Plastic Surgery Research laboratory (Philip Lab)
Our overarching goal is to understand the cellular mechanisms underlying the regulation of transforming growth factor-beta (TGF-beta) signaling pathways and their role in diseases such as organ fibrosis, osteoarthritis, and squamous cell carcinoma. Our team uses a combination of molecular and genetic approaches employing in vitro, in vivo and ex vivo models to study the regulation of distinct TGF-beta signaling pathways, their cross-talk with other signaling pathways and networks.
Project 1: Skin and Lung Fibrosis
Fibrosis is the final, common pathological outcome of many chronic inflammatory diseases. Fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin, in and around the inflamed or damaged tissue. If the disease is progressive such as in scleroderma, fibrosis can lead to disruption of tissue architecture, organ malfunction and, ultimately, death. TGF-beta is a pleiotropic cytokine and potent pro-fibrotic factor that has been implicated in fibrosis. We have identified CD109 as a TGF-beta co-receptor that potently inhibits TGF-beta signaling in vitro and in vivo. Our goal is to understand the molecular mechanisms underlying the pathology of skin and lung fibrosis using a combination of in vitro studies using cell lines, patient samples and in vivo studies using pre-clinical mouse models of fibrosis. We are also developing CD109-based peptides as novel TGF-beta antagonists that have potential therapeutic applications for the treatment of fibrosis. A better understanding of the molecular mechanisms underlying the pathology of fibrosis may lead to novel strategies for the therapeutic treatment of fibrosis.
Project 2: Squamous Cell Carcinoma
Squamous cell carcinoma (SCC), is one of the most prevalent types of malignancy and its incidence is increasing globally. Despite intensive research, there has been limited success in blocking recurrence and metastasis that occurs in a sizable proportion of SCC patients. Our goal is to determine the molecular mechanisms by which CD109, a TGF-beta co-receptor, may regulate oncogenic potential in SCC cells in vitro and whether CD109 regulates SSC tumor growth or metastasis in vivo. Results from these studies may lead to the development of a novel CD109-based strategy for the treatment of SCC.
Project 3: Cartilage Repair/Osteoarthritis
Mature articular cartilage displays poor intrinsic healing in response to injury and its degradation is a hallmark of osteoarthritis (OA). Despite intensive research, a successful treatment for cartilage repair remains elusive. Transforming growth factor-beta (TGF-β) is a cytokine with a unique ability to maintain cartilage homeostasis. Our goal is to determine the molecular mechanisms by which distinct TGF-b signaling pathways control cartilage repair and homeostasis and to understand how aberrant regulation of TGF-b signaling may contribute to the pathogenesis of OA. Results from these studies will provide novel insights into the mechanisms underlying aberrant TGF-β action in OA and may lead to an avenue to enhance cartilage repair.
Project 4: Estrogen Receptor Related Receptors (ERRs) and their ligands in Cancer
Estrogen-receptor related receptors (ERRs) belong to the orphan nuclear receptor superfamily and consist of ERR-alpha, ERR-beta and ERR-gamma. ERRs are upregulated in breast cancer and are strongly implicated in cellular metabolism and breast cancer progression. Despite intensive efforts, no endogenous ligand other than cholesterol, has been identified for ERRs so far. We have identified a novel steroid (estradienolone, ED) in human pregnancy serum that acts as an ‘inverse agonist’ (inhibitor) of ERR activity. Our goal is to determine whether manipulation of ED or cholesterol action may be used to control ERR activity in breast cancer cells. The proposed research may lead to a unique strategy to target ED-ERR or cholesterol-ERR signaling pathway to block breast cancer progression and metastasis.
Our laboratory combines in vitro and in vivo approaches to address specific questions related to the above projects. For in vitro studies, we emphasize the use of patient samples including those obtained from scleroderma (fibrosis) and oral cancer patients. We use proteomic and genomic approaches and perform cell-based assays that measure cell proliferation, migration, invasion, ECM production, epithelial-mesenchymal transition, stemness and tumorigenicity as well as intracellular signaling mechanisms. For in vivo studies, we use several well-established mouse models including bleomycin-induced skin and lung fibrosis models and tumor growth and metastasis assays. Development of novel state of the art techniques including organoid culture and patient-derived xenograft (PDX) models are ongoing.
The research in our laboratory is supported by the Canadian Institute for Health Research (CIHR), Natural Sciences and Engineering Research Council (NSERC) and the United States Department of Defence (DOD).