Member Biography

As Assistant Professor in the Department of Obstetrics and Gynecology at Indiana University School of Medicine (IUSM), I am involved in understanding the molecular and biochemical mechanisms that enable ovarian cancer (OC) to acquire resistance to traditional chemotherapies and correlate with the metastatic progression. My current research is focused on the role of tissue transglutaminase (TG2), a protein we found to be highly expressed in OC, as a key regulator of ovarian cancer stem cells (OCSC) and on novel modalities to inhibit its functions in order to block the formation of multicellular spheroids and prevent OC metastasis. The high mortality rate correlated with OC progression is directly linked to the difficulty diagnosing the disease at early-stage and the nearly universal development of chemo-resistance. OC relapse has been related to a chemo-resistant small population of cancer stem cells (CSCs) which possess the capacity to self-renew and initiate tumors in vivo. The tumor microenvironment (TME) within spheroids acts as a favorable milieu that protects quiescent CSCs during chemotherapy and supports their tumorigenic functions. The multifunctional protein tissue transglutaminase (TG2), with enzymatic and scaffold functions, is secreted in the TME where it modulates oncogenic signaling by interacting with fibronectin (FN) and integrins. My recent data indicate that the formation of the TG2/FN complex at the cell membrane is upregulated in CSCs and activates the oncogenic Wnt/beta-catenin pathway by engaging the Wnt receptor frizzled7 (Fzd7). This receptor has been proposed as a novel stem cell-specific receptor. I proposed to use this discovery to design a new treatment for OC by generating an antibody and/or small molecule inhibitors that could disrupt the TG2/Fzd7 complex and eliminate cancer residual after chemotherapy. To accomplish this research plan, I will focus on: 1) the role of TG2 as a key modulator of Fzd7-mediated Wnt signaling in OCSC maintenance; and 2) novel modalities to inhibit its functions to prevent OC recurrence. The possible interactions between TG2 and Fzd receptors will be mapped in OC cells by using full length recombinant tagged-Fzd proteins with tagged TG2-wild type and TG2 mutants. Currently, we are using site directed mutagenesis and next generation sequencing technologies to specifically target and validate the amino acid sequences responsible for TG2/Fzd complexes interaction. In collaboration with the Chemical Genomics Core Facility at IUSM, we are building a 3D structure of TG2/Fzd7 complex. This model will be used to predict the interacting amino acid sequences and to design specific antibodies or small molecule inhibitors directed against TG2 interaction sites with Fzd7. The newly generated anti-TG2/Fzd7 monoclonal antibodies and/or the small molecule inhibitors targeting the CSC population will be tested alone or in combination with current chemotherapeutics in OC cells, organoids, and mouse models for their efficacy in blocking Wnt/beta-catenin activation, spheroids formation, clonogenic ability, and tumor initiating capacity. The development of novel strategies targeting CSCs is highly relevant. The research plan developed in my laboratory has the potential of bringing a new therapy and a new target to block tumor relapse after chemotherapy.

Post-doctoral Fellowship - University of Messina, Messina, Italy 2010

Post-doctoral Fellowship - Indiana University, Indianapolis, IN 12/2015

Ph.D. - University of Messina, Messina, Italy 01/2007