Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.03.02.583088

Investigating the effects of protons versus x-rays on radiation-induced lymphopenia after brain irradiation

Coupey, J.·Pham, T. N.·Toutain, J.·Ivanova, V.·HUE, E.·Helaine, C.·Ismail, A.·Saulnier, R.·Simonin, G.·Rousseau, M.·Moignier, C.·Thariat, J.·Valable, S.
View original source ↗Export metadata ↓

Abstract

BackgroundConventional x-ray-based radiotherapy is a standard treatment for patients with brain tumors. However, is associated with systemic effects like lymphopenia that correlates with poor prognosis. Proton therapy has emerged as a new radiation strategy, given that the lower entry dose and absence of exit dose can be exploited to spare healthy brain tissues and reduce side-effects caused by systemic inflammation. We evaluated if brain irradiation with protons could spare circulating leukocytes along with other variables in rodent models. MethodsTumor-free C57BL/6 mice were irradiated with a total dose of 20Gy in 2.5Gy twice-daily sessions over four consecutive days with either x-rays or protons. Groups of mice were defined according to irradiation volume (whole-brain or hemisphere) and dose rate (1 or 2Gy/min). Blood was withdrawn at various time points and circulating lymphoid, with myeloid subpopulations analyzed using flow cytometry. Brain tissue histochemical analyses were performed late after irradiation. ResultsBlood sampling showed severe and acute radiation-induced lymphopenia after x-rays, with marked depletion of 50% CD4+ and CD8+, as well as B and NK cells. With protons, the decrease was 20% on average for whole-brain irradiations, suggesting a conservative effect on circulating lymphocytes. The data showed no effect in CD11b+ myeloid cells for both x-rays and protons. Histological analyses revealed a more intense expression level of CD68 and Iba1 immunostaining after x-ray irradiation. GFAP staining was well detected after both beams. ConclusionProton therapy for brain tumors differs from photon therapy in terms of its effects on circulating cells and tissues. Key pointsO_LIX-ray brain irradiation induced an acute severe lymphopenia, with a reduction of at least 50% lymphocytes. The whole-brain irradiation caused a more pronounced decrease in lymphocytes than hemisphere irradiation. Proton brain irradiation exhibited a conservative effect on circulating leukocytes. C_LIO_LIX-ray irradiation-induced lymphopenia is followed by a recovery of all lymphocyte subpopulations to control levels. However, this recovery is longer for CD3+ lymphocytes, and B and NK cells, depending on irradiation modalities. C_LIO_LILong-term brain tissue histochemical analyses demonstrated differences between the two beams, consisting of a macrophage/microglial activation seen mostly after x-rays while an astrocyte reaction was seen after brain exposure to the two beams. These differences may explain the disparities observed in leukocytes, thereby favoring a specific biological reaction between the brain and blood. C_LI Importance of the StudyOur study demonstrated that while whole-brain or hemispheric irradiation with x-rays resulted in lymphopenia, proton brain irradiation exhibited a conservative effect on circulating lymphocytes, which was paralleled by a less intense brain tissue reaction.

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Coupey, J., Pham, T. N., Toutain, J., Ivanova, V., HUE, E., Helaine, C., Ismail, A., Saulnier, R., Simonin, G., Rousseau, M., Moignier, C., Thariat, J., Valable, S.. 2024-03-06. Investigating the effects of protons versus x-rays on radiation-induced lymphopenia after brain irradiation. https://doi.org/10.1101/2024.03.02.583088

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Functional characterization of Rho GTPase activating proteins SYDE1 and SYDE2

The human genome encodes more than 60 proteins containing Rho GTPase activating protein (RhoGAP) domains, many of which remain understudied with respect to their target specificity and biological roles. SYDE1 and SYDE2 are two such orphan RhoGAPs, for which there are few studies characterizing their biochemical and cellular functions and conflicting reports identifying their cognate GTPases. We previously identified SYDE1 and SYDE2 in a screen for substrates of the c-Jun N-terminal kinases. Here, we show that SYDE1 and SYDE2 are preferentially phosphorylated by JNK1 relative to other mitogen-activated protein kinases (MAPKs) at sites proximal to a kinase docking region. Purified SYDE1 and SYDE2 are shown to have significant catalytic GAP activity toward RhoA, Rac1, and Cdc42. However, neither up- nor down-regulation of SYDE1/2 expression leads to detectable changes in bulk GTP loading of any of these GTPases. Nevertheless, we demonstrate that SYDE1 and SYDE2, in a partially GAP-dependent manner, increase cell spreading and number of focal adhesions, and promote more directionally persistent migration in HEK293 cells. Together, these findings establish SYDE1 and SYDE2 as robust JNK substrates with catalytic activity toward a set of Rho GTPases and reveal basic functions of SYDE1 and SYDE2 in regulating cell morphology, adhesion, and migration.

cell biology↗
bioRxiv2026

The filopodial scaffold polyphosphate dictates cell adhesion-versus-invasion decisions

Inorganic polyphosphate (polyP) is an ancient polymer conserved across all life, serving cell type and location specific functions in every major compartment. Yet its role at the plasma membrane, where it accumulates to peak levels in many primary cells, is largely unknown. Here we identify polyP as a stabilizing component of filopodia, actin based membrane protrusions that govern cell adhesion, contact inhibition, and chemotaxis. Elevating cellular polyP increases filopodial stability and enhances cell adhesion, whereas reducing polyP accelerates filopodial disassembly and promotes cell migration. Mechanistically, we find that polyP acts as a structural filopodial scaffold, recruiting and organizing IRSp53, a membrane curvature inducing protein. We show that metastatic fibroblasts and breast cancer organoids carry markedly reduced and intracellularly reorganized polyP levels relative to their non transformed counterparts. Restoring endogenous polyP via lipid nanoparticle delivery suppresses their invasive phenotypes and reverses prometastatic gene expression signatures, implicating polyP as a primordial tumor suppressor.

cell biology↗
bioRxiv2026

Mitochondrial transfer mediates metabolic communication between beta cells and islet macrophages

Pancreatic islet macrophages support islet homeostasis and adapt their metabolic program in response to environmental cues, including beta cell released factors. Intercellular mitochondrial transfer is a biological process that modulates cellular responses. To test whether beta cells, which are strongly secretory, transfer mitochondria to islet macrophages, we generated mice with beta cell-specific expression of mitochondrial GFP (PhAMfloxIns1Cre). We demonstrate that beta cells transfer mitochondria to islet macrophages in vivo and in vitro. Diabetogenic stressors did not alter the frequency of mitochondrial transfer and macrophages containing beta cell-derived GFP exhibit increased protein synthesis rates. RNA-seq identified upregulation of activity-regulated cytoskeleton associated protein (Arc) in macrophages receiving beta cell-derived mitochondria, while disruption of actin cytoskeleton dynamics prevented mitochondrial transfer. Together, these findings identify mitochondrial transfer as a previously unrecognized mechanism of beta cell-macrophage communication that may contribute to islet homeostasis and immune regulation.

cell biology↗