CCBIO seminar: Valerie M. Weaver
Forcing tumor risk, transformation and aggression
Valerie M. Weaver
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), CA, USA
Cells experience force and possess mechanotransduction machinery to detect physical cues from their microenvironment and to transduce and biochemically amplify these signals to modulate their differentiation, growth, survival, migration and morphogenesis. Tumors are highly fibrotic and stiff and transformed cells exhibit a perturbed mechanophenotype. We have been studying how cells transduce mechanical cues to regulate their fate and how altered force compromises tissue homeostasis to increase risk to malignancy and to drive malignancy and metastasis. We found that the extracellular matrix (ECM) in breast, pancreas, skin and glioblastomas is remodeled during malignancy such that the ECM stiffens as a function of tumor progression and aggression. We determined that the stroma in the breast of women with high mammographic density who have a significantly elevated risk to malignancy contains substantially more fibrillar collagen and is significantly stiffer than that of women with moderate to low mammographic density.
A stiff ECM compromises tissue differentiation by promoting integrin focal adhesion (FA) assembly that potentiate transmembrane receptor signaling and induce cytoskeletal remodeling and actomyosin contractility. A stiff ECM also increases the frequency of stem cell in the normal tissue to elevate risk to malignancy and promotes stem-like cell expansion in tumors to drive tumor aggression. High mechanosignaling increases tumor risk in normal tissues and promotes the malignant transformation of pre-malignant cells, drives tumor cell growth, invasion and metastasis by tuning the cells actomyosin tension to enhance signaling through RhoGTPases, ERK, PI3 kinase, Myc and Wnt and by altering the function of key transcription factors and hormones such as progesterone. Tension-induced amplification of signaling promotes stem cell expansion, cell proliferation and survival and invasion and stimulates cytokine and chemokine expression that foster inflammation and drive ECM remodeling and stiffening.
I will present data supporting a role for tension in risk to malignancy and tumor progression and aggression and discuss how such findings could improve cancer therapy and prevent cancer.
Chairperson: Lars A. Akslen, CCBIO