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My Chem/Biochem

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    Tumor tissue IHC

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    receptor copatching

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    spheroids

Mythreye Karthikeyan Group Site

Research

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1. TGF-β and Integrin signaling in epithelial cell survival and matrix remodeling.

Diseases such as cancer are characterized by a loss of tissue homeostasis, due to changes in the Extracellular Matrix (ECM) and adhesion molecules expressed by epithelial cells. In the absence of adhesion-derived signals, cells undergo cell death through a regulated process termed anoikis, ensuring survival only when cells are in their physiological environment. Several factors contribute to resistance to anoikis including oncogenes and modulation of integrin activity. We have recently determined that TGF-β coreceptors traffic with integrins to impact their activity, and subcellular distribution in cells and cancer tissues. While much is known about TGF-β receptor trafficking and integrin trafficking, gaps exist in understanding the cross talk between TGF-β receptors and integrins that may impact trafficking, cell survival and matrix reorganization. Our goal is to define the relationship between of TGF-β signaling and integrin biology and the impact on cancer progression in the context of breast and ovarian cancers. Figure 1. Integrin localization in tumors.

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2. Defining the intersection between growth factor/biochemical signals and mechanical cues received by cells.

Several lines of evidence have demonstrated that as cells become more invasive, they exhibit changes in the mechanical properties that may impact not just their ability to move and invade but also their ability to respond to mechanical cues. We utilize the highly dynamic model of Epithelial to Mesenchymal Transition (EMT) in cancer to study such responses. EMT is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype and is observed in both differentiated primary tumors and metastases in regions of de-differentiation, particularly at the invasive front. While there is broad experimental support for an important role of TGF-β in oncogenic EMT associated with cancer progression and a recent appreciation of the contribution of mechanical properties of cancer cells to cell invasion, less is known about how cells respond to changes in mechanical cues provided by the Extracellular Matrix and if this response is altered in cancer.  Our studies examine the functional relationship between extracellular mechanical cues (provided by an expanding stroma and ECM), and intracellular biochemical signaling pathways in cancer. Figure 2. Fibronectin fibrillogeensis visualized by TIRF.

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3. Exploring new roles for TGF-β coreceptors TGFBR3 and Endoglin in cancer.

We have recently demonstrated many novel functions for the co-receptors TGFBR3 and Endoglin. The overall objective here is to define new roles for thesecoreceptors in regulating Inhibin and GDF function in cancers that rely heavily on the presence of these co-receptors. The role of the Glycosaminoglycan modifications on the coreceptors in mediating growth factor function will also be further explored. Figure 3. Homology Model of a TGFb superfmaily member interacting with a TGFb receptor. Image by Yuri Peterson, Ph.D.

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