{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T11:27:52Z","timestamp":1774006072611,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,18]]},"group-title":"Cancer Biology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["Spirit IZSTZ0_198747\/1"],"award-info":[{"award-number":["Spirit IZSTZ0_198747\/1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["MAGIC-FNS CRSII5_186369"],"award-info":[{"award-number":["MAGIC-FNS CRSII5_186369"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P01CA244091"],"award-info":[{"award-number":["P01CA244091"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA254892"],"award-info":[{"award-number":["R01CA254892"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CONACYT","award":["PBZ's sabbatical in Switzerland"],"award-info":[{"award-number":["PBZ's sabbatical in Switzerland"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>FLASH-RT defines a promising treatment modality against medulloblastoma, as it minimizes treatment-related complications. To support its clinical translation, we dissected the cellular and molecular determinants of the FLASH response in the tumor-microenvironment (TME) and healthy hippocampus using an orthotopic human medulloblastoma mouse model treated with a hypo-fractionated FLASH regimen.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Five cohorts of 4 weeks-old UW228-MB-bearing female nude mice (n=57) were irradiated, or sham-irradiated using 3\u00d710 Gy (BED=60), delivered 48h apart at 0.1 Gy\/s (CONV) or 5.5\u00d710\n                    <jats:sup>6<\/jats:sup>\n                    Gy\/s (FLASH) using an electron beam (eRT6). Digital spatial profiling (DSP) was performed 24h after radiotherapy in one cohort, while the four other cohorts were followed for long-term tumor response, cognition, and neuroinflammation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Both CONV and FLASH-RT induced a complete and long-lasting anti-tumor response in 100% of animals associated with cognitive decline. However, more mice maintained a very good discrimination score after FLASH exposure (38%) than CONV (7%). DSP revealed a sustained microglial activation in the cerebellar tumor micro-environment, where FLASH enhanced expression of genes with phagocytic and proteolytic activity. In the tumor free hippocampus, FLASH exposure induced a preferential neuron\/astrocyte transcriptional crosstalk, which manifested over protracted times to minimize neuroinflammation and cognitive complications.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The study shows the tumor-ablative efficacy of hypo-fractionated FLASH-RT in a human medulloblastoma mouse model. It is associated with qualitatively distinct transcriptional signatures prone to tumor and debris clearance mediated by microglial cells of the TME. Moreover, in the hippocampus, FLASH mitigates radiation-induced neurotoxicity by enhancing genes involved in synaptic plasticity, attenuating neuroinflammation, and preserving metabolic function.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Complete response of medulloblastoma and reduction of neurotoxicity with hypo-fractionated FLASH regimen.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Clearance-prone phagocytic and proteolytic activity in the microglia of the TME.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Neuron\/astrocyte transcriptional crosstalk in the hippocampus.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Importance of the study<\/jats:title>\n                  <jats:p>This study constitutes a milestone for the future implementation of FLASH-RT in the treatment of children with brain cancer. It shows that FLASH does not protect medulloblastoma and on the contrary can be ablative when delivered in 3 fractions of 10 Gy. FLASH promotes a metabolically active, phagocytosis-prone phenotype in microglial cells consistent with immune activation and tumor surveillance, in contrast to the proliferative and immunosuppressive signaling programs induced by CONV. It also shows how FLASH may differentially shape long-term brain function in patients with brain tumors by modifying the transcriptional program of hippocampal subregions known to be critical for memory encoding, pattern separation, and consolidation. In summary, this study supports the idea that FLASH has the potential to shift treatment paradigms and change the dismal therapeutic outcome in patients with brain cancer.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.16.712103","type":"posted-content","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T10:00:25Z","timestamp":1773828025000},"source":"Crossref","is-referenced-by-count":0,"title":["Early microglial activation in the TME enables FLASH-RT to eradicate medulloblastoma while promoting neuron-astrocyte crosstalk to minimize toxicity in the hippocampus"],"prefix":"10.64898","author":[{"given":"Mich\u00e8le","family":"Knol","sequence":"first","affiliation":[{"name":"LiRR - Laboratory of Innovation in Radiobiology Applied to Radiotherapy\/Faculty of Medicine\/University of Geneva, Geneva, Switzerland"},{"name":"Radiotherapy and Radiobiology Sector, Radiation Therapy Service, University Hospital of Geneva, Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Franco-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Laboratorio Patolog\u00eda Vascular Cerebral, Instituto Nacional de Neurolog\u00eda y Neurocirug\u00eda MVS, Mexico City, Mexico"},{"name":"Former affiliation: Laboratory of Radiation Oncology\/Radiation Oncology Service\/Department of Oncology\/CHUV, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aymeric","family":"Almeida","sequence":"additional","affiliation":[{"name":"LiRR - 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