Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity

Schniewind, Iñaki; Hadiwikarta, Wahyu Wijaya; Grajek, Julia; Poleszczuk, Jan; Richter, Susan; Peitzsch, Mirko; Müller, Johannes; Klusa, Daria; Beyreuther, Elke; Löck, Steffen; Lühr, Armin; Frosch, Susanne; Groeben, Christer; Sommer, Ulrich; Krause, Mechthild; Dubrovska, Anna; Neubeck, Cläre von; Kurth, Ina; Peitzsch, Claudia

doi:10.1016/j.celrep.2022.110422

Cited by 12 publications

(6 citation statements)

References 73 publications

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“…We demonstrate that proton irradiation leads to a more pronounced loss of histone H3K9Me and downregulation of the histone variants H3f3a and H3f3b at 6 days, pivotal factors in TE silencing 53 . Consistent with our findings, previous studies have shown a differential epigenetic modulation and downregulation of histone H3 methylation in various tumors following proton irradiation 12 .…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, the normal tissue response may vary depending on the complexity of DNA damage induced by different radiation modalities, as evidenced in the context of proton therapy compared to conventional photon-based radiotherapy for cancer treatment 10 . Indeed, recent studies have revealed that proton irradiation can elicit distinct DNA damage responses and activate specific pathways [11][12][13] , leading to more effective killing of cancer cells 11,14 . However, to date, the understanding of the molecular effects of proton versus photon irradiation on normal tissue is still limited.…”

Section: Introductionmentioning

confidence: 99%

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Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Cinat,

van der Wal,

Baanstra

et al. 2024

Preprint

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The release and subsequent detection of nucleic acids into the cytoplasm constitute a hallmark of the radiation-induced DNA damage response. However, different radiation types, such as photons and protons, may elicit distinct DNA damage responses, uniquely influencing normal stem cell activity and tissue regeneration. Here, we show that proton irradiation leads to enhanced derepression of transposable elements (TEs) with consequent activation of salivary gland stem/progenitor cells. This response is mediated by a pronounced loss of heterochromatin regulators and accumulation of cytoplasmic TE-derived dsRNA, resulting in upregulation of RIG-I and augmented interferon-beta (IFN-β) signaling. Single cell RNA sequencing (scRNA-seq) and TE dynamics analyses corroborate these findings, specifically in a subpopulation of Sox9-expressing stem/progenitor cells with increased INF-β response. These data reveal that the presence of TE-derived IFN-β in the microenvironment of irradiated organoids increases stem/progenitor cell activity and organoid growth, pointing to advantages of proton therapy over photon-based radiotherapy.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Cinat,

van der Wal,

Baanstra

et al. 2024

Preprint

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“…After 24 hours, we observed a sustained increased in γH2AX+ foci expression in 2 Gy irradiated organoids, whereas signal expression in 0.5 Gy irradiated organoids resembled the control group. Accordingly, previous studies show that exposure to increasing doses of IR correlates with more complex DNA damage and delayed repair [ 80 ]. After 48 hours, γH2AX expression was similar between the 2 Gy irradiated organoids and the control group.…”

Section: Discussionmentioning

confidence: 99%

Effects of acute low-moderate dose ionizing radiation to human brain organoids

Oyefeso,

Goldberg,

Opoku

et al. 2023

PLoS ONE

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Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult to identify diagnostic and predictive biomarkers of exposure using traditional research models due to factors including lack of 3D structure in monolayer cell cultures, limited ability of animal models to accurately predict human responses, and technical limitations of studying functional human brain tissue. To address this gap, we generated brain/cerebral organoids from human induced pluripotent stem cells to study the radiosensitivity of human brain cells, including neurons, astrocytes, and oligodendrocytes. While organoids have become popular models for studying brain physiology and pathology, there is little evidence to confirm that exposing brain organoids to LMD-IR will recapitulate previous in vitro and in vivo observations. We hypothesized that exposing brain organoids to proton radiation would (1) cause a time- and dose-dependent increase in DNA damage, (2) induce cell type-specific differences in radiosensitivity, and (3) increase expression of oxidative stress and DNA damage response genes. Organoids were exposed to 0.5 or 2 Gy of 250 MeV protons and samples were collected at 30 minute, 24 hour, and 48 hour timepoints. Using immunofluorescence and RNA sequencing, we found time- and dose-dependent increases in DNA damage in irradiated organoids; no changes in cell populations for neurons, oligodendrocytes, and astrocytes by 24 hours; decreased expression of genes related to oligodendrocyte lineage, astrocyte lineage, mitochondrial function, and cell cycle progression by 48 hours; increased expression of genes related to neuron lineage, oxidative stress, and DNA damage checkpoint regulation by 48 hours. Our findings demonstrate the possibility of using organoids to characterize cell-specific radiosensitivity and early radiation-induced gene expression changes within the human brain, providing new avenues for further study of the mechanisms underlying acute neural cell responses to IR exposure at low-to-moderate doses.

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“…Although gluconeogenesis is only seen in certain specific cells, such as liver cells, the cumulation of fumarate, a well-known oncometabolite, has been shown to occur in cancer cells. The missing piece is the requisite evidence to show an altered fumarate level or fumarate hydratase activity in head and neck cancer cells, namely, FaDu cells; however, evidence has revealed metabolic reprogramming [ 36 , 37 ] and increased 2-hydroxyglutarate [ 38 ] levels in head and neck squamous cell carcinoma. The normalization of the altered metabolism could explain the elevated aspartate and malate levels after irradiation, since fumarate can be converted to malate, oxaloacetate, and then aspartate.…”

Section: Discussionmentioning

confidence: 99%

Developing a Method to Estimate the Downstream Metabolite Signals from Hyperpolarized [1-13C]Pyruvate

Hsieh

Sung

Shen

et al. 2022

Sensors

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Hyperpolarized carbon-13 MRI has the advantage of allowing the study of glycolytic flow in vivo or in vitro dynamically in real-time. The apparent exchange rate constant of a metabolite dynamic signal reflects the metabolite changes of a disease. Downstream metabolites can have a low signal-to-noise ratio (SNR), causing apparent exchange rate constant inconsistencies. Thus, we developed a method that estimates a more accurate metabolite signal. This method utilizes a kinetic model and background noise to estimate metabolite signals. Simulations and in vitro studies with photon-irradiated and control groups were used to evaluate the procedure. Simulated and in vitro exchange rate constants estimated using our method were compared with the raw signal values. In vitro data were also compared to the Area-Under-Curve (AUC) of the cell medium in 13C Nuclear Magnetic Resonance (NMR). In the simulations and in vitro experiments, our technique minimized metabolite signal fluctuations and maintained reliable apparent exchange rate constants. In addition, the apparent exchange rate constants of the metabolites showed differences between the irradiation and control groups after using our method. Comparing the in vitro results obtained using our method and NMR, both solutions showed consistency when uncertainty was considered, demonstrating that our method can accurately measure metabolite signals and show how glycolytic flow changes. The method enhanced the signals of the metabolites and clarified the metabolic phenotyping of tumor cells, which could benefit personalized health care and patient stratification in the future.

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Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity

Cited by 12 publications

References 73 publications

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Effects of acute low-moderate dose ionizing radiation to human brain organoids

Developing a Method to Estimate the Downstream Metabolite Signals from Hyperpolarized [1-13C]Pyruvate

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