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Published on: July 16, 2018
Optogenetic Control of the Integrated Stress Response Limits Glioblastoma Invasion
Lisa K Månsson1, Ethan Dickson2, Lun Hao3
1Materials Department, University of California Santa Barbara, Santa Barbara, California, USA.
Abstract:
The integrated stress response (ISR) is a highly conserved signaling network, allowing cells to adapt and respond to various stressors. With its aggressive spread and high recurrence rates, glioblastoma multiforme (GBM) is one of the toughest cancers to date, yet the role of the ISR is still to be well understood, whether activation may suppress or promote this disease, and drug-treatment of GBM has thus far shown inconclusive results. In this work, we use an optogenetic tool, opto-PKR, to specifically trigger ISR activation via light-induced oligomerizing PKR-kinases, offering high spatiotemporal and reversible control, while avoiding potential upstream damage or side effects from drugs. Using immunofluorescence and RNA-sequencing, we show that targeted ISR activation reaching levels where both adaptive (ATF4) and terminal responses (CHOP) are activated results in subsequent downregulation of genes associated with the extracellular environment and glial cell migration, further supported by ECM-stain and scratch assays. Next, we show inhibition of aggressive spread for ISR-activated GBM spheroids in collagen 3D culture. Photopatterning of ISR activation in spheroids demonstrates a cell-intrinsic effect at the tissue scale, and recovery studies indicate a tunable, non-ablative intervention space. These findings suggest a route to containment and motivate ISR-activating small molecule screening in GBM models.
Insights
Activating the integrated stress response (ISR) in glioblastoma multiforme (GBM) using light controls cancer cell spread. This novel optogenetic approach offers a tunable method to potentially treat aggressive GBM tumors.
Area of Science:
- Oncology
- Cellular Biology
- Biophysics
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain cancer with high recurrence rates.
- The role of the integrated stress response (ISR) in GBM progression is not well understood.
- Current GBM drug treatments have yielded inconclusive results.
Purpose of the Study:
- To investigate the role of ISR activation in GBM.
- To develop a spatiotemporal and reversible method for ISR activation in GBM.
- To assess the impact of ISR activation on GBM cell migration and spread.
Main Methods:
- Utilized an optogenetic tool (opto-PKR) to trigger ISR activation with light.
- Employed immunofluorescence and RNA-sequencing to analyze cellular responses.
- Performed ECM-stain and scratch assays to evaluate cell migration.
- Cultured GBM spheroids in 3D collagen to assess spread inhibition.
- Used photopatterning to study ISR activation effects at the tissue scale.
Main Results:
- Targeted ISR activation downregulated genes related to the extracellular environment and glial cell migration.
- ISR activation inhibited the aggressive spread of GBM spheroids in 3D culture.
- Photopatterning demonstrated a cell-intrinsic effect of ISR activation.
- Recovery studies indicated a tunable, non-ablative intervention space.
Conclusions:
- ISR activation can suppress GBM cell migration and spread.
- Optogenetic control of ISR offers a potential therapeutic strategy for GBM.
- Findings support ISR-activating small molecule screening for GBM treatment.
