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Genetic Events Underlying Radiation-Induced Gliomagenesis

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Presentation on theme: "Genetic Events Underlying Radiation-Induced Gliomagenesis"— Presentation transcript:

1 Genetic Events Underlying Radiation-Induced Gliomagenesis
Cristel V Camacho, PhD Sandeep Burma, PhD Department of Radiation Oncology June 27, 2013

2 The Space Radiation Problem
Solar Energetic Particles Solar particle events Coronal mass ejections NASA needs to close the knowledge gap on a broad range of biological questions Galactic Cosmic Rays (GCR) Protons (85%) Alpha particles (14%) High atomic number and high energy (HZE) particles (1%) Solar Energetic Particles Galactic Cosmic Rays I would like to start first with a brief intro into the space radiation problem, from NASA’s point of view. The space environment is very hazardous, and astronauts exposed to ionizing radiation from various sources. In particular, galactic cosmic rays are composed of ……….. This exposure poses a significant health risk for astronauts, especially for projected long-term missions to mars. In order to estimate these risks, NASA needs to close the ………. The main threat to astronauts health is the risk of cancer from …… Space radiation, comprised of energetic protons and heavy nuclei, has been shown to produce distinct biological damage compared with radiation on Earth, leading to large uncertainties in the projection of cancer and other health risks, science1.nasa.gov

3 Ionizing Radiation and Carcinogenesis
X-rays 1 GeV/n Fe γ The main threat to astronauts health is the risk of cancer from …… Heavy ion irradiation has been shown to produce distinct biological damage compared with, for example, gamma rays or x-rays, which we are more commonly exposed to on Earth. The critical target in every human cells is the genetic material. These images are 3d recontructions of DNA damage induced by either x-rays or fe particles. H2ax and 53bp1 are both markers of DNA double strand breaks. Sparse vs dense. If the double strand breaks are not properly repaired they can lead to loss of genetic material, or translocations which are hallmarks of cancer. Space radiation, comprised of energetic protons and heavy nuclei, has been shown to produce distinct biological damage compared with radiation on Earth, leading to large uncertainties in the projection of cancer and other health risks, science1.nasa.gov

4 NASA Space Radiation Laboratory (NSRL)
The heavy ion irradiations were carried out here at the NSRL. And the project anbe summarized in three parts. Frst…. Biological consequences Longterm tumorigenesis in vitro then switch to mouse models. DNA damage responses to gamma- versus particle- irradiation Cellular transformation by gamma- versus particle- irradiation Mouse models of radiation-induced gliomagenesis science1.nasa.gov

5 I. DNA damage responses to HZE particles versus gamma-rays
1 GeV/n Fe Gamma 1 GeV/n Fe Gamma γH2AX p53 (ser15) 0.5 h p53 p21 % foci remaining 1 GeV/n Fe p16/ Ink4a 1 GeV/n Fe actin Gamma 24 h Mock Gamma 1 GeV/n Fe γH2AX Time (hrs) 53BP1 ~3% ~24% ~84% Fe ions produce more complex DNA damage Fe ion-induced damage is incompletely repaired persistent DNA damage signaling damage-induced senescence reduced cell survival Survival Density of tracks, complex damage not as easily repaired. The cells responds by activating a signaling cascade that serves to halt the cell cycle, long enough for repair to take place, or permanently, blue staining. Extensive damage, cells die. To look longterm, we need to remove those road blocks, or genes known as tumor suppressors Dose (Gy) What are the long term carcinogenic consequences of persistent DSBs such as those induced by Fe ions? Mukherjee B, Camacho CV, et al., DNA Repair 2008

6 II. Ink4a/Arf-null astrocytes: A sensitive paradigm for rapidly evaluating the tumorigenic potential of HZE particles Cyclin D CDK 4/6 p16/Ink4a pRB Exon 1β Exon 1α Exon 2 Exon 3 IR p19/Arf MDM2 p53 NSCs Astrocytes IR Tumor suppressor loss Ink4a/Arf-/- Oncogene activation Tumorigenesis McEllin B, Camacho CV, et al., Cancer Research 2010 Mukherjee B, McEllin B, Camacho CV, et al., Cancer Research 2009

7 Ink4a/Arf-/- astrocytes irradiated with Fe ions are potently tumorigenic
Mock IR 20 40 60 50 100 150 200 250 Fe Gamma Mock (0/8) g 1Gy (0/8) 4Gy (2/8) Fe 1 Gy (12/12) DAY Fe 1 Gy Vol mm3 Gamma 4Gy Exon 1β Exon 1α Exon 2 Exon 3 p16/Ink4a p19/Arf Exon 1 p15/Ink4b #2 #1 Tumor Ch 4 Ctrl p15 Fe-irradiated cells generate tumors with high frequency and short latency This gene could modulate tumor growth and was there fore a critical event in the tranform proc

8 III. Transgenic mouse models of radiation-induced gliomagenesis
Ink4a+/+;Arf+/+ Ink4a/Arf f/f Ink4a-/-;Ink4b-/-;Arf f/f Ink4a-/-;Ink4b-/-;Arf f/f PTEN f/+ Rapid induction of high-grade gliomas by DNA double-strand breaks Fe 1 Gy (acute) 3 months post-IR Mock Fe Days Post-IR

9 Genomic amplification of Met is a frequent event in radiation-induced gliomas
Met FISH Amp Met Non-Amp Non-Amp Met Amp pMet pMet Sox2 Actin Par βGal Met V5-tagged V5 Merge NSC Soft-agar

10 Nestin-Cre Ink4a/Arf f/f Whole Genome aCGH Copy Number Analysis
Project Overview Nestin-Cre Ink4ab-/-;Arf f/f PTEN f/+ Nestin-Cre Ink4a+/+;Arf +/+ Nestin-Cre Ink4a/Arf f/f Nestin-Cre Ink4ab-/-;Arf f/f Mock-IR 40 40 40 40 1Gy Fe (600 MeV/n) 40 40 40 40 4Gy Gamma-rays 40 40 40 40 HZE particles vs Gamma-rays RNA Expression Profiling Whole Genome aCGH Copy Number Analysis Molecular Profiling and Validation Models slide To beettter understand the events inv in the trasfor process, which may help develop rad pro and miti strategies. Radiation Protection/Mitigation 10

11 Acknowledgements Sandeep Burma, PhD Bipasha Mukherjee, PhD
Nozomi Tomimatsu, PhD Xiaohuan Gao, PhD Brian McEllin, PhD Mariya Ilcheva Carlos Gil del Alcazar Pavlina Todorova Molly Gillam Thesis Committee Robert M Bachoo, MD, PhD David A Boothman, PhD Chaitanya S Nirodi, PhD UTSW Michael D Story, PhD Liang-Hao Ding, PhD Debabrata Saha, PhD Amyn A Habib, MD Xian-Jin Xie, PhD Kimmo Hatanpaa, MD, PhD Adayabalam S Balajee, PhD (Columbia U.) Past Members Brandon Hahm, MD Nandini Pichamoorthy Kaushik Amancherla Katherine Deland BNL/ NSRL Peter Guida, PhD Adam Rusek, PhD Funding CBP Training Grant (PI: Jerry Shay, PhD) NASA


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