Research Summary

My laboratory studies ionizing radiation, both as a carcinogen and a therapeutic. I discovered that radiation activates transforming growth factor β (TGFβ) and that TGFβ mediates DNA damage repair by homologous recombination, non-homologous end-joining and alternative end-joining. TGFβ also regulates the composition of the irradiated tumor microenvironment, particularly immune cell phenotypes. Detailed understanding of how TGFβ contributes to therapeutic response in preclinical models of breast, brain, lung and head and neck cancer has generated new rationales for clinical applications of TGFβ inhibitors.

In carcinogenesis, we use mouse models to study the mechanisms by which radiation increases breast cancer. Understanding the etiology of cancer is founded upon understanding of normal tissue biology and is advanced by application of systems biology approaches. We study the mammary gland in terms of stromal-epithelial interactions, regulation of mammary hierarchy and differentiation, and the functions of TGFβ and BRCA1. We have described radiation effects in cell-cell interactions, tissue composition and cell phenotype as a function of radiation type, dose and age at exposure in normal mammary gland and their consequences in carcinogenesis. These studies have generated new understanding of the biological mechanisms underlying radiation risks and insights for the means to protect irradiated populations after exposure.

Research Funding

  • April 1, 2019 - March 31, 2024 - Definition of Immune Infiltrate Phenotype and DNA Damage Response Deficits Across Diverse Murine Mammary Carcinomas, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01CA239235
  • February 1, 2019 - January 31, 2024 - Reorienting the Glioblastoma Microenvironment to Respond to Immunotherapy, Principal Investigator. Sponsor: NIH/NINDS, Sponsor Award ID: R01NS109911
  • January 1, 2017 - December 31, 2020 - Dual benefit of TGFß inhibition on tumor control in the context of radiotherapy for breast cancer brain metastasis, Co-PI. Sponsor: DOD-BCRP, Sponsor Award ID: BC160513
  • July 1, 2015 - December 31, 2020 - Contribution of development and age to breast cancer etiology, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: R01CA190980

Education

University of Chicago, A.B., 1978, Biopsychology
University of California, San Francisco, Ph.D., 1986, Experimental Pathology
University of California, Berkeley, Postdoctoral training, 1988, Biophysics

Honors & Awards

  • 1982
    Basic Science Research Award, University of California, San Francisco
  • 1984
    Basic Science Research Award, University of California, San Francisco
  • 1984
    Student Travel Award, Radiation Research Society
  • 1986
    Student Travel Award, Radiation Research Society
  • 1985
    Student Travel Award, Cell Kinetics Society
  • 1986 - 1988
    NIH Fellowship Biophysics Training Grant, University of California, Berkeley
  • 2001
    Co-Chair, Mammary Gland, Gordon Research Conference
  • 2003
    Chair, Mammary Gland Gordon Research Conference
  • 2003 - 2008
    Susan Love MD Breast Cancer Foundation
  • 2003 – 2009
    NASA Radiation Discipline Working Group
  • 2006 - 2010
    Chief Scientist, DOE OBER Low Dose Program
  • 2012 - 2013
    Vice Chair, AACR Tumor Microenvironment Steering Committee
  • 2014
    Co-Chair, AACR 2014 Annual Meeting

