Tumor Progression and Metastasis Projects
These projects are interdisciplinary, primarily utilizing ovarian and breast cancer models for examining distinct aspects of metastasis
Late stage ovarian cancer is marked by poor patient survival due to metastatic spread in the peritoneal cavity. Malignant ascites in the peritoneal cavity of ovarian cancer patients, harbor tumor cells that exhibit survival capabilities and adaptations to a variety of stress responses required for metastasis. Our ongoing efforts are focused on defining key signals that support stress adaptations. The goal here is to identify and define context dependent signals that serve as convergence points for cytokines/morphogens of the TGFβ superfamily such as TGFβ/BMP/Inhibin/Activin . We anticipate that in the long-term, developing unifying principals for growth factors will lead to improvements in cancer therapy and human health.
These efforts are partially supported by CA219494 on hypoxia, inhibins and angiogenesis in ovarian cancer and a multi PI R01 (CA230628) grant on Sox2 in cell survival in ovarian cancer with Nadine Hempel
Regulation of ligand availability and receptor biology projects
These projects utilize a combination of biochemical and molecular tools to address the overarching question of how cells fine tune response to ligands. Emphasis is on post translational modifications of receptors and the impact on receptor-ligand interactions.
Alterations in signaling in response to secreted growth factors such as TGFβ, Wnt and FGF has been linked to diseases. Using the TGFβ superfamily signaling system as a model system, we are beginning to define mechanisms that control their availability and thereby fine tune responses . Receptors for most growth factors are ubiquitously distributed precluding a cell-specific, regulated response in the absence of a way to regulate immediate interaction between the released ligand and the cognate receptor. Coreceptors of the Type III TGFB receptor family namely betaglycan and endoglin are such key mediators in fine tuning receptor- ligand interactions and ligand availability .
1. Defining the cellular impact of post translational modifications on the proteoglycan coreceptor - Betaglycan/ TβRIII that can regulate availability of multiple ligands including TGFβ, Inhibin, Wnt and FGF. The goal is to utilize cell lines models, CRISPR based knock ins in cells and in mice, to better understand the role of the individual post translational modifications.
2. We will also define whether post translational modifications on the coreceptors impact intracellular trafficking routes and shedding of their extracellular domains into the environment. These are likely to affect both intracellular ligand availability/signaling and availability for paracrine responses.
3. An unbiased proteomics and genomics approach is being utilized for new discoveries that will unravel new and specific binding partners and ligands impacted by post translational modifications on the coreceptors.
These efforts are partially supported by R01CA219494