Biochemistry & Cancer Biology

Kathryn M. Eisenmann, Ph.D.

 

ke Kathryn M. Eisenmann, Ph.D.
Assistant Professor 
Biochemistry and Cancer Biology
kathryn.eisenmann@utoledo.edu 


RESEARCH INTERESTS: 

My lab is interested in how tumor cells modify their actin cytoskeleton to adapt to and move within their local environment. This is of particular importance in the context of cancer progression, where more than 90% of cancer-related deaths are attributed to metastasis. One family of proteins shown to modify the actin cytoskeleton in motile cancer cells is the mammalian Diaphanous-related formins, which act as Rho GTPase effectors. mDia proteins have been recently shown to have critical roles in diverse cellular activities, including actin and microtubule dynamics, gene transcription, cell cycle and membrane trafficking. mDia proteins act as nanomachines, nucleating, processively elongating, and (in some cases) bundling non-branched actin filaments.

DIP-mediated mDia2 functional suppression is required for CXCL12-dependent amoeboid motility programs.

I identified Diaphanous-interacting protein (DIP) as a negative regulator of mDia2 that inhibits both F-actin elongation and bundling. The functional consequence of the disruption of the cortical F-actin network was promotion of amoeboid morphological conversions and hallmark non-apoptotic blebbing (Eisenmann, K.M. et al, 2007). My lab expanded upon this finding by demonstrating that the chemokine CXCL12 is a physiological trigger driving the amoeboid interconversion by inducing the mDia2:DIP complex (Wyse, M. et al, 2012). CXCL12 stiimulation of breast cancer cells induces RhoA activation, which is required for the CXCL12-driven DIP:mDia2-dependent blebbing mechanism. We also recently discovered that the Rho GEF Net1 is required for the RhoA activation via CXCL12, and its suppression blocks blebbing. These findings are described in a manuscript recently submitted for publication (Wyse, M. et al, 2014, submitted). Collectively, these results begin to set the stage for mDia2-dependent mechanisms driving amoeboid conversions in response to the chemokine CXCL12. As CXCL12 and its receptor are frequently overexpressed in sights of distant metastasis, targeting this signaling node may lend insights into novel molecular targets for blocking tumor cell invasion and metastasis.

Relevant lab papers to this project:

Eisenmann, K.M., Harris, E., Kitchen, S.M., Holman, H.A., Higgs, H.N., and A.S. Alberts. 2007. Dia-Interacting Protein Modulates Formin-Mediated Actin Assembly at the Cell Cortex. Current Biology. 17: 579-91. Current Biology. 17: 579-91.

Eisenmann, K.M.*, DeWard, A.D.*. Matheson, S., and Alberts, A.S. (*equal contributors). 2010. The Role of Formins in Human Disease.  Biochimica et Biophysica Acta. 1803(2): 226-233.

Wyse, M., Lei, J., Nestor-Kalinoski, A., and K.M. Eisenmann. 2012. Dia-Interacting Protein (DIP) Imposes Migratory Plasticity in mDia2-Dependent Tumor Cells in Three-Dimensional Matrices. PLoS ONE. 7(9): e45085.

Wyse, M., Garcia-Mata, R., Nestor-Kalinoski, A.L., and K.M. Eisenmann. CXCL12 mediated CXCR4 engagement induces a Net1-driven RhoA-mDia2-DIP signaling node to induce tumor cell migratory plasticity. Submitted. 2014.

Wyse, M, Lavik, K., Pettee, K., Arden, J., Gunning, W., Nestor-Kalinoski, A., and K.M. Eisenmann. mDia2 suppression enhances breast cancer tumorigenicity and reorients the tumor-stromal collagen microenvironment. In preparation. 2014.


mDia2 hyperactivation is superior to its inactivation as an anti-invasive strategy for glioblastoma.

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 therapeutic attack. Rho GTPases coordinate actin dynamics to support GBM invasion, but little is known about the contribution of their downstream effectors, the mDia formins, to GBM invasion. Small molecules that directly inhibit mDia-mediated f-actin assembly or that activate mDia formins have been developed. Using these small molecules, we have explored the role of mDia formins in GBM invasion. Through this comparison, we have uncovered a role for GBM proteins in GBM cell motility and identified a possible anti-invasive therapeutic strategy for GBM. This work was recently submitted for publication (Arden, J. et al, 2014, submitted).

We revealed a role for mDia in the directional, 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 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 blocked invasion and no invasive cells were visualized on the periphery of these spheroids. Our recent results point 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.

Relevant lab papers to this project:

Arden, J.D., Chiaia, N., Kuder, S.A., Howard, M.J., Nestor-Kalinoski, A.L., Alberts, A.S. and K.M. Eisenmann. Diaphanous-related forming hyperactivation is superior to its inactivation as a glioblastoma anti-invasion strategy. Submitted. 2014.


mDia2 regulates invasive egress from ovarian cancer spheroids.

Epithelial ovarian cancer (EOC) is a particularly deadly disease often detected after it has metastasized within the peritoneal cavity. Multi-cellular spheroids are enriched in the ascites of EOC patients and they represent an invasive and chemoresistant cellular population fundamental to metastatic dissemination. The molecular mechanism triggering single cell invasive egress from spheroids has remained enigmatic, but we hypothesized that mDia formins, through regulation of the F-actin cytoskeleton, was important for this transition.

