biosensor and Imaging Center, Carnegie Mellon University||Department of Chemistry, Carnegie Mellon UniversityDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science UniversityDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science University||Computational Biology Program, Oregon Health and Science UniversityDepartment of Biomedical Engineering, Oregon Health and Science University||Center for Spatial Systems Biomedicine, Oregon Health and Science UniversityDepartment of Biomedical Engineering, Oregon Health and Science University
肿瘤学基础医学分子生物学
Mostofian Barmak,Jorgens Danielle,Kwon Sunjong,Chin Koei,Jacob Thomas,Heiser Katie,Agrawal Anurag,Gray Joe,Lidke Keith A.,Carpenter M. Alexandra,Vu Tania Q.,Nan Xiaolin,Bruchez Marcel,Wang Yi,Wang Jing,Chang Young Hwan,Zuckerman Daniel M.,Lam Wai Yan.HER2 Cancer Protrusion Growth Signaling Regulated by Unhindered, Localized Filopodial Dynamics[EB/OL].(2025-03-28)[2025-04-24].https://www.biorxiv.org/content/10.1101/654988.点此复制
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