Mary Helen Barcellos-Hoff, PhD

Professor
Vice Chair of Research
Department of Radiation Oncology
[email protected]
+1 415 476-8091
Research Overview: 

Understanding the action of TGFβ in irradiated tissues and cells led us to define its role in genomic instability and a previously understudied role in the DNA damage response.  This led us to test whether TGFβ inhibition improve the response to radiotherapy, which substantiated its critical role in the irradiate tumor. 

  1. Bouquet, S.F., A. Pal, K.A. Pilones, S. Demaria, B. Hann, R.J. Akhurst, J.S. Babb, S.M. Lonning, J.K. DeWyngaert, S. Formenti, and M.H. Barcellos-Hoff. 2011. Transforming growth factor β1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res. 17:6754-6765. PMID: 22028490
  2. Hardee, M.E., A.E. Marciscano, C.M. Medina-Ramirez, D. Zagzag, A. Narayana, S.M. Lonning, and M.H. Barcellos-Hoff. 2012. Resistance of Glioblastoma-Initiating Cells to Radiation Mediated by the Tumor Microenvironment Can Be Abolished by Inhibiting Transforming Growth Factor-β. Cancer Res. 72 (16):4119-29. PMC3724539  
  3. Kirshner, J., M.F. Jobling, M.J. Pajares, S.A. Ravani, A. Glick, M. Lavin, S. Koslov, Y. Shiloh, and M.H. Barcellos-Hoff. 2006. Inhibition of TGFb1 signaling attenuates ATM activity in response to genotoxic stress. Cancer Res. 66:10861-10868. PMID: 17090522
  4. Maxwell, C.A., M.C. Fleisch, S.V. Costes, A.C. Erickson, A. Boissiere, R. Gupta, S.A. Ravani, B. Parvin, and M.H. Barcellos-Hoff. 2008. Targeted and non-targeted effects of ionizing radiation that impact genomic instability. Cancer Res. 68:8304-8311. PMID:18922902

Radiation carcinogenesis is classically understood in terms of DNA damage and the potential increase in oncogenic mutations.  Based on our studies showing that radiation alters critical signaling and cell-cell interactions, we developed a radiation chimera mammary model that unequivocally demonstrates that radiation effects on the microenvironment strongly promote carcinogenesis.  Remarkably, the expression data from tumors arising in irradiated mice can be used to cluster cancers from irradiated humans and supports the contention that this mechanism of action contributes to radiation-preceded cancer in humans and that similar processes may underlie the origin of sporadic human cancers.

  1. Barcellos-Hoff, M.H., and S.A. Ravani. 2000. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res. 60:1254-1260. PMID:10728684
  2. Nguyen, D.H., H.A. Oketch-Rabah, I. Illa-Bochaca, F.C. Geyer, J.S. Reis-Filho, J.H. Mao, S.A. Ravani, J. Zavadil, A.D. Borowsky, D.J. Jerry, K.A. Dunphy, J.H. Seo, S. Haslam, D. Medina, and M.H. Barcellos-Hoff. 2011. Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type. Cancer Cell. 19:640-651. PMC3110779
  3. Nguyen, D.H., E. Fredlund, W. Zhao, C.M. Perou, A. Balmain, J.-H. Mao, and M.H. Barcellos-Hoff. 2013. Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes. Clin Cancer Res. 19:1353-1362.  PMC3732211
  4. Zhang, P., Lo, A., Huang, Y., Huang, G., Liang, G., Mott, J., Karpen, G.H., Blakely, E.A., Bissell, M.J. Barcellos-Hoff, M.H., Snijders, A.M., Mao, J.H.  Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. Sci Rep. 2015 Mar 9;5:8919. PMC4352890
Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Studies of radiation as carcinogen in breast, and its application as a cancer treatment using mouse models and human tissues and cell cultures.

Websites

Publications: 

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 : the preprint server for biology

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

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.

Scientific reports

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

Lack of TGFβ signaling competency predicts conversion of immune poor cancer to immune rich and response to checkpoint blockade.

bioRxiv : the preprint server for biology

Moore J, Gkantalis J, Guix I, Chou W, Yuen K, Lazar AA, Spitzer M, Combes AJ, Barcellos-Hoff MH

Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

Cell

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

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