Sparing effects of FLASH irradiation in patient-derived lung tissue
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PROVIDER: PRJNA1097629 | ENA |
REPOSITORIES: ENA
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Project description:This study aims to assess the effect of conventional radiotherapy compared to FLASH radiotherapy on healthy human lung tissue. FLASH radiotherapy, characterized by ultra-high dose rates, is hypothesized to spare healthy tissue from radiation-induced damage while maintaining efficacy against tumors. To achieve this goal and better characterize this sparing effect, bulk RNA sequencing analysis was conducted on 3 patients to study the molecular and cellular responses of lung tissue to both types of radiotherapy. The main objectives are to evaluate if FLASH radiotherapy effectively spares healthy lung tissue from radiation-induced damage and to understand the underlying molecular mechanisms behind this potential protective effect.
2025-09-08 | GSE263484 | GEO
Project description:We performed single-cell RNA sequencing to analyze murine lung tissues exposed to either conventional dose rate (CONV) or FLASH radiation therapy (FLASH-RT). This approach elucidated distinct early immune responses in radiation-induced lung injury and revealed protective mechanisms specific to FLASH irradiation. Systematic characterization of over 135,000 cells within the pulmonary microenvironment uncovered critical immune and stromal cell dynamics that differentiate CONV and FLASH-RT responses. These findings provide mechanistic insights into FLASH-RT's biological effects and its potential clinical applications in thoracic oncology.
2025-06-06 | GSE298566 | GEO
Project description:Ultra-high dose-rate FLASH radiotherapy spares normal tissue while promoting tumor control, yet the basis of this protection remains unknown. Using whole-abdominal irradiation, intestinal organoids, single-cell transcriptomics, spatial vascular phenotyping, and genetic, pharmacological, and physiological perturbations, we show that the intestinal FLASH effect is the result of active heterotypic vascular-epithelial crosstalk rather than passive radiochemical protection. FLASH preserves endothelial tone and perfusion along the crypt–villus axis, averting phospho-MLC–dependent vascular collapse caused by conventional irradiation. This maintains the physiological oxygen gradient and licenses early, YAP-dependent regeneration that shields transit-amplifying secretory progenitors from persistent DNA damage and drives rapid crypt reconstitution. Disrupting the oxygen gradient directly, or indirectly through endothelial VEGFR2 blockade, abolishes FLASH sparing—reinstating progenitor DNA damage, loss of DCLK1⁺ and CHGA⁺ cells, and impaired regeneration. We identify an oxygen–vasculature–YAP–progenitor axis as a central regulator of radiation-induced repair and a target to widen the therapeutic window.
2026-07-17 | GSE338639 | GEO
Project description:Ultra-high dose-rate FLASH radiotherapy spares normal tissue while promoting tumor control, yet the basis of this protection remains unknown. Using whole-abdominal irradiation, intestinal organoids, single-cell transcriptomics, spatial vascular phenotyping, and genetic, pharmacological, and physiological perturbations, we show that the intestinal FLASH effect is the result of active heterotypic vascular-epithelial crosstalk rather than passive radiochemical protection. FLASH preserves endothelial tone and perfusion along the crypt–villus axis, averting phospho-MLC–dependent vascular collapse caused by conventional irradiation. This maintains the physiological oxygen gradient and licenses early, YAP-dependent regeneration that shields transit-amplifying secretory progenitors from persistent DNA damage and drives rapid crypt reconstitution. Disrupting the oxygen gradient directly, or indirectly through endothelial VEGFR2 blockade, abolishes FLASH sparing—reinstating progenitor DNA damage, loss of DCLK1⁺ and CHGA⁺ cells, and impaired regeneration. We identify an oxygen–vasculature–YAP–progenitor axis as a central regulator of radiation-induced repair and a target to widen the therapeutic window
2026-07-17 | GSE337790 | GEO
Project description:Subcutaneous white adipose tissue (scWAT), a key metabolic and endocrine organ, is inevitably exposed during radiotherapy (RT). Although RT is a cornerstone of cancer treatment, its clinical use is limited by damage to surrounding healthy tissues. Ultra-high-dose-rate FLASH-RT has emerged as a promising approach that preserves tumor control while reducing normal tissue toxicity. Notably, conventional (CONV) RT has been associated with long-term metabolic dysfunction and white adipose tissue (WAT) impairment, particularly following childhood exposure; however, the impact of FLASH-RT on WAT remains unknown. Here, we compared the effects of FLASH- and CONV-RT on adipocyte function and scWAT homeostasis, integrating molecular, structural, and functional analyses. Experiments were conducted using the human SGBS preadipocyte/adipocyte cell line and a mouse model of proximal hind limb irradiation, employing a dedicated linear accelerator capable of delivering both modalities. In vivo analyses were performed 70 days after irradiation. In vitro, RT impaired adipogenic differentiation in a dose-dependent manner, with a relative sparing effect of FLASH-RT at 4–8 Gy, while mature adipocytes exhibited radioresistance with partial protection at 8 Gy. In vivo, both irradiation modalities reduced fat mass without affecting body weight, with a more pronounced loss following CONV-RT. Transcriptomic profiling of inguinal scWAT by RNA sequencing revealed a marked divergence between treatments. CONV-RT induced extensive transcriptional reprogramming of scWAT. Upregulated genes were enriched in inflammatory and immune-related pathways, as well as processes associated with chemotaxis, oxidative stress, and macrophage recruitment. Conversely, downregulated genes were linked to neuronal function, angiogenesis, and differentiation-related pathways, indicating a compromised neurovascular and adipogenic environment. In contrast, FLASH-RT elicited minimal transcriptional changes, with only three genes differentially expressed and no significant enrichment of biological processes. These molecular findings were supported by histological and ultrastructural analyses, which showed increased cellular damage, vacuolization, lipid spill-over, and reduced PLIN1 expression, predominantly in CONV-treated mice. In conclusion, our data suggest that WAT homeostasis is highly sensitive to conventional RT, which induces extensive transcriptional remodeling associated with inflammation and tissue dysfunction, whereas FLASH-RT largely preserves the scWAT transcriptome, tissue structure, and function, supporting its potential to mitigate long-term metabolic complications in cancer survivors.
