TY - JOUR
T1 - P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells
AU - Muthukrishnan, Sree Deepthi
AU - Kawaguchi, Riki
AU - Nair, Pooja
AU - Prasad, Rachna
AU - Qin, Yue
AU - Johnson, Maverick
AU - Wang, Qing
AU - VanderVeer-Harris, Nathan
AU - Pham, Amy
AU - Alvarado, Alvaro G.
AU - Condro, Michael C.
AU - Gao, Fuying
AU - Gau, Raymond
AU - Castro, Maria G.
AU - Lowenstein, Pedro R.
AU - Deb, Arjun
AU - Hinman, Jason D.
AU - Pajonk, Frank
AU - Burns, Terry C.
AU - Goldman, Steven A.
AU - Geschwind, Daniel H.
AU - Kornblum, Harley I.
N1 - Funding Information:
The authors thank the UCLA pathology, flow cytometry, TCGB and UNGC sequencing cores for their technical assistance with support from the Jonsson Comprehensive Cancer Center P30CA016042 and Dr. Paul Mischel for helpful discussions on the manuscript. This work was funded by Broad Stem cell postdoctoral fellowship (SDM), UCLA, The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (RK, SAG, DHG, HIK), the UCLA SPORE in Brain Cancer P50 CA211015-01A1 (FP, HIK), NIH RO1NS121617 (HK), NIH R01HL149687 (AD), NIH R01CA200234 (FP) and the UCLA Intellectual and Developmental Disability Research Center P50 HD103557 (HIK).
Funding Information:
The authors thank the UCLA pathology, flow cytometry, TCGB and UNGC sequencing cores for their technical assistance with support from the Jonsson Comprehensive Cancer Center P30CA016042 and Dr. Paul Mischel for helpful discussions on the manuscript. This work was funded by Broad Stem cell postdoctoral fellowship (SDM), UCLA, The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (RK, SAG, DHG, HIK), the UCLA SPORE in Brain Cancer P50 CA211015-01A1 (FP, HIK), NIH RO1NS121617 (HK), NIH R01HL149687 (AD), NIH R01CA200234 (FP) and the UCLA Intellectual and Developmental Disability Research Center P50 HD103557 (HIK).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.
AB - Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.
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U2 - 10.1038/s41467-022-33943-0
DO - 10.1038/s41467-022-33943-0
M3 - Article
C2 - 36261421
AN - SCOPUS:85140266953
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6202
ER -