We recently published (Pettee, K. et al, 2014) that RhoA-directed mDia2 activity is indeed required for tight spheroid formation and that mDia2 is enriched at the leading edge of invasive spheroids. Depletion or functional suppression of mDia2 enhanced single cell invasive egress from EOC spheroids through induction of an amoeboid phenotype. We further discovered that a balanced interplay between ROCK and mDia2 signaling was critical for promoting invasive egress, and that simultaneous inhibition of both pathways completely blocked spheroid invasion. Our results indicate that multiple GTPase effectors must be suppressed in order to fully block invasive egress from ovarian cancer spheroids, and that tightly regulated interplay between ROCK and mDia2 signaling pathways can dictate the invasive capacities and type of invasion program utilized by motile spheroid-derived EOC cells. These results may indicate a possible therapeutic anti-invasive avenue for targeting these highly invasive multicellular structures.

Relevant lab papers to this project:

Pettee, K., Dvorak, K.M., Nestor-Kalinoski, A., and K.M. Eisenmann. 2014. An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids.  PLoS ONE 9(2): e90371.



Member of the mentoring faculty for the Biomedical Sciences Graduate Program (Cancer Biology Track)


EDUCATION:

Ph.D. 2000 Molecular, Cellular, Developmental Biology & Genetics, University of Minnesota, Twin Cities
B.S.   1995 Biology, magna cum laude, Rider University, NJ


ACADEMIC APPOINTMENTS
:

2008-present Assistant Professor, Biochemistry & Cancer Biology, University of Toledo College of Medicine, 
                    Toledo, OH
2003-2008    Postdoctoral Fellow, Laboratory of Cell Structure & Signal Integration, Van Andel
                     Research Institute, Grand Rapids, MI


PEER-REVIEWED PUBLICATIONS:

Eisenmann, K.M., McCarthy, J.B., Simpson, M.A., Keely, P.J., Guan, J.L., Tachibana, K., Lim, L., Manser, E., Furcht, L.T. and Iida, J. 1999. Melanoma chondroitin sulfate proteoglycan regulated cell spreading through Cdc42, Ack-1 and p130cas. Nature Cell Biology. 1:507-513.

Chen, R., Kim, O., Yang, J., Sato, K. Eisenmann, K.M., McCarthy, J., Chen, H., and Qui, Y. 2001. Regulation of Akt/PKB activation by tyrosine phosphorylation. J Biol Chem. 276: 31858-31862.

Eisenmann, K.M., VanBrocklin, M., Staffend, N., Kitchen, S., and Koo, H-M. 2003. Mitogen-Activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein Bad. Cancer Research. 63:8330-8337.

Eisenmann, K.M., Harris, E., Kitchen, S.M., Holman, H.A., Higgs, H.N., and A.S. Alberts. 2007. Dia-Interacting Protein Modulates Formin-Mediated Actin Assembly at the Cell Cortex. Current Biology. 17: 579-591.

Eisenmann, K.M., West, R.A., Hildebrand, D., Kitchen, S.M., Peng, J., Sigler, R., Zhang, J., Siminovitch, K., and A.S. Alberts. 2007. T Cell Responses in Mammalian Diaphanous-Related Formin mDia1 Knockout Mice. J. Biol. Chem. 282(34): 25152-25158.

Peng, J., Kitchen, S.M., West, R., D., Sigler, R., Eisenmann, K.M., and A.S. Alberts, A.S. 2007. Myeloproliferative Defects Following Targeting of the Drf1 Gene Encoding the Mammalian Diaphanous-related Formin mDia1. Cancer Research. 67(16): 7565-7571.

Gupton, S., Eisenmann, K.M., Alberts, A.S., Waterman-Storer, C.L. 2007. mDia2 Regulates Actin and Focal Adhesion Dynamics and Organization in the Lamella for Efficient Epithelial Cell Migration. J Cell Sci. 120 (Pt 19):3475-3487.

Eisenmann, K.M., Dykema, K.J., Matheson, S.F., Kent, N.F., DeWard, A.D., West, R.A., Tibes, R., Furge, K.A., and Alberts, A.S. 2010. 5q-myelodysplastic Syndromes: Chromosome 5q Genes Direct a Tumor-Suppression Network Sensing Actin Dynamics.  Oncogene 28(39):3429-3441.

Eisenmann, K.M.*, DeWard, A.D.*, Matheson, S.F. and Alberts, A.S. 2010. The Role of Formins in Human Disease.  Biochim Biophys Acta 1803(2):226-233. (*equal contributors)

Wyse, M., Lei, J., Nestor-Kalinoski, A., and K.M. Eisenmann. 2012. Dia-Interacting Protein (DIP) Imposes Migratory Plasticity in mDia2-Dependent Tumor Cells in Three-Dimensional Matrices. PLoS ONE. 7(9): e45085.

Wagner, D.E., Eisenmann, K.M., Nestor-Kalinoski, A.L., Bhaduri, S. 2013. A Microwave-Assisted Solution Combustion Synthesis to Produce Europium-Doped Calcium Phosphate Nanowhiskers for Bioimaging Applications.  Acta Biomaterialia 9(9):8422-8432.

Pettee, K., Dvorak, K.M., Nestor-Kalinoski, A., and K.M. Eisenmann. 2014. An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids. PLoS ONE. 9(2): e90371.

Liu, J., Ramakrishnam, S.K., Kaw, M.K., Khuder, S.S., Lee, S.J., Lester, S.G., Fedorova, L.V., Kim, A., Mohamed, I.E., Gatto-Weiss, C., Eisenmann, K.M., Conran, P.B., and Najjar, S.M. 2014. High Fat Feeding Exacerbates Neoplasia in Mice with Haploinsufficiency of PTEN Tumor Suppressor.  Amer. J. Pathol.  (in minor revision), 2014.


Invited Reviews

Eisenmann, K.M., Peng, J., Wallar, B.J., and Alberts, A.S. 2004. Rho GTPase-Formin pairs in cytoskeletal remodeling. 2005. Novartis Found Symp. 269: 206-216.


Last Updated: 6/26/15