P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells

Muthukrishnan, Sree Deepthi; Kawaguchi, Riki; Nair, Pooja; Prasad, Rachna; Qin, Yue; Johnson, Mai; Wang, Qing; Vanderveer-Harris, Nathan; Pham, Amy Trinh; Alvarado, Alvaro G.; Condro, Michael C.; Gao, Fuying; Gau, Raymond; Castro, María G.; Löwenstein, Pedro R.; Deb, Arjun; Hinman, Jason D; Pajonk, Frank; Burns, Terry C.; Goldman, Steven A.; Geschwind, Daniel H.; Kornblum, Harley I.

doi:10.1038/s41467-022-33943-0

Cited by 20 publications

(21 citation statements)

References 57 publications

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“…However, as expected, the VC-Resist state exhibited the highest similarity to the G-STEM and 118-GS signatures (Supplementary Fig. 16A ), and some resemblance to the recently discovered p300-driven iGPC signature 51 . Indeed, it has been reported that the G-STEM state is highly dependent on YAP/TAZ pathway activation 45 and the 118-GS geneset spots a slow-cycling and resistant cell state 18 ; features that we highlighted in our own functional analyses of the VC-Resist cell state.…”

Section: Discussionsupporting

confidence: 81%

VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance

Pichol-Thievend,

Anezo,

Pettiwala

et al. 2024

Nat Commun

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Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells. Therefore, there is a pressing need to gain a deeper understanding of the mechanisms underlying GBM resistance to chemoradiation and its ability to infiltrate. Using a combination of transcriptomic, proteomic, and phosphoproteomic analyses, longitudinal imaging, organotypic cultures, functional assays, animal studies, and clinical data analyses, we demonstrate that chemoradiation and brain vasculature induce cell transition to a functional state named VC-Resist (vessel co-opting and resistant cell state). This cell state is midway along the transcriptomic axis between proneural and mesenchymal GBM cells and is closer to the AC/MES1-like state. VC-Resist GBM cells are highly vessel co-opting, allowing significant infiltration into the surrounding brain tissue and homing to the perivascular niche, which in turn induces even more VC-Resist transition. The molecular and functional characteristics of this FGFR1-YAP1-dependent GBM cell state, including resistance to DNA damage, enrichment in the G2M phase, and induction of senescence/stemness pathways, contribute to its enhanced resistance to chemoradiation. These findings demonstrate how vessel co-option, perivascular niche, and GBM cell plasticity jointly drive resistance to therapy during GBM recurrence.

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Section: Discussionsupporting

confidence: 81%

VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance

Pichol-Thievend,

Anezo,

Pettiwala

et al. 2024

Nat Commun

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“…Previous studies have demonstrated that the tumor vascular niche provides protection to GBM cells against radiotherapy (IR) 39 . Therefore, we sought to determine the role of Endocan signaling in this process.…”

Section: Endocan Protects Glioblastoma Cells From Radiotherapymentioning

confidence: 99%

“…ATAC sequencing and analysis: WTD and KOD tumor cells were processed for ATAC sequencing and repeated at least 2 independent times as previously described 39 . Briefly, 50,000 cells were washed with 50mL ice cold PBS and re-suspended in 50mL lysis buffer (10 mM Tris-HCl pH 7.4, 10 mM NaCl, 3 mM MgCl 2 , 0.2% (v/v) IGEPAL CA-630).…”

mentioning

confidence: 99%

Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma

Bastola

Ghochani³

et al. 2020

Preprint

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Glioblastoma is a lethal brain cancer with active infiltration of tumor cells at the periphery where the vascular supply is enriched to create its own niche. Given that tumor recurrence is predominantly local, most of the seeds for lethal recurrence are hidden at the tumor edge and are surgically inaccessible. Here, we found that the spatial identity of the edge-located glioblastoma cells is, in the tested models, constructed by inter-cellular signals derived from the soluble factor endocan (protein product of Esm1) that is secreted by tumor-associated vascular endothelial (VE) cells. Injection of two distinct mouse glioblastoma models into Esm1 knockout (KO) mice resulted in tumors that failed to form typical edge lesions, resulting in the formation of compact core-only lesions. In sharp contrast, tumors derived in WT (Esm1-intact) mice harbored both tumor core and edge structures. Despite these obvious phenotypic differences, the aggressiveness of these two tumor types was indistinguishable in vivo. Surprisingly, regardless of the host system, co-injection of mixture of these two tumor subpopulations gave rise tumors with much worse survival, indicating that the accumulating tumor cell heterogeneity contributes to elevate malignancy. Mechanistically, endocan competes with PDGF to bind and activate PDGFRα in human glioblastoma cells, accompanied with the upregulation of the Myc transcriptional activity via alterations in its promoter chromatin structure. One of the mainstays of glioblastoma treatment, radiation, induces endocan secretion from VE cells, which promotes the radioresistance of the edge-located glioblastoma cells, allowing for the persistence of the edge structure. Collectively, these data suggest that intra-tumoral spatial heterogeneity is initiated by the VE cell-derived endocan signals through PDGFRα to construct tumor edge-to-core (E-to-C) architecture to cause lethal tumor recurrence.

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“…Also, GSK3α/β signaling is known to have differential effects in naïve and primed embryonic stem cells (44, 45). Our previous studies suggested that radiation induced a transient multipotent state in surviving GBM cells through epigenetic remodeling (8, 46). This induced multipotent state could explain the differential effects of dopamine receptor antagonists on GBM cells and lineage committed NSCs, given the potential differences in the GSK3α/β signaling for those two cell populations.…”

Section: Discussionmentioning

confidence: 99%

Effects of Dopamine Receptor Antagonists and Radiation on Mouse Neural Stem/Progenitor Cells

Bhat

Ioannidis

et al. 2023

Preprint

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Background: Dopamine receptor antagonists are psychotropic drugs that have been originally developed against psychiatric disorders. We recently identified dopamine receptor antagonists as potential anti-cancer agents and some have entered clinical trials against glioblastoma. Radiotherapy is known to cause cognitive impairment in patients receiving cranial irradiation through the elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Methods: Using transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of enhanced green fluorescent protein, the effects of dopamine receptor antagonists alone or in combination with radiation on murine neural stem/progenitor cells were assessed in sphere-formation assays, flow cytometry and immunofluorescence in vitro and in vivo. Results: We report that several dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells both in vitro and in vivo. Hydroxyzine, trifluoperazine, amisulpride, nemonapride or quetiapine alone or in combination with radiation significantly increased the number of neural stem/progenitor cells in female neurospheres but not in male mice. Dopamine receptor antagonists either protected neural stem/progenitor cells from radiation or expanded the stem cell pool, thus indicating that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Conclusions: We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exist, making it a novel combination therapy against glioblastoma. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be taken into consideration when designing clinical trials.

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P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells

Cited by 20 publications

References 57 publications

VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance

VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance

Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma

Effects of Dopamine Receptor Antagonists and Radiation on Mouse Neural Stem/Progenitor Cells

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