University of Vermont

College of Medicine

Department of Pharmacology


Howe Lab

Cellular interactions with the extracellular matrix (ECM) modulate nearly every major cellular behavior, including growth, division, survival and movement. A prime example of this is the concept of anchorage-dependent growth, a characteristic of most normal cells whereby division is prevented and survival is compromised in the absence of interaction with a physiologically relevant ECM. Importantly, the loss of this trait is a hallmark of malignant tumor cells and correlates with their metastatic potential. In addition to binding to and interpreting the composition of their ECM, both normal and tumor cells can sense not only the composition of the surrounding extracellular matrix (ECM), but also the topography, rigidity, and anisotropy of the ECM. Moreover, cells dynamically react to changes in applied force or tension generated by, or in response to, ECM dynamics. Cells respond to extrinsic forces from the ECM by modifying their behavior, remodeling the ECM itself, and exerting counter-tension through actomyosin-dependent contractility. In normal cells, this ‘mechanoreciprocity’ is in controlled equilibrium and is important for tissue homeostasis. In tumor cells, however, mechanical changes in the environment are exploited to facilitate local growth, invasion, and spread. In fact, the loss of mechanical tissue homeostasis can also often serve as a hallmark of neoplastic disease. However, the molecular mechanisms through which cells sense and respond to the mechanical nature of their ECM are not well understood. Furthermore, while the importance of microenvironmental tension for the pathogenesis of breast cancer has been elegantly established, its importance for the pathogenesis of other cancers is poorly understood.

The Howe Laboratory’s main interest is in the mechanisms through which the extracellular microenvironment regulates cell behavior, with a specific interest in how this regulation contributes to the invasion and spread of metastatic tumors. As a postdoctoral fellow, Dr. Howe published and contributed to several articles that helped establish the field of integrin- and matrix-dependent signal transduction, in particular the regulation of MAPK activity by integrin-mediated cell adhesion. There, he also began his investigation of the role of the cAMP-dependent protein kinase (PKA) as a target for regulation by adhesion as well as a regulator of cytoskeletal dynamics and cell migration. After joining the UVM Department of Pharmacology, Dr. Howe’s lab established that, through interaction with A-kinase anchoring proteins (AKAPs), PKA is enriched within the leading edge of migrating cells and that this subcellular localization of PKA is required for efficient chemotaxis (Fig.1). The laboratory’s ongoing efforts focused on three major questions:

  1. How does PKA become localized to the leading edge?
  2. What are the targets for PKA that are important for cell migration?
  3. How does this signaling paradigm contribute to tumor cell invasion and metastasis?

To answer these questions, the laboratory combines multi-dimensional live-cell imaging, microfabrication and microfluidics, and matrix-coupled polymer hydrogels to precisely control and change the extracellular environment and to assess the molecular mechanisms used by cells to sense these changes.

Howe Lab Graphic

Last modified November 24 2014 10:15 AM