Selected Publications

  1. Ruiz de Garibay G, Fernandez-Garcia I, Mazoyer S, Leme de Calais F, Ameri P, Vijayakumar S, Martinez-Ruiz H, Damiola F, Barjhoux L, Thomassen M, Andersen LVB, Herranz C, Mateo F, Palomero L, Espín R, Gómez A, García N, Jimenez D, Bonifaci N, Extremera AI, Castaño J, Raya A, Eyras E, Puente XS, Brunet J, Lázaro C, GEMO , CIMBA , Radice P, Barnes DR, Antoniou AC, Spurdle AB, de la Hoya M, Baralle D, Barcellos-Hoff MH, Pujana MA. Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants. Hum Mutat. 2021 Aug 22.  View on PubMed
  2. Herskind C, Barcellos-Hoff MH. Editorial: Cell Signaling Mediating Critical Radiation Responses. Front Oncol. 2021; 11:695355.  View on PubMed
  3. Liu Q, Palomero L, Moore J, Guix I, Espín R, Aytés A, Mao JH, Paulovich AG, Whiteaker JR, Ivey RG, Iliakis G, Luo D, Chalmers AJ, Murnane J, Pujana MA, Barcellos-Hoff MH. Loss of TGFß signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types. Sci Transl Med. 2021 02 10; 13(580).  View on PubMed
  4. Ma L, Gonzalez-Junca A, Zheng Y, Ouyang H, Illa-Bochaca I, Horst KC, Krings G, Wang Y, Fernandez-Garcia I, Chou W, Barcellos-Hoff MH. Inflammation Mediates the Development of Aggressive Breast Cancer Following Radiotherapy. Clin Cancer Res. 2021 Mar 15; 27(6):1778-1791.  View on PubMed
  5. Barcellos-Hoff MH, Weaver VM. In Memoriam - Zena Werb 1945-2020. J Mammary Gland Biol Neoplasia. 2020 09; 25(3):179-180.  View on PubMed
  6. Gonzalez-Junca A, Reiners O, Borrero-Garcia LD, Beckford-Vera D, Lazar AA, Chou W, Braunstein S, VanBrocklin H, Franc BL, Barcellos-Hoff MH. Positron Emission Tomography Imaging of Functional Transforming Growth Factor ß (TGFß) Activity and Benefit of TGFß Inhibition in Irradiated Intracranial Tumors. Int J Radiat Oncol Biol Phys. 2021 02 01; 109(2):527-539.  View on PubMed
  7. Omene C, Ma L, Moore J, Ouyang H, Illa-Bochaca I, Chou W, Patel MS, Sebastiano C, Demaria S, Mao JH, Karagoz K, Gatza ML, Barcellos-Hoff MH. Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention. Cancer Immunol Res. 2020 02; 8(2):217-229.  View on PubMed
  8. Liu Q, Lopez K, Murnane J, Humphrey T, Barcellos-Hoff MH. Misrepair in Context: TGFß Regulation of DNA Repair. Front Oncol. 2019; 9:799.  View on PubMed
  9. Vapiwala N, Thomas CR, Grover S, Yap ML, Mitin T, Shulman LN, Gospodarowicz MK, Longo J, Petereit DG, Ennis RD, Hayman JA, Rodin D, Buchsbaum JC, Vikram B, Abdel-Wahab M, Epstein AH, Okunieff P, Goldwein J, Kupelian P, Weidhaas JB, Tucker MA, Boice JD, Fuller CD, Thompson RF, Trister AD, Formenti SC, Barcellos-Hoff MH, Jones J, Dharmarajan KV, Zietman AL, Coleman CN. Enhancing Career Paths for Tomorrow's Radiation Oncologists. Int J Radiat Oncol Biol Phys. 2019 09 01; 105(1):52-63.  View on PubMed
  10. Gonzalez-Junca A, Driscoll KE, Pellicciotta I, Du S, Lo CH, Roy R, Parry R, Tenvooren I, Marquez DM, Spitzer MH, Barcellos-Hoff MH. Autocrine TGFβ Is a Survival Factor for Monocytes and Drives Immunosuppressive Lineage Commitment. Cancer Immunol Res. 2019 02; 7(2):306-320.  View on PubMed
  11. Liu Q, Ma L, Jones T, Palomero L, Pujana MA, Martinez-Ruiz H, Ha PK, Murnane J, Cuartas I, Seoane J, Baumann M, Linge A, Barcellos-Hoff MH. Subjugation of TGFß Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End Joining. Clin Cancer Res. 2018 12 01; 24(23):6001-6014.  View on PubMed
