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3D collagen architecture regulates cell adhesion through degradability, thereby controlling metabolic and oxidative stress.

ABSTRACT: 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.

SUBMITTER: Velez DO

PROVIDER: S-EPMC6657753 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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3D collagen architecture regulates cell adhesion through degradability, thereby controlling metabolic and oxidative stress.

Velez Daniel O DO Ranamukhaarachchi Sural K SK Kumar Aditya A Modi Rishi N RN Lim Esther W EW Engler Adam J AJ Metallo Christian M CM Fraley Stephanie I SI

Integrative biology : quantitative biosciences from nano to macro 20190501 5

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 intera ...[more]

PMID: 31251330

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Project description:The dynamic features of a genetic network's response to environmental fluctuations represent essential functional specifications and thus may constrain the possible choices of network architecture and kinetic parameters. To explore the connection between dynamics and network design, we have analyzed a general regulatory architecture that is commonly found in many metabolic pathways. Such architecture is characterized by a dual control mechanism, with end product feedback inhibition and transcriptional regulation mediated by an intermediate metabolite. As a case study, we measured with high temporal resolution the induction profiles of the enzymes in the leucine biosynthetic pathway in response to leucine depletion, using an automated system for monitoring protein expression levels in single cells. All the genes in the pathway are known to be coregulated by the same transcription factors, but we observed drastically different dynamic responses for enzymes upstream and immediately downstream of the key control point-the intermediate metabolite alpha-isopropylmalate (alphaIPM), which couples metabolic activity to transcriptional regulation. Analysis based on genetic perturbations suggests that the observed dynamics are due to differential regulation by the leucine branch-specific transcription factor Leu3, and that the downstream enzymes are strictly controlled and highly expressed only when alphaIPM is available. These observations allow us to build a simplified mathematical model that accounts for the observed dynamics and can correctly predict the pathway's response to new perturbations. Our model also suggests that transient dynamics and steady state can be separately tuned and that the high induction levels of the downstream enzymes are necessary for fast leucine recovery. It is likely that principles emerging from this work can reveal how gene regulation has evolved to optimize performance in other metabolic pathways with similar architecture.

Dataset Information

3D collagen architecture regulates cell adhesion through degradability, thereby controlling metabolic and oxidative stress.

Publications

3D collagen architecture regulates cell adhesion through degradability, thereby controlling metabolic and oxidative stress.

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