bims-malgli 2023-08-13 papers

Issue of 2023‒08‒13
four papers selected by
Oltea Sampetrean
Keio University

bioRxiv. 2023 Jul 25. pii: 2023.07.23.550205. [Epub ahead of print]

Activation of the mevalonate pathway in response to anti-cancer treatments drives glioblastoma recurrences through activation of Rac-1.

Ling He, Angeliki Ioannidis, Evelyn Arambula, Carter J Hoffman, Purva Joshi, Anoushka Kathiravan, Julian Whitelegge, Linda M Liau, Harley I Kornblum, Frank Pajonk.

Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level. Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.

DOI: https://doi.org/10.1101/2023.07.23.550205

Sci Rep. 2023 Aug 11. 13(1): 13093

Transcriptional induction of NF-κB-inducing kinase by E2F4/5 facilitates collective invasion of GBM cells.

Kathryn M Pflug, Dong W Lee, Kassandra McFadden, Linda Herrera, Raquel Sitcheran.

The prognosis of high-grade gliomas, such as glioblastoma multiforme (GBM), is extremely poor due to the highly invasive nature of these aggressive cancers. Previous work has demonstrated that TNF-weak like factor (TWEAK) induction of the noncanonical NF-κB pathway promotes the invasiveness of GBM cells in an NF-κB-inducing kinase (NIK)-dependent manner. While NIK activity is predominantly regulated at the posttranslational level, we show here that NIK (MAP3K14) is upregulated at the transcriptional level in invading cell populations, with the highest NIK expression observed in the most invasive cells. GBM cells with high induction of NIK gene expression demonstrate characteristics of collective invasion, facilitating invasion of neighboring cells. Furthermore, we demonstrate that the E2F transcription factors E2F4 and E2F5 directly regulate NIK transcription and are required to promote GBM cell invasion in response to TWEAK. Overall, our findings demonstrate that transcriptional induction of NIK facilitates collective cell migration and invasion, thereby promoting GBM pathogenesis.

DOI: https://doi.org/10.1038/s41598-023-38996-9

Neuro Oncol. 2023 Aug 08. pii: noad143. [Epub ahead of print]

CDK7 and CDK9 inhibition interferes with transcription, translation and stemness, and induces cytotoxicity in GBM irrespective of temozolomide sensitivity.

Isha Bhutada, Fatema Khambati, Shi-Yuan Cheng, Deanna M Tiek, Derek Duckett, Harshani Lawrence, Michael A Vogelbaum, Qianxing Mo, Srikumar P Chellappan, Jaya Padmanabhan.

BACKGROUND: Glioblastoma (GBM) is refractory to current treatment modalities while side effects of treatments result in neurotoxicity and cognitive impairment. Here we test the hypothesis that inhibiting CDK7 or CDK9 would effectively combat GBM with reduced neurotoxicity.METHODS: We examined the effect of a CDK7 inhibitor, THZ1, and multiple CDK9 inhibitors (SNS032, AZD4573, NVP2, and JSH150) on GBM cell lines, patient-derived temozolomide (TMZ)-resistant and responsive primary tumor cells and glioma stem cells (GSCs). Biochemical changes were assessed by western blotting, immunofluorescence, multispectral imaging, and RT-PCR. In vivo efficacy was assessed in orthotopic and subcutaneous xenograft models.
RESULTS: CDK7 and CDK9 inhibitors suppressed the viability of TMZ-responsive and resistant GBM cells and GSCs at low nanomolar concentrations, with limited cytotoxic effects in vivo. The inhibitors abrogated RNA Pol II and p70S6K phosphorylation and nascent protein synthesis. Furthermore, the self-renewal of GSCs was significantly reduced with a corresponding reduction in Sox2 and Sox9 levels. Analysis of TCGA data showed increased expression of CDK7, CDK9, SOX2, SOX9, and RPS6KB1 in GBM; supporting this, multispectral imaging of a TMA revealed increased levels of CDK9, Sox2, Sox9, phospho-S6 and phospho-p70S6K in GBM compared to normal brains. RNA-Seq results suggested that inhibitors suppressed tumor promoting genes while inducing tumor suppressive genes. Further, the studies conducted on subcutaneous and orthotopic GBM tumor xenograft models showed that administration of CDK9 inhibitors markedly suppressed tumor growth in vivo.
CONCLUSION: Our results suggest that CDK7 and CDK9 targeted-therapies may be effective against TMZ-sensitive and resistant GBM.

Keywords: CDK7; CDK9; GBM; GSCs; Self-renewal; xenograft model

DOI: https://doi.org/10.1093/neuonc/noad143

Cancer Discov. 2023 Aug 11. OF1

Recurrent DNA Methylation Events Promote IDH-Mutant Gliomagenesis.

Combining Pdgfra overexpression and Cdkn2a inhibition drives gliomagenesis in vivo.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-127