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Principal Investigator: Mingli Liu
Organization: MOREHOUSE SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $355,000
Funding agency: National Institute of General Medical Sciences
The current standard of care of surgery and radiochemotherapy for glioblastomas (GBM) is inadequate and has
not resulted in improved prognosis. Accumulating evidences show that the failure of using current chemo
(temozolomide, TMZ)- and radio- therapies to treat GBM and the resultant high tumor recurrence are attributed
to the presence of a small subpopulation of glioma stem cells (GSC), which is characterized by their stem cell-
like properties and aggressive behavior. Under hypoxic conditions, GSC increase the activation of several Notch
genes, which hold a prognostic implication, as upregulated Notch genes are associated with poor survival. Notch
signaling is highly active in GSC, inhibits differentiation, maintains stem-like properties, and, therefore, is
responsible for GBM tumorigenesis and stemness. Our project highlights transient receptor potential melastatin-
related-7 (TRPM7)’s role in Notch signaling and glioma treatment failure. TRPM7 encodes a Ca2+ permeable
nonselective cation channel fused with a serine/threonine kinase at its carboxyl terminus. Our group found that
the suppression of TRPM7 channels inhibits proliferation, migration, and invasion of malignant human gliomas,
indicating that TRPM7 channels may represent a novel and promising target for therapeutic intervention of
malignant glioma. Furthermore, the effect of TRPM7 on the proliferation and invasion of human glioma cell is
mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation
and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7
channels regulate GSC growth and proliferation through STAT3 and Notch signaling pathways. In addition, the
preliminary data in this proposal show that decreased expression of TRPM7 is correlated with decreased active
Notch1 intracellular domain (NICD) from the Notch1 receptor and reduced GSC marker CD133 expression in
the glioma cell lines/xenoline tested. Our results indicate that TRPM7 regulates the Notch pathway in most glioma
cell lines/xenoline despite the high heterogeneity and variations in glioma’s biological characteristics. In this
proposal, we hypothesize that TRPM7 molecular pathway is functionally connected to Notch-induced stemness,
and TRPM7 may be a novel GBM drug target. In this project, we will utilize patient-derived xenolines (PDX) that
closely mimics the biological and physiological features of in vivo real cells and tissues to test our hypothesis.
Aim 1: Determine the role of TRPM7 in the regulation of Ca2+ and Mg2+ homeostasis in GBM PDX and PDX-
GSC. Aim 2: Determine the role of the Notch signaling pathway regulated by TRPM7 in the progression of glioma
and maintenance of self-renewal and tumorigenicity of GSC using PDX and PDX-GSC. Aim 3: Investigate
whether targeting TRPM7 reduces tumor growth in mouse PDX glioma models and sensitizes tumor to TMZ-
mediated apoptosis. Accomplishing this study will delineate the molecular mechanisms of TRPM7 in the
development and progression of glioma tumorigenesis and stemness, as well as develop TRPM7 as a novel
drug target for glioma patients.
Terms: <ALDH1><ALDH1 enzyme><Aggression><Aggressive behavior><Apoptosis><Apoptosis Pathway><Autoregulation><Biologic Characteristic><Biological><Biological Characteristics><Body Tissues><CNS Cancer><CNS Tumor><CNS neoplasm><Cations><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><Central Nervous System Cancer><Central Nervous System Neoplasms><Central Nervous System Tumors><DNA-6-O-Methylguanine[protein]-L-Cysteine S-Methyltransferase><Data><Development><Down-Regulation><Drug Targeting><EC 2.1.1.63><Failure><Gene Inactivation><Gene Silencing><Genes><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Guanine-O(6)-Alkyltransferase><Heterogeneity><Homeostasis><Human><Hypoxia><Hypoxic><Infiltration><Intracellular Communication and Signaling><Invaded><Kinases><L-Serine><Ligands><MGMT><MGMT gene><Maintenance><Malignant><Malignant - descriptor><Malignant CNS Neoplasms><Malignant Glial Neoplasm><Malignant Glial Tumor><Malignant Glioma><Malignant Neuroglial Neoplasm><Malignant Neuroglial Tumor><Malignant Tumor of the CNS><Malignant Tumor of the Central Nervous System><Malignant neoplasm of central nervous system><Mediating><Methylated-DNA Protein-Cysteine Methyltransferase><Methylated-DNA-Protein-Cysteine S-Methyltransferase><Methylguanine-DNA Methyltransferase Gene><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Neuroglial Neoplasm><Neuroglial Tumor><Notch Signaling Pathway><O(6)-AGT><O(6)-Alkylguanine-DNA Alkyltransferase><O(6)-MeG-DNA Methyltransferase><O(6)-Methylguanine DNA Transmethylase><O(6)-Methylguanine Methyltransferase><O(6)-Methylguanine-DNA Methyltransferase><O6-Alkylguanine DNA Alkyltransferase><Oncogenesis><Operative Procedures><Operative Surgical Procedures><Oxygen Deficiency><Pathway interactions><Patients><Permeability><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Physiological Homeostasis><Progenitor Cells><Prognosis><Programmed Cell Death><Proliferating><Property><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><Proteolysis and Signaling Pathway of Notch><RAS Superfamily Proteins><Radiation therapy><Radiotherapeutics><Radiotherapy><Ras-Related Protein><Receptor Protein><Recurrent Neoplasm><Recurrent tumor><Regulation><Reporting><Resistance><Role><STAT3><STAT3 gene><Serine><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Stem Cell like><Surgical><Surgical Interventions><Surgical Procedure><System><Temodal><Temodar><Testing><Therapeutic Intervention><Threonine Kinase><Tissues><Trace metal><Transphosphorylases><Treatment Failure><Tumorigenicity><Variant><Variation><Vertebrate Animals><Vertebrates><Xenograft Model><aldehyde dehydrogenase 1><alkylguanine DNA alkyltransferase><biologic><biological signal transduction><cancer of the central nervous system><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemoradiation><chemoradiation therapy><chemoradiation treatment><chemoradiotherapy><developmental><expression subtypes><glial-derived tumor><glioblastoma multiforme><glioma cell line><improved><in vivo><intervention therapy><methazolastone><methylguanine DNA methyltransferase><migration><molecular sub-types><molecular subsets><molecular subtypes><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm recurrence><neuroglia neoplasm><neuroglia tumor><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><notch><notch protein><notch receptors><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><pathway><progenitor Cell growth><progenitor cell markers><progenitor growth><progenitor markers><progenitor stem cell markers><prognostic><radiation treatment><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><receptor><resistant><response><self-renew><self-renewal><siRNA><social role><spongioblastoma multiforme><standard of care><stem><stem cell biomarkers><stem cell characteristics><stem cell growth><stem cell markers><stem cells><stemness><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><temozolomide><therapy failure><transcriptional silencing><treatment with radiation><tumor><tumor growth><tumor xenograft><tumorigenesis><tumors in the central nervous system><vertebrata><xenograft transplant model><xenotransplant model>