Papers by Elizabeth Zulick
International Journal of Molecular Sciences, May 7, 2018
We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages ... more We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER − /PR − /Her2 − and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin, VCAM1, Thrombospondin, MMP1) and an increase in CDH1/E-cadherin, previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and/or 3,3-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.
Stem Cells, Apr 1, 2018
Induced pluripotent stem cells (iPSCs) stand to revolutionize the way we study human development,... more Induced pluripotent stem cells (iPSCs) stand to revolutionize the way we study human development, model disease, and eventually, treat patients. However, these cell sources produce progeny that retain embryonic and/or fetal characteristics. The failure to mature to definitive, adulttype cells is a major barrier for iPSC-based disease modeling and drug discovery. To directly address these concerns, we have developed a chemically defined, serum and feeder-freedirected differentiation platform to generate hematopoietic stem-progenitor cells (HSPCs) and resultant adult-type progeny from iPSCs. This system allows for strict control of signaling pathways over time through growth factor and/or small molecule modulation. Through direct comparison with our previously described protocol for the production of primitive wave hematopoietic cells, we demonstrate that induced HSPCs are enhanced for erythroid and myeloid colony forming potential, and strikingly, resultant erythroid-lineage cells display enhanced expression of adult b globin indicating definitive pathway patterning. Using this system, we demonstrate the stage-specific roles of two key signaling pathways, Notch and the aryl hydrocarbon receptor (AHR), in the derivation of definitive hematopoietic cells. We illustrate the stage-specific necessity of Notch signaling in the emergence of hematopoietic progenitors and downstream definitive, adult-type erythroblasts. We also show that genetic or small molecule inhibition of the AHR results in the increased production of CD34 1 CD45 1 HSPCs while conversely, activation of the same receptor results in a block of hematopoietic cell emergence. Results presented here should have broad implications for hematopoietic stem cell transplantation and future clinical translation of iPSC-derived blood cells. STEM CELLS 2018;36:1004-1019 SIGNIFICANCE STATEMENT Induced pluripotent stem cells (iPSCs) stand to revolutionize the way we study human development, model disease, and eventually, treat patients. However, these cell sources produce progeny that retain primitive characteristics, a major barrier for disease modeling and drug discovery. We have developed a differentiation platform to create hematopoietic stemprogenitor cells from iPSCs that can produce adult-type blood cells. We demonstrate the stagespecific roles of two key signaling pathways, Notch and the aryl hydrocarbon receptor, in the derivation of definitive hematopoietic cells. These results have broad implications for hematopoietic stem cell transplantation and clinical translation of iPSC-derived blood cells.
Higher Education, Skills and Work-based Learning, Mar 28, 2023
Purpose-Amidst continued calls for the democratization of access to higher education for historic... more Purpose-Amidst continued calls for the democratization of access to higher education for historically underrepresented populations alongside the first global health crisis in a century lies the opportunity to address persistent societal needs: increasing access for underrepresented minority students to educational pathways that lead to careers in lucrative fields of science, technology, engineering and math (STEM). Design/methodology/approach-Student participants enrolled in the biotechnology pathway Associates, Bachelors and Masters programs share programmatic experience in an accelerated biotechnology program through a biannual survey grounded in the central tenets of social-cognitive career theory aimed at understanding requisite academic, social and financial support for student success. Findings-The pathway program described in this paper emerged to address the need to support underrepresented students in degree attainment and taking on roles in the growing field of biotechnology through a novel, multi-degree, multi-institutional pathway to STEM degree attainment and career success. Social implications-This work has advanced understanding about how to effectively align higher education institutions with each other and with evolving STEM labor market demands while documenting the impact of essential academic, career and social supports recognized in the literature as high impact practices in broadening participation and increasing retention of underrepresented minority students in lucrative STEM careers. Originality/value-Pathway programs which best support student success include robust mentoring, experiential learning and robust student scholarship support, part of the design of this unique pathway program. The authors share how this program utilizes high impact practices to provide low-income, underrepresented minority students with supportive, accelerated biotechnology degrees in preparation for success in the job market. What's more, of all our BS-level graduates thus far, 100% are employed and 93% within the biotechnology field. For many, the opportunity to raise their family out of poverty via a stable, high paying job is directly tied to their successes within this program.
International journal of molecular sciences, Jan 7, 2018
We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages ... more We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER/PR/Her2 and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated...
Stem cells (Dayton, Ohio), Jan 23, 2018
Induced pluripotent stem cells (iPSCs) stand to revolutionize the way we study human development,... more Induced pluripotent stem cells (iPSCs) stand to revolutionize the way we study human development, model disease, and eventually, treat patients. However, these cell sources produce progeny that retain embryonic and/or fetal characteristics. The failure to mature to definitive, adult-type cells is a major barrier for iPSC-based disease modeling and drug discovery. To directly address these concerns, we have developed a chemically defined, serum and feeder-free-directed differentiation platform to generate hematopoietic stem-progenitor cells (HSPCs) and resultant adult-type progeny from iPSCs. This system allows for strict control of signaling pathways over time through growth factor and/or small molecule modulation. Through direct comparison with our previously described protocol for the production of primitive wave hematopoietic cells, we demonstrate that induced HSPCs are enhanced for erythroid and myeloid colony forming potential, and strikingly, resultant erythroid-lineage cells ...
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Papers by Elizabeth Zulick