Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence

Abstract

Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21−/− mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. Significance: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.

Mechanistic insights of radiation-induced endothelial senescence impelling glioblastoma genomic instability at relapse

“…This simple view has recently shifted towards recognizing the central importance of the TME 15 and a growing body of literature are now investigating the impacts of RT on TME and tumor resistance. At least, three recent publications reported that an irradiated TME increases GBM aggressiveness in orthotopic murine models 6,16,17 with no or limited investigation of underlying mechanisms. In the present work, using relevant in vitro and in vivo models, we demonstrate that alteration of the vascular TME by RT directly impacts relapsing tumor aggressiveness upon radiation.…”

“…By conferring diverse fitness advantages to tumor cells, genomic remodeling gives rise to multiple and heterogeneous subpopulations of RT-surviving GBM cells and contributes to intratumoral heterogeneity, which has been described as the root cause of tumor relapse aggressiveness and resistance to treatments. A recent study proposed a different hypothesis where pre-irradiation of the brain accelerates GBM relapse in orthotopic mouse models, in particular through radio-induced astrocyte senescence 6 .…”

Sorafenib, rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells

“…This was best demonstrated in acute myeloid leukemia models where relapse is mediated by a senescence-like resilience phenotype induced by exposure to therapy ( Duy et al, 2021 ). In addition to the precipitation of senescence in tumor cells, exposure to therapy also induces senescence in the tumor microenvironment which has also been implicated in cancer relapse ( Fletcher-Sananikone et al, 2021 ). In this case, relapse is propagated through the non-cell-autonomous effect of senescence mediated through the senescence-associated secretory phenotype ( Demaria et al, 2017 ).…”

The Inhibitory Effects of Terminalia catappa L. Extract on the Migration and Invasion of Human Glioblastoma Multiforme Cells

“…The high lethality of GBM is largely caused by its infiltrative invasion and recurrence at adjacent or distant regions of the brain after surgery [8,9]. The metastasis of cancer cells commences with the invasion of adjacent cells and the formation of new tumors [10][11][12].…”