We have pointed out the importance of proteolysis as a mechanism of altering extracellular signaling when most people regarded proteolysis as destructive only. We discovered several matrix metalloproteinases (MMPs), including MMP-3 and -12, found that MMPs regulate pericellular proteolysis and are activated by proteinase cascades and demonstrated the significance of the tissue inhibitors of metalloproteinases (TIMPs) in regulating MMP activity. The Werb lab discovered that fragments of ECM proteins have distinct functions compared to the full-length molecules and pioneered the concept that ECM was linked to the cytoskeleton and that integrin ECM receptors were able to signal. These observations revolutionized the view of how external cues control the cellular program of gene expression, differentiation and pathogenesis.
These studies also resulted in new concepts that challenged the conventional wisdom in processes as diverse as embryonic implantation, mammary and skeletal development, wound healing, angiogenesis, stem cell biology and neoplastic progression in vivo. A central paradigm arising from these studies is that proteolysis by MMPs controls the extracellular microenvironment. These discoveries have fostered new paradigms about the role of MMPs, the microenvironment, inflammation in development and cancer and changed the way that biomedical researchers view proteolysis, from ECM destruction to extracellular signal transduction.
Work from the Werb group has provided compelling evidence that innate inflammatory cells contribute to tumorigenesis, in both pre-malignant lesions and tumors. We have shown that colleagues proteolysis mediated by MMPs was a discrete event in vascular development. It regulates VEGF bioavailability, in which the recruitment of inflammatory cells make the MMPs the key event in the angiogenic switch. This precedes progression to solid tumors.
More recently, research in the Werb laboratory has focused on the nature of the stem cell niche in development and cancer. Stem cells exist within specific niches in a quiescent state or are instructed to mobilize and proliferate following specific physiological stresses. We have found that MMPs are the key factor in regulating the transfer of stem cells from the quiescent niche to the proliferative niche, and since tumors also have stem-like cells, this paradigm is likely to be the case for neoplasia. We have developed technology for targeting stem cells for studies in development and breast cancer.
The Werb laboratory is currently focused on the nature and programming of adult tissue-specific stem cells and how these are related to stem-like tumor initiating cells, the nature of the stem cell niche in mammary development and breast cancer. They are elucidating the in vivo substrates of the MMPs and other proteases in these physiologic and disease processes.