期刊
INTEGRATIVE BIOLOGY
卷 11, 期 5, 页码 221-234出版社
OXFORD UNIV PRESS
DOI: 10.1093/intbio/zyz019
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资金
- Burroughs Wellcome Fund Career Award at the Scientific Interface [1012027]
- National Science Foundation Faculty Early Career Development Program (CAREER) Awards [1651855, 145442]
- American Cancer Society Institutional Research Grant through the Moores Cancer Center at the University of California San Diego [15-172-45-IRG]
- University of California San Diego Frontiers of Innovation Scholar Program
- National Institutes of Health [R01CA206880, R01CA188652, T32AR060712, T32EB009380]
- National Science Foundation Graduate Research Fellowships Program
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1651855] Funding Source: National Science Foundation
The collagen-rich tumor microenvironment plays a critical role in directing the migration behavior of cancer cells. 3D collagen architectures with small pores have been shown to confine cells and induce aggressive collective migration, irrespective of matrix stiffness and density. However, it remains unclear how cells sense collagen architecture and transduce this information to initiate collective migration. Here, we tune collagen architecture and analyze its effect on four core cell-ECM interactions: cytoskeletal polymerization, adhesion, contractility, and matrix degradation. From this comprehensive analysis, we deduce that matrix architecture initially modulates cancer cell adhesion strength, and that this results from architecture-induced changes to matrix degradability. That is, architectures with smaller pores are less degradable, and degradability is required for cancer cell adhesion to 3D fibrilar collagen. The biochemical consequences of this 3D low-attachment state are similar to those induced by suspension culture, including metabolic and oxidative stress. One distinction from suspension culture is the induction of collagen catabolism that occurs in 3D low-attachment conditions. Cells also upregulate Snail1 and Notch signaling in response to 3D low-attachment, which suggests a mechanism for the emergence of collective behaviors.
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