RESEARCH PROJECTS

Tumor Progression and Metastasis Projects

These projects are interdisciplinary, primarily utilizing ovarian and breast cancer models for examining distinct aspects of metastasis  

 

1. Late stage ovarian cancer is marked by poor patient survival due to metastatic spread in the peritoneal cavity.We utilize the highly dynamic model of Epithelial to Mesenchymal Transition (EMT) in cancer to examine intitiation of metastasis that leads to cells becoming more invasive, exhibiting changes in mechanical properties, response to mechanical cues and altered survival capabilities. Role of TGFβ members in mediating this change, and identification of key targetable mediators of this process are the central goal.

 

 

 2. Malignant ascites in the peritoneal cavity of ovarian cancer patients, harbor tumor cells that exhibit  anchorage independent survival capabilities required for metastasis.Thus, defining key signals that support anchorage independent survival in the ascites will result in new approaches to control  mortality associated with ovarian cancer. The goal here is to identify and define context dependent oncogenic signals that serve as convergence points for  cytokines such as TGFβ and Wnt that we find elevated in the ascites of patients. We anticipate that in the long-term, developing  unifying principals for growth factors will lead to improvements in cancer therapy and human health.

3. For both tumor growth and metastasis  oxygen supply is a critical requirement.  Hence cells in the tumor are actively engaged in remodeling blood vessels for this purpose. Anti-angiogenic agents are thus used in the clinic for management of multiple cancers including ovarian.

While these can be effective, side effects and toxicities  limit their use and there remains a great need to define safer and more cancer specific ways to regulate angiogenesis for the long term management of cancer . The goal here is to define novel roles for distinct TGFβ family members that are produced in a tumor specific manner. Emphasis here is on Inhibins and the role of hypoxia in ovarian cancer. These studies are also significant beyond cancer due to the broaderer physiological outcomes of hypoxia and Inhibins .

 

 

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. Thus defining mechanisms that control their availability  and  response is vital. 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.

 

 R01CA219495

 R01CA230628