Towards this quest, we have discovered a new molecular mechanism (signal transduction pathway) that we named the “STAT3-Ser/Hes3 Signaling Axis”. Various cell types use this pathway to regulate their growth and function including neural stem cells, cancer stem cells from brain tumors, and pancreatic islet cells. When we manipulate this pathway using a number of pharmacological and genetic treatments we can demonstrate its relevance to neurodegenerative disease, oncology, and diabetes.
We are constantly broadening our understanding of this pathway by performing detailed molecular studies using cell culture systems. In this way we come up with new potential manipulators of the pathway. We validate our findings using a number of in vitro systems. For example, we demonstrate that activating this pathway increases the number of cultured neural stem cells whereas inhibiting it reduces the number of cancer stem cells from aggressive brain tumors. Next, we validate key observations using disease models, opening the door towards future clinical translation. At the same time, we interact with both Academia and Industry in order to prepare for clinical translation.
Our work has resulted in several key publications in high-tier journals, including Nature, PNAS, JBC, Diabetes, etc.
We have acquired funding from government sources, foundations, and industry.
Masjkur, J., S.W. Poser, P. Nikolakopoulou, G. Chrousos, R.D. McKay, S.R. Bornstein, P.M. Jones, and A. Androutsellis-Theotokis, Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology. Diabetes, 2016. 65(2): p. 314-30.
Poser, S.W., J.G. Chenoweth, C. Colantuoni, J. Masjkur, G. Chrousos, S.R. Bornstein, R.D. McKay, and A. Androutsellis-Theotokis, Concise Review: Reprogramming, Behind the Scenes: Noncanonical Neural Stem Cell Signaling Pathways Reveal New, Unseen Regulators of Tissue Plasticity With Therapeutic Implications. Stem Cells Transl Med, 2015. 4(11): p. 1251-7.
Masjkur, J., C. Arps-Forker, S.W. Poser, P. Nikolakopoulou, L. Toutouna, R. Chenna, T. Chavakis, A. Chatzigeorgiou, L.S. Chen, A. Dubrovska, P. Choudhary, I. Uphues, M. Mark, S.R. Bornstein, and A. Androutsellis-Theotokis, Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release. J Biol Chem, 2014. 289(51): p. 35503-16.
Park, D.M., J. Jung, J. Masjkur, S. Makrogkikas, D. Ebermann, S. Saha, R. Rogliano, N. Paolillo, S. Pacioni, R.D. McKay, S. Poser, and A. Androutsellis-Theotokis, Hes3 regulates cell number in cultures from glioblastoma multiforme with stem cell characteristics. Sci Rep, 2013. 3: p. 1095.
Androutsellis-Theotokis, A., M.A. Rueger, D.M. Park, H. Mkhikian, E. Korb, S.W. Poser, S. Walbridge, J. Munasinghe, A.P. Koretsky, R.R. Lonser, and R.D. McKay, Targeting neural precursors in the adult brain rescues injured dopamine neurons. Proc Natl Acad Sci U S A, 2009. 106(32): p. 13570-5.
Androutsellis-Theotokis, A., M.A. Rueger, H. Mkhikian, E. Korb, and R.D. McKay, Signaling pathways controlling neural stem cells slow progressive brain disease. Cold Spring Harb Symp Quant Biol, 2008. 73: p. 403-10.
Androutsellis-Theotokis, A., R.R. Leker, F. Soldner, D.J. Hoeppner, R. Ravin, S.W. Poser, M.A. Rueger, S.K. Bae, R. Kittappa, and R.D. McKay, Notch signalling regulates stem cell numbers in vitro and in vivo. Nature, 2006. 442(7104): p. 823-6.