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CoBRE Community

WVU HSC supported initiatives include:

Grant Writing skill development seminars

Technology-oriented demonstrations/workshops

Research Compliance training

Innovation, Entrepreneurship, and Commercialization Bootcamps and Lunch Series

Internal Study section review/support

 

Project Researchers:

Andrey Bobko, PhD

The importance of the tumor microenvironment (TME) in tumor progression, invasion, and therapy is widely recognized. Intermittent and hypoxic oxygenation (pO2) and extracellular acidosis (pHe) of tumor tissues are among the most established hallmarks in solid TME, while extracellular inorganic phosphate (Pi) has been recently identified as a new signaling molecule of importance in tumorigenesis (marker of metastatic potential). The αvβ3 and αvβ5 integrins are usually expressed at low levels in most adult epithelia but can be highly upregulated in some tumors. These integrins are involved in angiogenesis and metastasis of solid tumors, and their inhibition resulted in significant reduction of functional vessel density, retardation of tumor growth, and metastasis in vivo. We are developing theranostic multifunctional paramagnetic trityl probes for in vivo monitoring of basic physiological parameters (pO2, pH, Pi) using electron paramagnetic resonance-based techniques and patient-derived tumor xenograft (PDX) models. We hypothesize that the TME signature can predict levels of success for αvβ integrins based on antiangiogenic therapy. Successful completion of this proposed project will result in development of new theranostic paramagnetic multifunctional probes which can be easily modified with appropriate targeting motif to study drug therapeutic effects.

Christopher Cifarelli, MD, PhD

Wei Du, PhD

Hematopoietic stem cell transplantation (HSCT) is considered the gold standard for treatment of hematologic malignancies including leukemia. One major hurdle, which has been hampering scientific and clinical advance in the leukemia HSCT field, is the frequently observed anergy or exhaustion of donor-derived anti-tumor T cells after exposure to the intratumoral microenvironment. While bi-directional crosstalk between mesenchymal niche and leukemic cells is well documented, critical cell signaling between the mesenchymal niche cells in a patient with leukemia and transplanted donor hematopoietic stem and progenitor cells (HSPCs) remains poorly understood. We have recently employed Fanconi anemia (FA), a cancer-prone disease with extremely high incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), to study the interaction between leukemic mesenchymal niche and donor HSPCs and identified a novel immunometabolism-regulatory axis that serves as a point of convergence, connecting inflammation, cellular metabolism and cancer immunity. We will employ molecular and genetic approaches to determine the mechanistic link between leukemic mesenchymal niche and immunometabolism-regulatory axis in the formation and function of leukemia-reactive cytotoxic T-lymphocytes, and the contribution to donor anti-leukemia immunity. Successful completion of the proposed study will not only advancing our understanding of mechanisms governing the recipient niche-donor cellular crosstalk in leukemia HSCT, but also leading to a new avenue of research designed to target a novel AML-MSC secretome regulatory axis for developing innovative therapeutic strategies in leukemia and other hematologic malignancies. 

Ivan Martinez, PhD

Although recent findings have shown the importance of the newly discovered circular non-coding RNAs (circRNAs) in the process carcinogenesis, studies showing the expression of circRNAs by oncogenic viruses or the potential regulation of human circRNAs by this type of viruses have not been described in detail. Our preliminary findings suggest the discovery of two viral circRNAs expressed by the high-risk Human Papillomavirus type 16 (HPV-16) and type 18 (HPV-18) in cervical cancer (CaCx) and head and neck cancer (HNSCC) cells. Several experiments suggest that these viral circRNAs are involved in the regulation of cell proliferation and early apoptosis. Additionally to these results, we found that expression of HPV-16 oncoprotein E6 is able to change the global expression of human circRNAs in primary human cells. Some of these circRNAs such as circGSK3B, circMYBL2 and circFN1 are expressed from alternative splicing regions of genes involved in cell metabolism, cell cycle and tumor microenvironment regulation, respectively. Finally, our data shows that HPV16 E6 can regulate the expression of ADAR1, an RNA-editing factor involved in circular RNA biogenesis. The overall goals of this project are to analyze the newly discovered HPV-encoded circRNAs, to understand the regulation of human circRNAs by HPV in cancer, and to develop new therapeutic strategies for cancer therapy in a patient-derived xenograft (PDX) mouse model of HPV-related cancers.

Ed Pistilli, PhD

Immunotherapies and cytokine-based therapies have the potential to enable a patient’s own immune system to attenuate tumor growth. The cytokine interleukin-15 (IL-15) has been shown to promote NK cell maturation and CD8+ T cell numbers, making this cytokine an attractive supportive therapy for cancer patients. In addition to these effects in the immune system, we have established a role for IL-15 in promoting mitochondrial biogenesis within skeletal muscle, which would increase a skeletal muscle’s resistance to fatigue. Therefore, experiments in the laboratory are focused on these dual roles for IL-15 during tumor growth: 1) mechanisms of IL-15 in altering the tumor microenvironment by promoting tumor infiltration of NK cells and CD8 T cells; and 2) mechanisms of IL-15 in promoting mitochondrial biogenesis within skeletal muscle to attenuate muscle fatigue commonly experienced in cancer patients. We utilize a combination of cell biology methods, small animal pre-clinical models, and cancer patient tissue biopsies in our experiments. The long-term goals of the laboratory are to acquire robust data on the dual roles of IL-15 that can be translated into new therapeutic options for cancer patients, targeting the immune system and skeletal muscle.