Photo of Joan S. Brugge,  PhD

Joan S. Brugge, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-3974
Fax: (617) 432-3969


joan_brugge@hms.harvard.edu

Joan S. Brugge, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Louise Foote Pfeiffer Professor of Cell Biology, Cell Biology, Harvard Medical School
  • Chair, Cell Biology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

The Brugge laboratory is investigating the cellular processes and pathways that are involved in normal morphogenesis of epithelial tissues and the initiation and progression of epithelial tumors. Currently, most of our studies involve investigations relating to breast cancer. One of the major approaches that we use to investigate these processes involves culturing breast epithelial cells reconstituted basement membrane gels which allows the cells to organize into 3-dimensional structures that resemble the hollow, spherical glandular units of the breast. This culture system allows us to model events that control the proliferation, survival and migration of normal epithelial cells, to identify cellular genes that allow escape from these controls and induce phenotypic changes resembling those associated with tumor progression, and to elucidate the mechanisms responsible for these events.

One of the major focuses of this project involves studies of cell death processes that are critically involved in the formation of a lumen in the spheroid, gland-like breast epithelial structures and how oncogenes escape these death processes to allow filling of the luminal space. One of the hallmarks of early-stage carcinomas filling of the lumen. We have found that multiple processes contribute to the death or clearance of cells from the lumen, including apoptosis, metabolic impairment and autophagy, and intercalation into the outer cell monolayer. Our studies indicate that the induction of apoptosis and autophagy may be a consequence of lack of matrix protein deposition by the inner cells of the acinar structures, so we are investigating how matrix proteins regulate apoptosis and metabolic activity and how oncogenes suppress apoptosis and allow rescue from metabolic impairment. Lastly, we have identified a novel, non-apoptotic mechanism of cell death that involves invasion of one cell into the other, followed by lysosomal degradation of the invading cell. We are exploring the role of this process in tumor surveillance and other physiological processes.

Another major focus is on cellular pathways that regulate the aberrant migration and invasion of tumor cells. We are carrying out siRNA screens to identify genes that inhibit or enhance cell migration and invasion, investigating the mechanisms responsible for these events, and establishing whether these pathways are involved in invasion in vivo.

Other studies involve investigations of cellular pathways that control normal differentiation of breast epithelial cells in order to understand the contribution of factors and pathways that regulate these events in tumorigenesis.

