Research

The extracellular matrix (ECM), the noncellular component of the microenvironment, influences cell growth, survival, migration and tissue-specific differentiation through a repertoire of receptors including integrins, syndecans and discoidin receptors. My group is exploring the molecular mechanisms whereby ECM receptors modulate cell fate and tumorigenesis. We investigate how mechanical and topological properties of the ECM, which are related to its composition and organization, alter integrin expression and function to modify stem cell fate and tumor progression.

One part of our research program focuses on clarifying how mechanical force (ECM stiffness and cell contractility) modulate breast tumor progression and treatment efficacy with a focus on signaling and epigenetics using two and three dimensional (2D/3D) monolayer and organotypic culture models, xenograft/syngeneic and transgenic mouse models and clinical specimens and a repertoire of approaches to measure and manipulate mechanical force. The second part of our research is directed towards characterizing the role of and molecular mechanisms whereby mechanical force regulates human embryonic stem cell fate using 2D/3D natural and synthetic matrices and a force reactor with a focus on adhesion signaling and epigenetics.

Analysis of MCF10A mammary epithelial cell acinar morphogenesis within well-defined 3-dimensinal systems

Epithelial tissue morphogenesis proceeds within the context of a three dimensional (3D) extracellular matrix (ECM). Accordingly, to clarify the molecular basis of tissue-specific differentiation and disease, a variety of 3D systems exploiting natural ECMs have been developed, such as reconstituted basement membrane (rBM) and purified collagen hydrogels. These natural hydrogels recapitulate epithelial tissue architecture and behaviors in vitro with reasonable fidelity. Nevertheless, natural matrices suffer from considerable preparation variability and remain poorly defined biochemically and biophysically. To understand epithelial cell ...

Biomechanical Regulation of Breast Cancer Migration

The transition of the mammary epithelium to a metastatic state is an important event that drastically increases mortality during breast cancer progression. Metastatic progression depends on the ability of tumor cells to migrate to nearby blood vessels and lymphatics before they can successfully metastasize and colonize into other tissues. An understanding of how biomechanical and biochemical signals influence directional migration to these sites of tissue escape could help develop therapies to slow or halt metastasis. To understand how the mechanical ...

Exploring functional links between matrix stiffness, micro RNAs and HoxA9 dependent regulation of BRCA1 and mammary cell survival and tumorigenesis.

Stromal-epithelial interactions drive development and maintain tissue homeostasis through a network of soluble and insoluble factors that operate within a three-dimensional (3D) tissue. Genetic and epigenetic changes in mammary epithelial cells (MECs) cooperate with a modified tissue microenvironment to drive malignant transformation of the breast. We have been studying how altered expression of developmental regulators contributes to breast tumorigenesis and have specifically focused on investigating their influence on integrin expression and/or adhesion activity. Homeobox genes play a critical role in ...

Exploring the link between human embryonic stem cell organization and fate using tension-calibrated extracellular matrix functionalized polyacrylamide gels

Human embryonic stem cell (hESc) lines are likely the in vitro equivalent of the pluripotent epiblast. hESc express high levels of the extracellular matrix (ECM) laminin integrin receptor α6β1 and consequently can adhere robustly and be propagated in an undifferentiated state on tissue culture plastic coated with the laminin rich basement membrane preparation, MatrigelTM, even in the absence of supporting fibroblasts. Such cultures represent a critical step in the development of more defined feeder free cultures of hESc; a goal ...

Force characterization of tissue from normal, pre-invasive and invasive breast cancer

Historically, cancer research has focused on understanding the genetic and biochemical regulation of tumor progression while the biomechanical influences have only recently been studied. Clear evidence has emerged indicating that mechanical forces are closely associated with tumor progression. In fact, biomechanical cues are integrated with biochemical and genetic cues at every step. To investigate how micro-environment stiffness may affect progression in human breast tumors, we use atomic force microscopy (AFM) to probe the mechanical properties of tissue from patients diagnosed ...

Roles of collagen crosslinking and ECM remodeling in mammary tumor malignant transformation

In vivo, cells are maintained in mechanical balanced microenvironments. We showed that ECM stiffness alters cell proliferation, survival and polarity via integrin clustering, focal adhesion maturation, and cell-generated force. Increased tissue stiffness, changes of ECM (e.g. collagen) remodeling and ECM remodeling enzymes (such as MMPs, lysyl oxidase LOX) are strongly associated with breast cancer progression. We therefore hypothesis ECM remodeling affects tumor progression via increasing tissue stiffness. Since crosslinking of collagen I increases its mechanical strength, we tested if collagen ...

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