  12. Bayin NS, Ma L, Placantonakis DG, Barcellos-Hoff MH. Evaluation of Radioresponse and Radiosensitizers in Glioblastoma Organotypic Cultures. Methods Mol Biol. 2018; 1741:171-182.  View on PubMed
  13. Bayin NS, Frenster JD, Sen R, Si S, Modrek AS, Galifianakis N, Dolgalev I, Ortenzi V, Illa-Bochaca I, Khahera A, Serrano J, Chiriboga L, Zagzag D, Golfinos JG, Doyle W, Tsirigos A, Heguy A, Chesler M, Barcellos-Hoff MH, Snuderl M, Placantonakis DG. Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells. Oncotarget. 2017 Sep 12; 8(39):64932-64953.  View on PubMed
  14. Citrin DE, Prasanna PGS, Walker AJ, Freeman ML, Eke I, Barcellos-Hoff MH, Arankalayil MJ, Cohen EP, Wilkins RC, Ahmed MM, Anscher MS, Movsas B, Buchsbaum JC, Mendonca MS, Wynn TA, Coleman CN. Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016. Radiat Res. 2017 07; 188(1):1-20.  View on PubMed
  15. Iizuka D, Sasatani M, Barcellos-Hoff MH, Kamiya K. Hydrogen Peroxide Enhances TGFß-mediated Epithelial-to-Mesenchymal Transition in Human Mammary Epithelial MCF-10A Cells. Anticancer Res. 2017 03; 37(3):987-995.  View on PubMed
  16. Mateo F, Arenas EJ, Aguilar H, Serra-Musach J, de Garibay GR, Boni J, Maicas M, Du S, Iorio F, Herranz-Ors C, Islam A, Prado X, Llorente A, Petit A, Vidal A, Català I, Soler T, Venturas G, Rojo-Sebastian A, Serra H, Cuadras D, Blanco I, Lozano J, Canals F, Sieuwerts AM, de Weerd V, Look MP, Puertas S, García N, Perkins AS, Bonifaci N, Skowron M, Gómez-Baldó L, Hernández V, Martínez-Aranda A, Martínez-Iniesta M, Serrat X, Cerón J, Brunet J, Barretina MP, Gil M, Falo C, Fernández A, Morilla I, Pernas S, Plà MJ, Andreu X, Seguí MA, Ballester R, Castellà E, Nellist M, Morales S, Valls J, Velasco A, Matias-Guiu X, Figueras A, Sánchez-Mut JV, Sánchez-Céspedes M, Cordero A, Gómez-Miragaya J, Palomero L, Gómez A, Gajewski TF, Cohen EEW, Jesiotr M, Bodnar L, Quintela-Fandino M, López-Bigas N, Valdés-Mas R, Puente XS, Viñals F, Casanovas O, Graupera M, Hernández-Losa J, Ramón Y Cajal S, García-Alonso L, Saez-Rodriguez J, Esteller M, Sierra A, Martín-Martín N, Matheu A, Carracedo A, González-Suárez E, Nanjundan M, Cortés J, Lázaro C, Odero MD, Martens JWM, Moreno-Bueno G, Barcellos-Hoff MH, Villanueva A, Gomis RR, Pujana MA. Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene. 2017 05 11; 36(19):2737-2749.  View on PubMed
  17. Martinez-Ruiz H, Illa-Bochaca I, Omene C, Hanniford D, Liu Q, Hernando E, Barcellos-Hoff MH. A TGFß-miR-182-BRCA1 axis controls the mammary differentiation hierarchy. Sci Signal. 2016 12 06; 9(457):ra118.  View on PubMed
  18. Bayin NS, Ma L, Thomas C, Baitalmal R, Sure A, Fansiwala K, Bustoros M, Golfinos JG, Pacione D, Snuderl M, Zagzag D, Barcellos-Hoff MH, Placantonakis D. Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-ß Small Molecule Inhibitor. Neoplasia. 2016 Dec; 18(12):795-805.  View on PubMed
  19. Formenti SC, Demaria S, Barcellos-Hoff MH, McBride WH. Subverting misconceptions about radiation therapy. Nat Immunol. 2016 Apr; 17(4):345.  View on PubMed
  20. Barcellos-Hoff MH, Mao JH. HZE Radiation Non-Targeted Effects on the Microenvironment That Mediate Mammary Carcinogenesis. Front Oncol. 2016; 6:57.  View on PubMed

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