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

  • September 1, 2022 - August 31, 2027 - Investigating the Genesis of Tumor Immune Microenvironment (TIME) as a function of Inflammation , PI . Sponsor: NIH NCI, Sponsor Award ID: R01 CA270332
  • 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
  • April 1, 2021 - March 30, 2024 - Evaluating TGFß mediated DNA damage response (DDR) to immunotherapy response , PI . Sponsor: Roche/Genetech ImCore, Sponsor Award ID: UCS-12
  • February 1, 2019 - January 31, 2024 - Reorienting the Glioblastoma Microenvironment to Respond to Immunotherapy , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01NS109911
  • January 5, 2022 - December 30, 2022 - Virotherapy Targeting TGFß to Overcome Therapeutic Resistance in Glioblastoma , Co-PI . Sponsor: UCSF Resource Allocation Program Team Science, Sponsor Award ID:
  • 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
  • April 26, 2018 - May 1, 2020 - Re-orienting the Radiation-Induced Tumor Microenvironment towards Immunotherapy , Principle Investigator . Sponsor: Roche/Genetech imCORE, Sponsor Award ID: USC-3
  • April 1, 2019 - March 31, 2020 - Functional Analysis to Stratify HNSCC Patients for PARP Inhibition , Principal Investigator . Sponsor: UCSF Resource Allocation Pilot, Sponsor Award ID:
  • February 1, 2019 - January 31, 2020 - CyTOF Analytics of Systemic Immune Responses to Radiation Therapy , Principle Investigator . Sponsor: Varian Medical Systems, Sponsor Award ID:
  • September 1, 2014 - August 31, 2016 - Contextual Glioblastoma Screening For Efficacious Radiation Sensitizers , Co-Principal Investigator . Sponsor: NIH/NINDS, Sponsor Award ID: R21NS088775
  • May 1, 2010 - February 28, 2015 - Intercellular Interactions Modulate Carcinogenesis Course: A Dynamic System Study , Co-Investigator . Sponsor: NIH, Sponsor Award ID: U54CA149233
  • September 30, 2004 - February 28, 2015 - Model-based predictions of responses RTK Pathway therapies , Co-Investigator . Sponsor: NIH, Sponsor Award ID: U54CA112970
  • August 10, 2006 - February 28, 2013 - Biological Basis of Breast Density and Cancer Risk , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01CA107584
  • September 30, 2003 - February 29, 2008 - TGFb Regulation of ER Receptor Positive Mammary Cells , Principal Investigator . Sponsor: NIH/NIA, Sponsor Award ID: R01AG022413
  • May 1, 2001 - April 30, 2004 - Gordon Research Conference on Mammary Gland Biology , Principal Investigator . Sponsor: NIH/NCI, Sponsor Award ID: R13CA090303
  • January 1, 1991 - December 31, 1996 - STROMAL INFLUENCE ON EXPRESSION OF PRENEOPLASIA , Principal Investigator . Sponsor: NIH/NCI, Sponsor Award ID: R29CA051841

