Kathryn M. Eisenmann, Ph.D.
Professor of Cell and Cancer Biology
Professor of Medical Education
Director, Human Blueprint System, Undergraduate Medical Education
Director, Thread 1, Undergraduate Medical System
kathryn.eisenmann@utoledo.edu
EDUCATION:
| B.S. | 1995 | Biology | Rider University, Lawrenceville, NJ |
| Ph.D. | 2000 | Cancer Biology | University of Minnesota, Minneapolis, MN |
| Post-Doc | 2003 | Cancer Genetics | Van Andel Research Institute, Grand Rapids, MI |
| Post-Doc | 2008 | Cytoskeletal Regulation | Van Andel Research Institute, Grand Rapids, MI |
RESEARCH INTERESTS:
Project 1: Cytoskeleton dynamics in glioblastoma invasion: A novel overlooked target
At the heart of the extreme lethality of glioblastoma (GBM) is an aggressive capacity to invade into surrounding healthy tissue, allowing these brain tumors to escape surgical and radiological interventions. Rho GTPases coordinate actin dynamics to support GBM invasion, but little is known about the contribution of their downstream cytoskeleton effectors, the mDia formins, to GBM invasion. Small molecules directly inhibiting mDia-mediated F-actin assembly or that activate mDia formins have been developed. Using these small molecules, we explored roles of mDia formins in GBM invasion and uncovered a role for mDia proteins in GBM cell motility and identified a possible anti-invasive therapeutic strategy for GBM (Arden, 2015).
We revealed a role for mDia in the directional and chemotactic migration of GBM cells. Loss of mDia function or expression robustly inhibited directional migration in a wound-healing assay while random migration was only modestly inhibited. Conversely, mDia hyperactivation through incubation with compounds called intramimics robustly inhibited both directional and random migration in wound healing assays. In Transwell invasion assays, both mDia inhibition and hyperactivation inhibited chemotactically-driven, single-cell tumor invasion. In contrast, in both an in vitro spheroid invasion assay and in an ex vivo rat brain-slice model of GBM spheroid invasion, loss of mDia function moderately inhibited GBM invasion, and cells on the periphery of spheroids whose mDia activity was inhibited could still be visualized invading away from the spheroid center. In contrast, mDia hyperactivation completely blocked invasion on the periphery of these spheroids. Our discovery points to a role for mDia in maintenance of glioma cell intrinsic directionality and offer compelling evidence that mDia hyperactivation may be an effective anti-invasive therapeutic strategy in GBM.
Through use of GBM patient-derived cell lines established from surgeries at UTMC and ProMedica hospitals from our IRB-approved protocol, we showed that patient cell lines invade using different mechanisms relative to established cultured cell lines. The patient-derived GBM cell lines extend ultralong cytoskeleton projection called tumor microtubes (TMs), which are pro-invasive structures that promote radio and chemoresistance in GBM, potentially through distributing cellular stresses throughout an interconnected cellular network. We found in multiple patient-derived cells lines, including matched primary and recurrent patient tumor cell lines, that mDia formin agonists dismantle the established TM network and halt invasion in GBM neurospheres in 3D. We are currently evaluating if small molecule formin agonists overcome radio and chemoresistance by dismantling the TM network in GBM patient-derived cells.
Relevant lab papers to this project:
Arden, J.D., Lavik, K.I., Rubinic, K.A., Chiaia, N., Kuder, S.A., Howard, M.J., Nestor-Kalinoski, A.L., Alberts, A.S. and K.M. Eisenmann. 2015. Small-molecule agonists of mammalian Diaphanous-related (mDia) formins reveal and effective glioblastoma anti-invasion strategy. Mol. Biol. Cell 26(21):3704-18.
LeCorgne, H., Tudosie, A.M., Lavik, K., Su, R., Becker, K.N., Moore, S., Walia, Y., Wisner, A., Koehler, D., Alberts, A.S., Williams, F.E., and Eisenmann, K.M. 2018. Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish. Front Pharmacol. 9:340. PubMed PMID: 29692731; PubMed Central PMCID: PMC5902741.
Pettee, K.M., Becker, K., Alberts, A.S., Reinard, K., Schroeder, J., and K.M. Eisenmann.
mDia formin agonism and cytoskeleton targeting is an effective anti-invasion strategy
in glioblastoma patient-derived neurospheres. Cancers (Basel). 2019 Mar 20;11(3) 392.
doi: 10.3390/cancers11030392.
Project 2: Glioblastoma patient tumor biobanking
In 2017, in collaboration with neurosurgeons Drs. Jason Schroeder and Kevin Reinard,
we established an IRB-approved protocol with UTMC and ProMedica hospitals to collect
central nervous system tumors. Our primary focus has been in glioblastoma tumors removed
through surgical resection - both primary as well as therapy-resistant secondary tumors
from the same patients. We have biobanked 56 tumors since 2017 and established primary
cell lines for nearly all tumors. We currently have at least 3 matched pairs (primary
and matched recurrences that have failed multiple therapies), and several unmatched
therapy failed recurrent tumors, amongst others. Availability of cell lines allows
our lab and our internal and external collaborators to investigate the efficacy of
experimental drugs in a more clinically-relevant system.
FUNDING:
Ongoing Research Support
University of Toledo Foundation
Schroeder (PI)
05/01/18-04/01/23
NeuroOncology Research Training Grant (private donor)
Role: Co-PI
University of Toledo, URFO Research Innovation Program
5/2/22-6/30/23
Role of formins in therapy resistance in glioblastoma patient cell lines
Role: PI
Completed Research Support
Beyond Spring Pharmaceutics, Inc.
02/02/21-01/30/22
GBM Drug Investigational Contract
Role: PI
203000, URAF Interdisciplinary Research Initiation Award
Vestal (PI)
06/01/18-05/31/19
GBP in Glioblastoma Invasion
Role: Co-I
STUDENT OPENINGS: Not currently accepting students