Valerie
M. Weaver, Ph.D.
vmweaver@mail.med.upenn.edu
Assistant Professor of Pathology and Laboratory Medicine; Member
of the Institute for Medicine and Engineering
B.Sc. Biochemistry/Chemistry, University of Waterloo
B.Sc. Biochemistry (Summa Cum Laude), University of Ottawa
Ph.D. Biochemistry, University of Ottawa
Vagelos Research Labs, Room 1170
215-573-7389 (office), 215-573-8500 (lab), 215-573-7227 (fax)
Research Interests
Our laboratory studies the relationship between tissue architecture
and the plasticity of gene expression. The present objective of
our work is to delineate the molecular mechanisms driving malignant
transformation of benign breast lesions, and to understand the pathophysiology
of multi-drug resistant, metastatic breast cancer.
Our thesis is that epigenetic phenomena such as cell shape and
the organizational features of a tissue conspire with the underlying
genetic composition of the cell, to regulate expression of the malignant
phenotype, and contribute to tumor behavior. We predict that cues
from the extracellular matrix (ECM; the proteinaceous material produced
by the mesenchymal cells of the mammary gland stroma) influence
the cytoskeletal dynamics (cell shape) and spatial asymmetry (polarity)
of the mammary epithelial cells (MEC) within the tissue, to modulate
their growth, death and differentiation. At present we are focusing
on determining how ECM-directed changes in tissue architecture modify
the responsiveness of MECs to exogenous growth and death cues. To
achieve our goals we are using an interdisciplinary strategy that
relies upon interfacing classical biochemical, cell biological and
genetic concepts and methods, with biophysical and engineering approaches.
It is our hope that by obtaining a more fundamental understanding
of the inter-relationship between tissue architecture and the genetic
composition of the cell we will be able to identify new therapeutic
targets and develop preventative treatments.
Selected Publications:
Weaver, V.M., Fischer, A.H., Petersen, O.W., and Bissell, M.J.
The importance of the
micro- environment in breast cancer progression: recapitulation
of mammary tumorigenesis using a unique human mammary epithelial
cell model and a 3-dimensional culture assay. Biochem. Cell Biol.
74:833-851, 1996.
Weaver, V.M., Petersen, O.W., Wang, F., Larabell, C.A., Briand,
P., Damsky, C. and Bissell, M.J. Reversion ofthe malignant phenotype
of human breast cells in 3- dimensional culture and in vivo by integrin
blocking antibodies. J.Cell Biol. 137:1-15, 1997.
Schmeichel, K.L., Weaver, V.M., and Bissell, M.J. Structural cues
from the tissue micro-environment are essential determinants of
the human mammary epithelial cell phenotype. Journal of Mammary
Gland Biology and Neoplasia. 3:201-213, 1998.
Weaver, V.M., Wang, F., Petersen, O.W., Larabell, C. Dedhar, S.,
Briand, P., Lupu, R. and Bissell, M.J. Beta1-integrins and epidermal
growth factor receptors are cross modulated in three dimension and
not in monolayer culture: a new perspective in normal and malignant
epithelial biology. Proc. Natl. Acad. Sci. USA. 95:14821-14826,
1998.
Lelievre, S., Weaver, V.M., Nickerson, J., Larabell, C.A., Bhaumik,
A., Petersen, O., and Bissell, M.J. Tissue phenotype is dependent
on reciprocal interactions between the extracellular matrix and
the structural organization of the nucleus. Proc. Natl. Acad. Sci.
USA. 95:14711-14716, 1998.
Spancake, K.M., Anderson, C.B., Weaver, V.M., Matsunami, N., Bissell,
M.J., White, R.L. E7-transduced human breast epithelial cells show
partial differentiation in three-dimensional culture. Cancer Res.
59:6042-6045, 1999.
Weaver, V.M. and Bissell, M.J. Functional culture models for studying
mechanisms governing mammary epithelial cell apoptosis in normal
and malignant breast. J. Mammary Gland Biology Neoplasia. 4:193-201,
1999.
Lelievre, S.A., Weaver, V.M., Larabell, A.A., Bissell, M.J. Directing
apoptosis from inside out: The supramolecular organization of NuMA
is involved in cell survival. (Submitted).
Weaver, V.M., Lelievre, S.A., Jones, J., Giancotti, F., Werb, Z.,
Bissell, M.J. Beta-4 integrins induce apoptosis-resistance in three-dimensional
mammary tissue structure. (Submitted).
Bioengineering
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