Research in my laboratory is focused on defining the molecular pathways regulating neuronal cell death during development and in neuropathological conditions. Using a combination of unique transgenic mouse models, sensitive detection methods, in vitro model systems and human samples, our laboratory helped define the role of both apoptotic and non-apoptotic cell death pathways in development and neurodegenerative disease. Most recently, we have focused on the cellular origins of malignant glial tumors of the central and peripheral nervous systems and the mechanisms of chemotherapy-induced tumor cell death.
Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1 (NF1) and are notoriously difficult to treat. Radiotherapy and chemotherapy have proven largely ineffective and median MPNST patient survival is approximately five years. We have been investigating the utility of a variety of agents including tamoxifen, BH3 mimetics, and lysosomtropic agents to induce cell death in human MPNST cell lines in vitro and in transgenic mouse models of MPNSTs in vivo. We are attempting to define the cellular and molecular pathways regulating MPNST responsiveness to chemotherapeutic agents and to develop novel MPNST prevention and treatment strategies.
Another project in the laboratory is to elucidate the role of autophagy in promoting glioblastoma (GBM) survival and/or cell death. Our ongoing studies have revealed that autophagy induction can be either survival promoting or death inducing depending on tumor and treatment specific factors. We are actively investigating combinatorial therapies to manipulate the autophagy-lysosomal pathway to enhance tumor cell cytotoxicity in specific subsets of GBMs. In total, these investigations will further refine our understanding of cell death regulation and potentially lead to more effective therapies for malignant glial neoplasms.
Kaza N, Kohli L, Graham CD, Klocke BJ, Carroll SL, and Roth KA
. BNIP3 regulates AT101 [(-)-Gossypol] induced death in Malignant Peripheral Nerve Sheath Tumor Cells. PLoS One
. 2014 May 13;9(5):e96733. eCollection 2014. PMCID: PMC4019476.
Brosius SN, Turk AN, Byer SJ, Brossier NM, Kohli L, Whitmire A, Mikhail FM, Roth KA
, Carroll SL. Neuregulin-1 Overexpression and TRP53 Haploinsufficiency Cooperatively Promote de novo Malignant Peripheral Nerve Sheath Tumor Pathogenesis. Acta Neuropathol
. 2014 Apr;127(4):573-91. PMCID: PMC3999224.
Kohli L, Kaza N, Coric T, Byer SJ, Borssier NM, Klocke BJ, Bjornsti MA, Carroll SL, Roth KA
. 4-Hydroxy Tamoxifen Induces Autophagic Death through K-Ras Degradation. Cancer Research
, 73(14) July 15, 2013: 4395-4405. PMCID: PMC3715566.
Ghosh AP, Klocke BJ, Ballestas ME, Roth KA
: CHOP Potentially Co-Operates with FOXO3a in Neuronal Cells to Regulate PUMA and BIM Expression in Response to ER Stress. PLoS One
; 2012; 7(6):e39586. epub 2012 June 28. PMCID: PMC3386252.
Kohli L, Kaza N. Lavalley NJ, Turner KL, Byer S, Carroll SL, Roth KA
: The pan erbB Inhibitor PD168393 Enhances Lysosomal Dysfunction-Induced Apoptotic Death in Malignant Peripheral Nerve Sheath Tumor Cells. Neuro-Oncology
, 2012; 14(3):266-277. PMCID: PMC3280808.
Kaza N, Kohli L, Roth KA
: Autophagy in Brain Tumors: A New Target for Therapeutic Intervention. Brain Pathol
. 2012; 22:89-98. PMCID: PMC3243074.
Geng Y, Kohli L, Klocke BJ, Roth KA
: Chloroquine-Induced Autophagic Vacuole Accumulation and Cell Death in Glioma Cells is p53 Independent. Neuro-Oncology
2010; 12(5):473-481. PMCID: PMC2940627.
Walls KC, Ghosh AP, Ballestas ME, Klocke BJ, Roth KA
: bcl-2/Adenovirus E1B 19-kd Interacting Protein 3 (BNIP3) Regulates Hypoxia-Induced Neural Precursor Cell Death. J Neuropathol Exp Neurol
2009 68:1326-38. PMCID: PMC2791349.
Walls KC, Ghosh AP, Franklin AL, Klocke BJ, Ballestas M, Shacka JJ, Zhang J, Roth KA
: Lysosome Dysfunction Triggers Atg7-Dependent Neural Apoptosis. J. Biol. Chem
. 2010; 285(14):10497-10507. PMCID: PMC2856257.
Geng Y, Walls KC, Ghosh AP, Akhtar RS, Klocke BJ, Roth KA
: Cytoplasmic p53 and Activated Bax Regulate p53-Dependent, Transcription-Independent Neural Precursor Cell Apoptosis. J Histochem Cytochem
2010; 58 (3): 265-275. PMCID: PMC2825492.
Honors and Awards
– Carpenter-Rasch Award – Acknowledgement of Contributions to the Histochemical Society2007
– Elected Member, American Association of University Pathologists – Pluto Club1995
– Weil Award for the Best Paper on Experimental Neuropathology, Annual Meeting of the American Association of Neuropathologists1992, 93, 94
– Selected Lecturer of the Year by the Washington University Medical School1982-1985
– Medical Scientist Training Program Fellow, Stanford University.
Committees , Council, and Professional Society Memberships
2001 – 2005
Treasurer, Histochemical Society2004 – 2006
Assistant Secretary – Treasurer, American Association of Neuropathologists2006 – 2010
Editor-in-Chief, Journal of Histochemistry and Cytochemistry2010 – 2014
Regular Member, Neural Oxidative Metabolism and Death Study Section (NIH)2014
Endorsee of the NIH Proposed Principles and Guidelines for Reporting Preclinical Research
. Signed on behalf of the American Journal of Pathology and the American Society for Investigative Pathology2014 – 2015
President, American Society for Investigative Pathology2014 – 2015
Chairperson, Neural Oxidative Metabolism and Death Study Section (NIH)2013 – Present
Editor-in-Chief, The American Journal of Pathology
Apoptosis, autophagy, glioblastoma, malignant peripheral nerve sheath tumor (MPNST), neurofibromatosis type 1 (NF1), neuropathology