NASA HRP Investigators Workshop

2016 NASA HRP IWS presentation in Galveston, TX

Transcript

1. Elijah Edmondson, DVM DACVP elijah.edmondson@colostate.edu Weil Lab, CSU Characterization of the Tumor Spectrum Arising in HZE ion Irradiated Outbred Mice NASA Human Research Program Investigators’ Workshop Galveston 2016
2. NNJ11ZSA001N The use of genetically diverse populations of mice to represent human heterogeneity that will elucidate the spectrum of tumor types caused by HZE nuclei as well as possible differences compared to γ-rays.
3. Uncertainties surrounding HZE ion exposures 1. Is the spectrum of HZE ion-induced tumors different from γ-induced tumors? 2. Are the mechanisms of tumorigenesis different? Dudley Goodhead, et al.
4. Heterogeneous Stock HS/Npt
5. Each mouse is a genetically unique mosaic of the 8 parental strains. *All of these strains have been completely sequenced. Mouse 20
7. 0.4 Gy HZE ions 240 MeV/n 28Si 600 MeV/n 56Fe 3.0 Gy 137Cs gamma rays Unirradiated Controls Experimental Design 613 mice, ♀ and ♂ 615 mice, ♀ and ♂ 622 mice, ♀ and ♂ • Irradiate at 7-12 weeks old, ♀ / ♂ • Monitor to 800 days of age • Necropsy, all organ systems • Tumor classification (Histo, IHC) • Neurobehavioral & Ocular exams • Map Quantitative Trait Loci (QTL)
8. Aim 1 Characterize the spectrum of tumors that arise in a genetically heterogeneous population of mice irradiated with HZE nuclei and compare it to the spectra of tumors arising in similar populations of γ-ray irradiated or unirradiated mice. 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
9. Burden of Malignant Tumors Overall Survival • Competing mortalities • Time at risk 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia HZE Gamma Unirradiated
10. Aim 2 Identify and compare quantitative trait loci (QTL) that underlie susceptibility to spontaneous, γ-ray-induced, and HZE ion-induced tumors. 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
11. 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
12. 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
13. HZE Thyroid Adenoma 3.4% γ Thyroid Adenoma 2.1% 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
14. Gamma-ray and HZE-ion Irradiated 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
15. 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia QTL Support Interval Radiation-induced Thyroid Adenoma
16. QTL Support Interval Radiation-induced Thyroid Adenoma 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
17. Key Points 1. Both HZE ions and γ-ray exposures significantly increase incidence of and decrease latency for Thyroid Adenoma 2. An identical susceptibility locus identified for both groups, indicating similar tumorigenesis mechanisms 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
18. AML Normal 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
19. * * 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
20. Most murine radiation-induced AML involve biallelic inactivation of the PU.1 gene, with one allele being lost through a radiation-induced chromosomal deletion. 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
21. ddPCR for PU.1 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
22. Deleted Not Deleted 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia ddPCR for PU.1
23. Conclusions • Both HZE ions and γ-rays increase the incidence of tumors and decrease survival of genetically diverse mice • The histotypes that are induced by γ-rays are also induced by HZE ions *However, the proportions of tumors in each group are different demonstrating different efficiencies for distinct radiation qualities • Mechanistically, HZE nuclei and γ-rays can produce tumors via similar pathways *Shared susceptibility locus (thyroid adenoma) *Shared molecular events (AML) 1.HZE vs γ: are histotypes the same? 2.HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia
24. Limitations for a mouse carcinogenesis study comparing acute Gamma-ray (3 Gy) and HZE ion (0.4 Gy) exposures Single doses—not dose responses Species differences—modeling carcinogenesis is a significant challenge Dose rate—technical limitations of protracted HZE exposures
25. Colorado State University Mike Weil Lab Chrissy Fallgren Elvin Garcia Paula Genik Todd Bass Debra Kamstock Jackson Labs Gary Churchill Daniel M. Gatti OHSU Ovidiu Dan Iancu John Belknap Jacob Raber Columbia Norman Kleiman Funded by NASA grant NNX12AB54G Acknowledgements Elijah Edmondson, DVM DACVP elijah.edmondson@gmail.com
26. Colorado State University Mike Weil Lab Chrissy Fallgren Elvin Garcia Paula Genik Todd Bass Debra Kamstock Jackson Labs Gary Churchill Daniel M. Gatti OHSU Ovidiu Dan Iancu John Belknap Jacob Raber Columbia Norman Kleiman Funded by NASA grant NNX12AB54G Questions Elijah Edmondson, DVM DACVP elijah.edmondson@gmail.com
27. Limitations for a mouse carcinogenesis study comparing acute Gamma-ray (3 Gy) and HZE ion (0.4 Gy) exposures Precise mapping of QTL is difficult for tumors: - Incomplete penetrance of a proposed susceptibility gene - Statistical power with low incidence neoplasms - Confounding causes of death after irradiation - Inherent stochastic nature of radiation tumorigenesis
28. Unirradiated Gamma HZE 1. HZE vs γ: are histotypes the same? 2. HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia 3. Osteosarcoma 3. HZE vs γ: are tumors more malignant? 1. Latency 2. Metastasis
29. Unirradiated Gamma HZE Gamma-ray HZE-ion Unirradiated Overall Tumor Burden ̧ ̦ ̧ ̦ ̧ ̦ 367 349 396 315 319 230 M:F Proportion 1.05 1.26 1.39 * p = 0.02 p = 0.10 p = 0.42 1. HZE vs γ: are histotypes the same? 2. HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia 3. Osteosarcoma 3. HZE vs γ: are tumors more malignant? 1. Latency 2. Metastasis
30. 1. HZE vs γ: are histotypes the same? 2. HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia 3. Osteosarcoma 3. HZE vs γ: are tumors more malignant? 1. Latency 2. Metastasis
31. 1. HZE vs γ: are histotypes the same? 2. HZE vs γ: is tumorigenesis the same? 1. Thyroid Adenoma 2. Myeloid Leukemia 3. Osteosarcoma 3. HZE vs γ: are tumors more malignant? 1. Latency 2. Metastasis