Valerie Weaver, PhD

All cells within tissues are exposed to mechanical stimuli and these forces regulate embryogenesis and tissue development and modulate tissue homeostasis. Tissue pathologies arise when cell and tissue level forces are corrupted such as in tissue fibrosis and in tumors. Aberrant cell and tissue level forces promote diseases including malignant transformation and metastasis and modulate cancer treatment response by altering membrane receptor signaling and chromatin organization. The research program in my laboratory aims to define these forces and then to understand how cell sense and respond to these forces at the subcellular, cellular and tissue level. The goal is to understand how force modulates cell and tissue fate during early embryogenesis (gastrulation) and tissue development (branching morphogenesis) and to clarify how these forces become deregulated in and contribute to breast, pancreatic and brain cancer(s). Our work focuses on clarifying how the mechanical stiffness and three dimensional organization of the extracellular matrix (ECM) (a noncellular component of the extracellular microenvironment) and the cells contractility synergistically influence cell growth, survival, migration and tissue-specific differentiation by modulating integrin transmembrane receptors and their crosstalk with receptor tyrosine kinases and GPCRs.

To delineate molecular mechanisms we use classic cell and molecular biology approaches (gain of function, loss of function; biochemical assays, array/ChIP seq etc) in combination with supra resolution imaging and quantitative analysis at the subcellular, cellular level and tissue level using three dimensional (3D) organotypic assays. Physiological relevance is explored using a series of unique transgenic, syngeneic and xenograft mice to study mammary tissue development and mammary, pancreatic and glioblastoma malignancy combined with intravital imaging, mechanical manipulations and quantitative analysis. We analyze and manipulate fresh breast, pancreatic and brain tumor biopsies in culture and in vivo to establish clinical translation.

Cancer Focused Projects:

1. Applying transgenic and syngeneic mouse models as well as human breast tumor biopsies, organotypic culture assays, mechanical manipulations in culture and in vivo and a unique 3D bioreactor to clarify the role of mechanical force in mammary tumor progression and treatment resistance -  focusing on microRNAs, tissue inflammation, metabolic reprogramming combined with novel therapeutic strategies.
2. Using transgenic models and syngeneic manipulations to explore links between oncogenic transformation, tumor tension, and stromal desmoplasia in pancreatic tumor development and treatment resistance - focusing on tissue inflammation, stromal fibroblast contributions and tumor cell contractility. 
3. Using xenograft, syngeneic and transgenic mouse models and intra vital imaging to define and understand the interplay between the unique forces that develop during brain tumor development and following therapy and glioblastoma aggression and recurrence - focusing on tissue inflammation and metabolic reprogramming.
4. Using human breast tumor biopsies and xenografts and mechanical manipulations in transgenic and immune compromised mice we are exploring the relationship between tissue tension and stem cell/progenitor cell expansion/commitment during malignant transformation of the mammary gland.
5. Exploring links between tissue tension, tissue inflammation and tumor aggression and histophenotype in human breast tumors.
6. Assessing the relationship in human patient tissue between tissue tension, microRNAs, mammographic density, obesity and risk to malignancy.
7. Examining the role of the tumor-associated glycocalyx and tumor metastasis and treatment resistance in culture and in vivo.

Developmental Studies:

1. We are studying how tissue mechanics regulates embryogenesis using a unique in vitro model of human gastrulation.
2. We are exploring engineering approaches to optimize hepatocyte iPS expansion in culture and we are clarifying the role of cell mechanics and ECM stiffness on hepatocyte differentiation.
3. We are using unique transgenic mouse models in which cellular mechanosignaling is genetically enhanced or repressed to study mammary stem cell fate specification and mammary branching morphogenesis.

Molecular studies:

1. We are using genetic manipulations and glycomimetics combined with supra resolution imaging to explore how the glycocalyx regulates receptor tyrosine kinase receptor organization and signaling.
2. We are using 2 and 3D mechanically-tuned defined ECM substrates, biochemical assays and live imaging to study the impact of ECM stiffness on receptor tyrosine kinase receptor recycling
3. We are using scanning angle interference microscopy, single molecule force measurements, Atomic force microscopy and traction force microscopy combined with classic cell and molecular biology to explore the interplay between cell mechanics an epithelial to mesenchymal transition and motility phenotypes in 2 and 3D ECMs.
4. We are exploring the impact of tissue mechanics and tissue organization on chromatin structure, epigenetics and gene expression using genomics and molecular approaches (ChIP Seq/arrays/4C/etc) combined with live imaging and mechanical manipulations in 2 and 3D culture formats.

Students interested in a rotation project are encouraged to contact Dr. Weaver to discuss available projects.