# Calcium dynamics and signaling in glioma

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $466,125

## Abstract

PROJECT SUMMARY/ABSTRACT
Glioma, the most common and aggressive primary brain malignancy, is in dire need of novel therapeutic
approaches. Recent findings suggest that neuronal activity promotes tumor proliferation at the tumor-brain interface
via excitation of calcium (Ca2+)-permeable glutamate receptors expressed by tumor cells, leading to robust
intracellular Ca2+ waves. These exciting observations ascribe a critical role for Ca2+ influx in glioma growth, but they
do not explain whether Ca2+ waves are also relevant in the core of tumors, where proliferation occurs in the absence
of neuronal activity and synaptic input. Our preliminary data reveal a novel mechanism that allows glioma cells to
utilize Ca2+ flux toward their proliferation in the absence of neuron-tumor synapses. Indeed, we found that glioma
cells express several types of Ca2+ channels and generate tumor cell-autonomous Ca2+ waves in the absence of
neurons or glia. Such waves can be observed with Ca2+ imaging of patient-derived glioblastoma cells cultured
without other cell types in vitro, as well as imaging of patient-derived xenografts in the mouse brain in the acute
brain slice preparation. These Ca2+ waves are blocked by Co2+ and Cd2+, ionic inhibitors of Ca2+ channels. In search
for possible effectors of Ca2+ waves, we performed an unbiased dropout CRISPR screen targeting the “druggable
genome” and identified Ca2+/calmodulin-dependent protein kinase 2B (CAMK2b) as a novel essential component
of glioma growth. Indeed, pharmacologic inhibition or short hairpin RNA (shRNA) knockdown of CAMK2b impair
proliferation of patient-derived glioblastoma cultures in vitro, suggesting CAMK2b essentiality. These preliminary
observations lead us to hypothesize that tumor cell-autonomous Ca2+ waves promote glioma growth via activation
of CAMK2b and phosphorylation of protein substrates that regulate tumorigenesis. To elucidate this mechanism,
we propose the following specific aims: 1) characterize the Ca2+ channels that generate Ca2+ waves in glioma cells
and determine their impact on tumor growth in vitro and in vivo; and 2) test the hypothesis that CAMK2b represents
a crucial effector of Ca2+ waves and phosphorylates substrates that promote tumor propagation. We have
assembled a multidisciplinary team of experts to test this novel hypothesis. The proposed work will lay the
foundation for linking glioma cell electroresponsiveness to tumorigenic signaling mechanisms and holds promise
for discovery of novel targetable vulnerabilities in this therapy-resistant tumor.

## Key facts

- **NIH application ID:** 10593608
- **Project number:** 1R21NS126806-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Dimitris G. Placantonakis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $466,125
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593608

## Citation

> US National Institutes of Health, RePORTER application 10593608, Calcium dynamics and signaling in glioma (1R21NS126806-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10593608. Licensed CC0.

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