The overall goal of the current project is to understand the impact of tissue transglutaminase (TG2) targeting in the context of ovarian cancer (OC) tumor microenvironment (TME). Our aproach is aimed at testing the hypothesis that interventions in targeting TG2 in the OC TME will disrupt pro-tumorigenic signaling cross-talk within tumors.
Ovarian cancer (OC) is the leading cause of death among gynecological malignancies. Due to the insidious symptoms, it is diagnosed in late stages (III/IV) when the cancer cells have already disseminated. A major issue in the management of this disease is that OC tumors develops resistance to drugs used in front line treatment (platinum- and taxol-based compounds). Over the past decade, several studies have reported tissue transglutaminase (TG2) overexpression in cancer. Specifically, in OC, TG2 has been shown to promote all stages of tumor progression and has been linked to chemotherapeutic resistance. Our recent data suggest decreased tumor burden concurrently with increased infiltration, activation and effector functions of T cells, and loss of immunosuppressive signals in the tumor microenvironment (TME) resulting in development of an anti-tumorigenic phenotype in TG2 knock-out mice. Based on this evidence, TG2 therapeutic targeting shows a lot of promise for the management of metastatic ovarian cancer. In OC, it is already known that stromal and immune factors in the tumor microenvironment are modulating cancer cells/spheroids adhesion and invasion capacity We propose here fundamental research activities aimed to generate a better understanding of the role of TG2 in the context of TME using inhibitors as tools for deciphering cell communication pathways between different lineages in the tumor and also, to test combinations of TG2 inhibitors and drugs targeting the metastatic niche signaling to evaluate their potential in blocking OC dissemination.
The first aim of this project is to identify the cell lineages expressing TG2 within the OC tumors (O1), and more specifically, to map the TG2/FN/integrin β1 complex to specific cell-cell communication partners. Further, we propose here the identification and co-targeting of compensatory signaling pathways enriched in cells non-responding to TG2-FN inhibitors. Also, we aim to identify druggable targets in the stromal niche that compensate against response to SMIs for potential combinatorial treatments (O2). Moreover, we will test for the first time combinations of TG2 inhibitors and signaling pathway inhibitors (O3) using a microfluidic-based approach, that will allow real time imaging of drug effects on tumor cells.
We estimate that the activities proposed within this project will allow us to identify the cell types within the tumor microenvironment that express TG2, a marker that is overexpressed in ovarian cancer (OC). The TG2-FN inhibitors are great research tools that will enable us to discover new roles played by TG2 within the communication crosstalk of different cell lineages participating in tumor progression. This knowledge can lead to identification of new druggable targets in the tumor microenvironment of patients with high TG2 expressing tumors. The generation of new 3D models of OC metastasis based on tissue engineering and microfluidic technology will allow testing the effect of inhibitors on microtumors in real time and potentially validate several combination treatments with other chemotherapeutics. Successful implementation of this project will lead to the establishment of a new research direction in the host institution consisting in the study of context-dependent cell communication in the tumor microenvironment.
We have provided evidence of an inverse correlation between high stroma TG2 expression and cytotoxic T lymphocytes intratumor infiltration (Sima LE et al., JITC, 2021), Upon implementation and development of new multiplex staining methods, we have succesfully identified stromal cells subtype expressing TG2 and mapped the interaction of TG2-integrin beta 1 in tumor microarrays. Using in vitro co-cultures, we have tested the impact of TG2 targeting by advanced imaging methods on microtissues containing relevant tumor cell lineages. Our phosphoproteomic approach generated new molecular co-targets in ovarian cancer cells that we validated by targeting with cell signaling inhibitors. Their synergistic activity was tested and we propose new combinations of potential drugs for further in vitro and preclinical development. A new microfluidics-based device was developed in collaboration with PhIL-CETAL (INFLPR), which allowed real time monitoring of apoptosis during the tested chemotherapeutic treatments.
Sima LE, Chen S, Cardenas H, Zhao G, Wang Y, Ivan C, Huang H, Zhang B, Matei D. Loss of host tissue transglutaminase boosts antitumor T cell immunity by altering STAT1/STAT3 phosphorylation in ovarian cancer. J Immunother Cancer. 2021 Sep;9(9):e002682. doi: 10.1136/jitc-2021-002682. IF = 13,75
Sima LE, Matei D, Condello S. The Outside-In Journey of Tissue Transglutaminase in Cancer. Cells. 2022 May 29;11(11):1779. IF = 7,66 (review)
Sima LE, Siqi Chen, Horacio Cardenas, Guanyuan Zhao, Cristina Ivan, Hao Huang, Yinu Wang, Bin Zhang, Daniela Matei, „Tissue transglutaminase in the tumor microenvironment: role in anti-tumor immune response”, Al XIII-lea Congres National de Citometrie, 16-18 December 2020 (virtual).
Monica Tudor, Cristian Munteanu, Gabriela Chiritoiu, Florin Jipa, Gary E. Schiltz, Daniela Matei, Livia E. Sima, „Targeting Tissue Transglutaminase in Ovarian Cancer”, Conferinta OncoHub, Editia a 2-a, organized by University of Bucharest at Poiana Brasov , 21-23 September 2022.
Sima LE, Siqi Chen, Horacio Cardenas, Guangyuan Zhao, Yinu Wang, Cristina Ivan, Hao Huang, Bin Zhang, Daniela Matei, Tissue transglutaminase as a potential therapeutic target in ovarian cancer tumor microenvironment, IUBMB-FEBS-PABMB Congress 2022 (9-14 iulie), Lisbon, Portugal