Department of Cancer Biology

Kathryn M. Eisenmann, Ph.D.

 

ke Kathryn M. Eisenmann, Ph.D.
Associate Professor 
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.

Project 1:  DIP-mediated mDia2 functional suppression is required for CXCL12-dependent amoeboid motility programs

I discovered Diaphanous-interacting protein (DIP) as the first known negative regulator of mDia2, inhibiting both F-actin elongation and bundling. The functional consequence of disruption of the cortical F-actin network was promotion of amoeboid morphological conversions and its hallmark non-apoptotic blebbing (Eisenmann, K.M. et al, 2007). Upon establishing my lab, we expanded upon this finding by identifying that the chemokine CXCL12 is a physiological trigger driving the amoeboid interconversion by inducing the mDia2:DIP complex (Wyse, M. et al, 2012; Wyse et al, 2017). This has recently been followed up by reporting that CXCL12 stimulation 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. We recently proved that carcinoma-associated fibroblasts (CAFs) are a physiological source of CXCL12 to drive an mDia2-dependent amoeboid conversion in breast cancer cells (Dvorak, 2018). Collectively, these results set the stage for our lab to be at the forefront of understanding mDia2-dependent mechanisms driving amoeboid conversions in response to the chemokine CXCL12. As CXCL12 and its receptor are frequently overexpressed in sites 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. 

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.M., Goicoechea, S., Garcia-Mata, R., Nestor-Kalinoski, A.L., Eisenmann, K.M. 2017. mDia2 and CXCL12/CXCR4 chemokine signaling intersect to drive tumor cell amoeboid morphological transitions. Biochem Biophys Res Commun. 484(2) 255-261.

Dvorak K.M., Pettee, K.M., Rubinic-Minotti, K., Su, R., Nestor-Kalinoski, A., and Eisenmann K.M. 2018. Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2). PLoS One. 13(3):e0195278. PubMed PMID: 29596520; PubMed Central PMCID: PMC5875872

Project 2: 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 mDia proteins in GBM cell motility and identified a possible anti-invasive therapeutic strategy for GBM. 

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 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 and no invasive cells were visualized 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. We are currently exploring this idea through screening of these small molecules affecting formin activity for suppression of GBM tumor cell growth and cell invasion in a zebrafish glioblastoma model, and identifying whether anti-formin drugs effectively target distinct populations of cells from human glioblastoma tumors obtained from patient surgeries. 

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., Schroeder, J., and K.M. Eisenmann.  mDia formin agonism and cytoskeleton targeting is an effective anti-invasion strategy in glioblastoma patient-derived neurospheres. Submitted 2018.

Project 3: 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 were the first group to discover (Pettee, K. et al, 2014) that RhoA-directed mDia2 activity is indeed required for tight EOC 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 uncovered 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 indicated a possible therapeutic anti-invasive avenue for targeting these highly invasive multicellular structures. This hypothesis held true when we combined chemotherapeutics such as taxol or cisplatin with formin inhibitors to potentiate the anti-proliferative effects of chemotherapeutics in ovarian cancer spheroids (Ziske et al, 2016).

We are currently exploring the role of mDia formins in supporting the actin-enriched cell-cell junctions that underlie adherens junctions that support 3D epithelial 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. 

Ziske, M., Pettee, K., Khaing, M., Rubinic, K., and K.M. Eisenmann. 2016. SMIFH2-mediated functional mDia formin inhibition potentiates chemotherapeutic targeting of human ovarian cancer spheroids. Biochem. Biophys. Res. Commun. 2016. 472(1) 33-39. 

Eisenmann bibliography

 Articles published in scientific journals
* denoted most significant since appointment
1340 citations (via Google scholar on 120418; h-index=12) 

1. 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. Melanoma chondroitin sulfate proteoglycan regulated cell spreading through Cdc42, Ack-1 and p130cas. Nature Cell Biology. 1:507-513. 1999. (cited 206 times) 

2. Chen, R., Kim, O., Yang, J., Eisenmann, K.M., Sato, K., Chan, S., Tsichilis, P.N., McCarthy, J.B., Guan, J.L., and Qui, Y. Tyrosine phosphorylation is required for Akt Activation. J. Biol. Chem. 276: 31858-31862. 2001. (cited 274 times) 

3. Eisenmann, K.M, VanBrocklin, M., Staffend, N., Kitchen, S., and Koo, H-M.  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. 2003. (Cited 166 times) 

4. Eisenmann, K.M., Peng, J., Wallar, B.J., and Alberts, A.S. Rho GTPase-Formin pairs in cytoskeletal remodeling. 2005. Novartis Found Symp. 269: 206-216. 2004. (cited 11 times) 

5. Eisenmann, K.M., Harris, E., Kitchen, S.M., Holman, H.A., Higgs, H.N., and A.S. Alberts. Dia-Interacting Protein Modulates Formin-Mediated Actin Assembly at the Cell Cortex. Current Biology. 17: 579-91. 2007. (cited 144 times) 

6. Eisenmann, K.M., West, R.A., Hildebrand, D., Kitchen, S.M., Peng, J., Sigler, R., Zhang, J., Siminovitch, K., and A.S. Alberts. T cell responses in mammalian diaphanous-related formin mDia1 knockout mice. J. Biol. Chem. 282(34): 25152-8. 2007. (cited 100 times) 

