Athanasia Panopoulos Elizabeth and Michael Gallagher Assistant Professor
During embryonic development, differentiation of embryonic stem cells (ESCs) results in a loss of lineage potential as cells become more committed and functionally restricted. This process was always thought to be unidirectional. However, the discovery that somatic cells could be reprogrammed back into a pluripotent state (referred to as induced pluripotent stem cells, or iPSCs) after the transduction of four defined transcription factors forever altered our initially restricted view of cellular plasticity (Takahashi and Yamanaka, 2006), and enabled researchers new ways to study development and disease.
The long-term research goals of my laboratory are to utilize somatic cell reprogramming to provide new opportunities in targeted cancer therapeutics and regenerative medicine.
Using reprogramming to understand cancer: Increasing evidence supports the concept that instances of cancer recurrence may be due to a subpopulation of cells within a tumor that behave as stem cells. Many studies have demonstrated that these populations contain specific markers, which can vary between types of cancer. Being able to identify and target these cells is a critical step. But the fundamental question remains: how do these specific cancer cell populations acquire stem cell properties? Previous studies from our laboratory and others have demonstrated that pathways critical in oncogenesis parallel those necessary for the induction of pluripotency, suggesting that similar mechanisms regulate both processes. Could iPSC research guide us towards understanding how a cancer cell acquires stem cell properties? Can we identify novel molecular mechanisms required for reprogramming that can be utilized to target cancer cells with stem cell characteristics? One focus of my laboratory is to examine the specific mechanisms that govern reprogramming that have also been implicated in cancer. This will enable us to gain insight into the methods by which cancer cells acquire and exploit stem cell properties, in the hopes that we may be able to strategically target these cell populations to prevent malignant relapse.
Using reprogramming to understand blood cell development: Although human pluripotent stem cells (i.e. ESCs and iPSCs) have the potential to differentiate into any cell lineage in the human body, researchers have not yet been able to obtain fully functional cells for some cell types. A long-standing hurdle in the hematopoietic field has been the inability to differentiate human pluripotent stem cells into functional hematopoietic stem cells (HSCs), the cells that enable long-term reconstitution of the entire blood system. One focus of my laboratory uses reprogramming and genetics to identify novel developmental deficiencies that exist in current blood cell differentiation protocols, in hopes of obtaining fully functional human HSCs in vitro from pluripotent cells. Why blood? If we were able to successfully make HSCs from human iPSCs, then it is our hope that patients in need of a bone marrow transplant would no longer have to wait to find a bone marrow matched donor, and we could treat numerous blood diseases in ways we were not able to before.
- Gallagher Family Assistant Professor of Stem Cell Biology, University of Notre Dame, IN 2014-Present
- Director, Flow Cytometry Core Facility 2015-Present
- Postdoctoral Fellow, The Salk Institute, CA 2007-2013
- Ph.D. Immunology, MD Anderson Cancer Center, TX 2007
- Conner C, Lager TW, Guldner IH, Wu MZ, Hishida Y, Hishida T, Ruiz S, Yamasaki AE, Gilson RC, Izpisua Belmonte JC, Gray PC, Kelber JA, Zhang S, Panopoulos AD#. GRP78 promotes stemness in normal and neoplastic cells. Scientific Reports 10:3474 (2020).
- Yamasaki AE, King NE, Matsui H, Jepsen K, Panopoulos AD#. Two iPSC lines generated from the bone marrow of a relapsed/refractory AML patient display normal karyotypes and myeloid differentiation potential. Stem Cell Research 41:101587 (2019).
- D’Antonio M, Woodruff G, Nathanson JL, D’Antonio-Chronowska A, Arias A, Matsui H, Williams R, Herrera C, Reyna SM, Yeo GM, Goldstein LSB , Panopoulos AD, Frazer KA. High-throughput and cost-effective characterization of induced pluripotent stem cells. Stem Cell Reports 8:1101-1111 (2017).
- Panopoulos AD*, Smith EN*, Shepard PJ, Arias A, Modesto V, Diffenderfer K, Hishida Y, Rao F, Biggs W, Sandoval E, Conner C, Berggren T, O’Connor DT, Izpisua Belmonte JC, Frazer KA. Aberrant DNA methylation in human iPSCs associates with MYC binding motifs in a clone-specific manner independent of genetics. Cell Stem Cell 20:505-517 (2017).
- Panopoulos AD, D’Antonio M, Arias AD, Benaglio P, DeBoever C, Williams R, Garcia M, Nelson B, Harismendy O, Grinstein JD, Drees F, Okubo J, Diffenderfer KE, Hishida Y, Modesto V, Dargitz CT, Feiring R, Zhao C, Jepsen K, McGarry TJ, Matsui H, Reyna J, Aguirre A, Rao F, O’Connor DT, Yeo GW, Evans SM, Chi NC, Goldstein LSB, Izpisua Belmonte JC, Berggren WT, Adler E, D’Antonio-Chronowska A, Smith EN, Frazer KA. iPSCORE: A resource of 222 iPSC lines enabling functional characterization of genetic variation across a variety of cell types. Stem Cell Reports 8:1086-1100 (2017).
- Yamasaki AE, Panopoulos AD#, Belmonte JCI#. Understanding the genetics behind complex human disease with large-scale iPSC collections. Genome Biology 18:135 (2017).
- Panopoulos AD, Izpisua Belmonte JC. Induced pluripotent stem cells in clinical hematology: potentials, progress, and remaining obstacles. Review. Current Opinion in Hematology 19:256-260 (2012).