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. Yan H, Mao AW, Li D, Pérez-Baena MJ, Jiménez-Navas A, Wang D, Hong R, Cai W, Pérez-Losada J, Jen KY, Wang S, Peng S, Barcellos-Hoff MH, Mao JH, Fu Y, Iczkowski KA, Gulati S, Chang H. AI-Powered cellular morphometric biomarkers discovered in needle biopsy of prostatic cancer predict neoadjuvant androgen deprivation therapy response and prognosis: an international multicenter retrospective study. medRxiv. 2024 Nov 18.  View on PubMed
  2. Arcuschin CD, Kahrizi K, Sayaman RW, DiBenedetto C, Shen Y, Salaberry PJ, Zakroui O, Schwarzer C, Scapozza A, Betancur P, Saba JD, Coppé JP, Barcellos-Hoff MH, Kappes D, van 't Veer L, Schor IE, Muñoz DP. Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4 + cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype. bioRxiv. 2024 Sep 25.  View on PubMed
  3. Jung J, Schneider EL, Zhang W, Song H, Zhang M, Chou W, Meher N, VanBrocklin HF, Barcellos-Hoff MH, Ozawa T, Gilbert MR, Santi DV. PLX038A, a long-acting SN-38, penetrates the blood-tumor-brain-barrier, accumulates and releases SN-38 in brain tumors to increase survival of tumor bearing mice. Sci Rep. 2024 06 19; 14(1):14175.  View on PubMed
  4. Moore J, Gkantalis J, Guix I, Chou W, Yuen K, Lazar AA, Spitzer M, Combes AJ, Barcellos-Hoff MH. Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade. bioRxiv. 2024 May 21.  View on PubMed
  5. Chowdhury S, Kennedy JJ, Ivey RG, Murillo OD, Hosseini N, Song X, Petralia F, Calinawan A, Savage SR, Berry AB, Reva B, Ozbek U, Krek A, Ma W, da Veiga Leprevost F, Ji J, Yoo S, Lin C, Voytovich UJ, Huang Y, Lee SH, Bergan L, Lorentzen TD, Mesri M, Rodriguez H, Hoofnagle AN, Herbert ZT, Nesvizhskii AI, Zhang B, Whiteaker JR, Fenyo D, McKerrow W, Wang J, Schürer SC, Stathias V, Chen XS, Barcellos-Hoff MH, Starr TK, Winterhoff BJ, Nelson AC, Mok SC, Kaufmann SH, Drescher C, Cieslik M, Wang P, Birrer MJ, Paulovich AG. Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer. Cell. 2024 Feb 15; 187(4):1016.  View on PubMed
  6. Chowdhury S, Kennedy JJ, Ivey RG, Murillo OD, Hosseini N, Song X, Petralia F, Calinawan A, Savage SR, Berry AB, Reva B, Ozbek U, Krek A, Ma W, da Veiga Leprevost F, Ji J, Yoo S, Lin C, Voytovich UJ, Huang Y, Lee SH, Bergan L, Lorentzen TD, Mesri M, Rodriguez H, Hoofnagle AN, Herbert ZT, Nesvizhskii AI, Zhang B, Whiteaker JR, Fenyo D, McKerrow W, Wang J, Schürer SC, Stathias V, Chen XS, Barcellos-Hoff MH, Starr TK, Winterhoff BJ, Nelson AC, Mok SC, Kaufmann SH, Drescher C, Cieslik M, Wang P, Birrer MJ, Paulovich AG. Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer. Cell. 2023 08 03; 186(16):3476-3498.e35.  View on PubMed
  7. Gregucci F, Spada S, Barcellos-Hoff MH, Bhardwaj N, Chan Wah Hak C, Fiorentino A, Guha C, Guzman ML, Harrington K, Herrera FG, Honeychurch J, Hong T, Iturri L, Jaffee E, Karam SD, Knott SRV, Koumenis C, Lyden D, Marciscano AE, Melcher A, Mondini M, Mondino A, Morris ZS, Pitroda S, Quezada SA, Santambrogio L, Shiao S, Stagg J, Telarovic I, Timmerman R, Vozenin MC, Weichselbaum R, Welsh J, Wilkins A, Xu C, Zappasodi R, Zou W, Bobard A, Demaria S, Galluzzi L, Deutsch E, Formenti SC. Updates on radiotherapy-immunotherapy combinations: Proceedings of 6th annual ImmunoRad conference. Oncoimmunology. 2023; 12(1):2222560.  View on PubMed
  8. Ma L, Gonzalez-Junca A, Chou W, Barcellos-Hoff MH. Monitoring TGFβ signaling in irradiated tumors. Methods Cell Biol. 2023; 180:49-67.  View on PubMed
  9. Barcellos-Hoff MH, Gulley JL. Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy. Clin Cancer Res. 2023 06 01; 29(11):2025-2033.  View on PubMed
  10. Guix I, Liu Q, Pujana MA, Ha P, Piulats J, Linares I, Guedea F, Mao JH, Lazar A, Chapman J, Yom SS, Ashworth A, Barcellos-Hoff MH. Validation of Anticorrelated TGFβ Signaling and Alternative End-Joining DNA Repair Signatures that Predict Response to Genotoxic Cancer Therapy. Clin Cancer Res. 2022 04 01; 28(7):1372-1382.  View on PubMed
  11. Yu T, Cazares O, Tang AD, Kim HY, Wald T, Verma A, Liu Q, Barcellos-Hoff MH, Floor SN, Jung HS, Brooks AN, Klein OD. SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal. Dev Cell. 2022 03 14; 57(5):624-637.e4.  View on PubMed
  12. Chang H, Yang X, Moore J, Liu XP, Jen KY, Snijders AM, Ma L, Chou W, Corchado-Cobos R, García-Sancha N, Mendiburu-Eliçabe M, Pérez-Losada J, Barcellos-Hoff MH, Mao JH. From Mouse to Human: Cellular Morphometric Subtype Learned From Mouse Mammary Tumors Provides Prognostic Value in Human Breast Cancer. Front Oncol. 2021; 11:819565.  View on PubMed
  13. Barcellos-Hoff MH. The radiobiology of TGFβ. Semin Cancer Biol. 2022 11; 86(Pt 3):857-867.  View on PubMed
  14. Gulley JL, Schlom J, Barcellos-Hoff MH, Wang XJ, Seoane J, Audhuy F, Lan Y, Dussault I, Moustakas A. Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment. Mol Oncol. 2022 06; 16(11):2117-2134.  View on PubMed
  15. Moore J, Ma L, Lazar AA, Barcellos-Hoff MH. Mammary Tumor-Derived Transplants as Breast Cancer Models to Evaluate Tumor-Immune Interactions and Therapeutic Responses. Cancer Res. 2022 02 01; 82(3):365-376.  View on PubMed
  16. Liu Q, Chen G, Moore J, Guix I, Placantonakis D, Barcellos-Hoff MH. Exploiting Canonical TGFβ Signaling in Cancer Treatment. Mol Cancer Ther. 2022 01; 21(1):16-24.  View on PubMed
  17. 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 11; 42(11):1488-1502.  View on PubMed
  18. Herskind C, Barcellos-Hoff MH. Editorial: Cell Signaling Mediating Critical Radiation Responses. Front Oncol. 2021; 11:695355.  View on PubMed
  19. 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 TGFβ 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
  20. 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 03 15; 27(6):1778-1791.  View on PubMed

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