7. Peng, J., Kitchen, S.M., West, R., D., Sigler, R., Eisenmann, K.M., and A.S. Alberts, A.S. Myeloproliferative Defects Following Targeting of the Drf1 Gene Encoding the Mammalian Diaphanous-related Formin mDia1Cancer Research. 67(16): 7565-71. 2007. (cited 73 times) 

8. Gupton, S., Eisenmann, K.M., Alberts, A.S., and Waterman-Storer, C.L. mDia2 Regulates Actin Dynamics and Organization in the Lamella for Efficient Epithelial Cell Migration. J. Cell Sci. 120 (Pt 19):3475-87. 2007. (cited 133 times) 

*9. Eisenmann, K.M., Dykema, K.J., Matheson, S.F., Kent, N.F., DeWard, A.D., West, R.A., Tibes, R., Furge, K.A., and A.S. Alberts. 5q- Myelodysplastic Syndromes: Chromosome 5q Genes Direct a Tumor Suppression Network Sensing Actin Dynamics. Oncogene.  Oct 1;28(39):3429-41. 2009. (cited 68 times) 

*10. Eisenmann, K.M.*, DeWard, A.D.*. Matheson, S., and Alberts, A.S. (*equal contributors). The role of formins in human disease. Biochim. Biophys. Acta. 1803(2): 226-233. 2010. (cited 56 times) 

*11. Wyse, M., Lei, J., Nestor-Kalinoski, A., and Eisenmann, K.M. Dia-Interacting Protein (DIP) Imposes Migratory Plasticity in mDia2-Dependent Tumor Cells in Three-Dimensional Matrices. PLoS ONE. 7(9): e45085. 2012. (cited 16 times) 

12. Wagner, D.E., Eisenmann, K.M., Nestor-Kalinoski, A.L., and Bhaduri, S.  A microwave-assisted solution combustion synthesis to produce europium-doped calcium phosphate nanowhiskers for bioimaging applicationsActa Biomaterialia. 9(9):8422-32. 2013. (cited 37 times) 

*13. Pettee, K., Dvorak, K.M., Nestor-Kalinoski, A., and K.M. Eisenmann. An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids. PLoS ONE. 9(2): e90371. 2014. (cited 20 times) 

14. Liu, J., Ramakrishnam, S.K., Khuder, S.S., Kaw, M.K., Muturi, H.T., Lester, S.G., Lee, S.J., Fedorova, L.V., Kim, A., Mohamed, I.E., Gatto-Weiss, C., Eisenmann, K.M., Conran, P.B., and Najjar, S.M. 2015. High Fat Feeding Exacerbates Prostate Neoplasia in Mice with Haploinsufficiency of PTEN Tumor Suppressor. Molecular Metabolism. 4(3): 186-98. (cited 6 times) 

*15. 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. (cited 10 times) 

16. Ziske, M., Pettee, K., Khaing, M., Rubinic, K., and K.M. Eisenmann, 2016. SMIFH2-mediated functional mDia formin inhibition potentiates chemotherapeutic targeting of human ovarian cancer spheroids. Biochem. Biophys. Res. Commun. 472(1) 33-39. (cited 1 time) 

17. Karki, S.B., Yildirim-Ayan, E., Eisenmann, K.M., and Ayan, H. 2017. Miniature Dielectric Barrier Discharge Nonthermal Plasma Induces Apoptosis in Lung Cancer Cells and Inhibits Cell Migration. Biomed. Res. Int. 2017. Epub 2017 Jan 24. (cited 6 times) 

18. Wyse, M.M., Goicoechea, S., Garcia-Mata, R., Nestor-Kalinoski, A.L., and Eisenmann, K.M., mDia2 and CXCL12/CXCR4 chemokine signaling intersect to drive tumor cell amoeboid morphological transitions. 2017. Biochem Biophys Res Commun. 484(2) 255-261. (5 citations) 

19. Karki, SB, Thapa Gupta, T, Yildirim-Ayan, E, Eisenmann, KM, and Ayan, H. 2017. Investigation of non-thermal effects on lung cancer cells within 3D collagen matrices. J Physics D: Applied Physics. 50(31): 1-13. (cited 5 times) 

20. Dvorak, K.M., Pettee, K.M., Rubinic-Minotti, K., Su, R., Nestor-Kalinoski, A., and K.M. Eisenmann. 2018. Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2). PLoS ONE. 13(3), e0195278. (cited 1 time) 

21. LeCorgne, H.*, Tudosie, A.*, Lavik, K., Su, R., Wisner, A., Koehler, Daniel, Williams, F.E. and Kathryn M. Eisenmann. 2018. Differential Toxicity of mDia formin-directed agonists and antagonists in developing zebrafish. Front. Pharmacol. 9:340. 

22. Amawi, H., Hussein, N.A., Ashby Jr., C.R., Alnafisah, R., Sanglard, L.M., Elangovan, M., Chandrabose, K., Trivedi, P., Eisenmann, K.M., Robey, R.R. and Tiwari, A.K. 2018. Bax/tubulin/epithelial-mesenchymal pathways determine the efficacy of silybin analog HM015k in colorectal cancer cell growth and metastasis. Front Pharmacol. 9(520). 

*23. Pettee, K.M., Becker, K., Alberts, A.S., Schroeder, J., and K.M. Eisenmann. 2018. mDia formin agonism and cytoskeleton targeting is an effective anti-invasion strategy in glioblastoma patient-derived neurospheres. Submitted

 

 

Last Updated: 6/30/19