2026-04-09 | GSE326864 | GEO
Project description:To elucidate the early mechanisms underlying the long-term neuroprotective effect of FLASH-RT in the normal brain, spatial transcriptomics (Nanostring) were performed after whole-brain irradiation of C57BL/6J mice with either 1 or 3 fractions of 10 Gy at 5.6 × 106 Gy/s (1 pulse-FLASH) or at conventional dose-rate 0.1 Gy/s. FLASH-RT induced a distinct transcriptomic signature in the cornu ammonis region 3 (CA3) and dentate gyrus (DG) neurons, with upregulation of genes encoding glutamate receptors involved in calcium signaling, long-term potentiation, and mitochondrial OXPHOS. Early transcriptional upregulation of Gria genes translated into increased AMPAR protein levels at 48 h in the DG and CA3 region and sustained higher AMPAR expression at 2 and 4 weeks post-FLASH. These findings support a durable activation of AMPAR. We propose a mechanism to explain FLASH-induced neuroprotection initiated by early calcium influx and subsequent sustained expression of glutamate AMPARs in neurons and/or neural progenitors of the CA3, potentially contributing to long-term cognitive sparing.
2026-07-07 | GSE305149 | GEO
Project description:Purpose: Tumor hypoxia is a major cause of treatment resistance, especially to radiation therapy at conventional dose rate (CONV), and we wanted to assess whether hypoxia does alter tumor sensitivity to FLASH. Methods and materials: We engrafted several tumor types (glioblastoma [GBM], head and neck cancer, and lung adenocarcinoma) subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply via vascular clamping or carbogen breathing. We irradiated tumors using a single 20-Gy fraction at either CONV or FLASH, measured oxygen tension, monitored tumor growth, and sampled tumors for bulk RNAseq and pimonidazole analysis. Next, we inhibited glycolysis with trametinib in GBM tumors to enhance FLASH efficacy. Results: Using various subcutaneous tumor models, and in contrast to CONV, FLASH retained antitumor efficacy under acute hypoxia. These findings show that in addition to normal tissue sparing, FLASH could overcome hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNAseq profiling uncovered a FLASH-specific profile in human GBM that involved cell-cycle arrest, decreased ribosomal biogenesis, and a switch from oxidative phosphorylation to glycolysis. Glycolysis inhibition by trametinib enhanced FLASH efficacy in both normal and clamped conditions. Conclusions: These data provide new and specific insights showing the efficacy of FLASH in a radiation-resistant context, proving an additional benefit of FLASH over CONV.
2024-01-24 | GSE223607 | GEO
Project description:Thoracic radiation therapy is limited by the development of acute (i.e. pneumonitis) and late (i.e. pulmonary fibrosis) side-effects. The goal of this study is to analyze, at the single cell level, the molecular impact of two radiation treatments : a conventional/clinical (CONV) modality vs. FLASH, a new radiation method that spares healthy tissue from late radiation-induced toxicities (Science Translational Medicine 6: 245ra293, 2014). We analyzed by single cell RNA sequencing (scRNAseq) dissociated lung cells from a non-irradiated control mouse (NI), a mouse 4 days after CONV thoracic irradiation (CONV) and a mouse 4 days after FLASH irradiation (FLASH). We identify transcriptional alterations induced in the distinct lung cell types after irradiation and show that FLASH irradiated lung cells present a reduced pro-inflammatory phenotype as well as a diminished activation of epithelial lung progenitor cells. In line with previous report (Radiother Oncol 124: 365-9, 2017), this study indicates that FLASH radiation therapy limits inflammation and preserves the regenerative capcity of the lung.
2019-12-07 | GSE133992 | GEO
Project description:FLASH Irradiation Modulates Immune Responses and Accelerates Lung Recovery: A Single-Cell Perspective
| PRJNA1269944 | ENA
Project description:Total body irradiation (TBI) of mice using two dose rates, conventional dose rate (CDR) versus flash dose rate (FLASH), induced transient decrease of number of LT-HScs in bone marrow and a total recovery of these cells 15 days after TBI We used microarrays to detail the global programme of gene expression underlying the recovery of LT-HSCs and identified distinct classes of up or down- regulated genes according the modality of irradiation
2015-01-01 | GSE54526 | GEO