Publications

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  • Stover DG, Coloff JL, Barry WT, Brugge JS, Winer EP, Selfors LM. The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis. Clin Cancer Res 2016. PubMed
  • Coloff JL, Murphy JP, Braun CR, Harris IS, Shelton LM, Kami K, Gygi SP, Selfors LM, Brugge JS. Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells. Cell Metab 2016; 23:867-80. PubMed
  • Bui DA, Lee W, White AE, Harper JW, Schackmann RC, Overholtzer M, Selfors LM, Brugge JS. Cytokinesis involves a nontranscriptional function of the Hippo pathway effector YAP. Sci Signal 2016; 9:ra23. PubMed
  • Gallegos LL, Ng MR, Sowa ME, Selfors LM, White A, Zervantonakis IK, Singh P, Dhakal S, Harper JW, Brugge JS. A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin. Sci Rep 2016; 6:27114. PubMed
  • Harris IS, Brugge JS. Cancer: The enemy of my enemy is my friend. Nature 2015; 527:170-1. PubMed
  • Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med 2015. PubMed
  • Ince TA, Sousa AD, Jones MA, Harrell JC, Agoston ES, Krohn M, Selfors LM, Liu W, Chen K, Yong M, Buchwald P, Wang B, Hale KS, Cohick E, Sergent P, Witt A, Kozhekbaeva Z, Gao S, Agoston AT, Merritt MA, Foster R, Rueda BR, Crum CP, Brugge JS, Mills GB. Characterization of twenty-five ovarian tumour cell lines that phenocopy primary tumours. Nat Commun 2015; 6:7419. PubMed
  • Gallegos LL, Brugge JS. Live free or die: cell-cell adhesion regulates sensitivity to trail-induced apoptosis. Dev Cell 2014; 30:3-4. PubMed
  • Godinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, Polyak K, Brugge JS, Théry M, Pellman D. Oncogene-like induction of cellular invasion from centrosome amplification. Nature 2014. PubMed
  • Davidowitz RA, Selfors LM, Iwanicki MP, Elias KM, Karst A, Piao H, Ince TA, Drage MG, Dering J, Konecny GE, Matulonis U, Mills GB, Slamon DJ, Drapkin R, Brugge JS. Mesenchymal gene program-expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance. J Clin Invest 2014. PubMed
  • Ng MR, Besser A, Brugge JS, Danuser G. Mapping the dynamics of force transduction at cell-cell junctions of epithelial clusters. Elife 2015; 3:e03282. PubMed
  • Vakifahmetoglu-Norberg H, Kim M, Xia HG, Iwanicki MP, Ofengeim D, Coloff JL, Pan L, Ince TA, Kroemer G, Brugge JS, Yuan J. Chaperone-mediated autophagy degrades mutant p53. Genes Dev 2013; 27:1718-30. PubMed
  • Buchwalter G, Hickey MM, Cromer A, Selfors LM, Gunawardane RN, Frishman J, Jeselsohn R, Lim E, Chi D, Fu X, Schiff R, Brown M, Brugge JS. PDEF promotes luminal differentiation and acts as a survival factor for ER-positive breast cancer cells. Cancer Cell 2013; 23:753-67. PubMed
  • Kaanta AS, Virtanen C, Selfors LM, Brugge JS, Neel BG. Evidence for a multipotent mammary progenitor with pregnancy-specific activity. Breast Cancer Res 2014; 15:R65. PubMed
  • Mouneimne G, Hansen SD, Selfors LM, Petrak L, Hickey MM, Gallegos LL, Simpson KJ, Lim J, Gertler FB, Hartwig JH, Mullins RD, Brugge JS. Differential remodeling of actin cytoskeleton architecture by profilin isoforms leads to distinct effects on cell migration and invasion. Cancer Cell 2012; 22:615-30. PubMed
  • Ng MR, Besser A, Danuser G, Brugge JS. Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility. J Cell Biol 2012; 199:545-63. PubMed
  • Kim JH, Cho A, Yin H, Schafer DA, Mouneimne G, Simpson KJ, Nguyen KV, Brugge JS, Montell DJ. Psidin, a conserved protein that regulates protrusion dynamics and cell migration. Genes Dev 2011; 25:730-41. PubMed
  • Albeck JG, Brugge JS. Uncovering a tumor suppressor for triple-negative breast cancers. Cell 2011; 144:638-40. PubMed
  • Krajcovic M, Johnson NB, Sun Q, Normand G, Hoover N, Yao E, Richardson AL, King RW, Cibas ES, Schnitt SJ, Brugge JS, Overholtzer M. A non-genetic route to aneuploidy in human cancers. Nat Cell Biol 2011; 13:324-30. PubMed
  • Grassian AR, Schafer ZT, Brugge JS. ErbB2 stabilizes epidermal growth factor receptor (EGFR) expression via Erk and Sprouty2 in extracellular matrix-detached cells. J Biol Chem 2011; 286:79-90. PubMed
  • Harrison SC, Brugge JS. Mechanistic biology in the next quarter century. Mol Biol Cell 2010; 21:3799-800. PubMed
  • Tushir JS, Clancy J, Warren A, Wrobel C, Brugge JS, D'Souza-Schorey C. Unregulated ARF6 Activation in Epithelial Cysts Generates Hyperactive Signaling Endosomes and Disrupts Morphogenesis. Mol Biol Cell 2010; 21:2355-66. PubMed
  • Janes KA, Wang CC, Holmberg KJ, Cabral K, Brugge JS. Identifying single-cell molecular programs by stochastic profiling. Nat Methods 2010; 7:311-7. PubMed
  • Zhou W, Hur W, McDermott U, Dutt A, Xian W, Ficarro SB, Zhang J, Sharma SV, Brugge J, Meyerson M, Settleman J, Gray NS. A structure-guided approach to creating covalent FGFR inhibitors. Chem Biol 2010; 17:285-95. PubMed
  • Mazzone M, Selfors LM, Albeck J, Overholtzer M, Sale S, Carroll DL, Pandya D, Lu Y, Mills GB, Aster JC, Artavanis-Tsakonas S, Brugge JS. Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci U S A 2010; 107:5012-7. PubMed
  • Wolfer A, Wittner BS, Irimia D, Flavin RJ, Lupien M, Gunawardane RN, Meyer CA, Lightcap ES, Tamayo P, Mesirov JP, Liu XS, Shioda T, Toner M, Loda M, Brown M, Brugge JS, Ramaswamy S. MYC regulation of a "poor-prognosis" metastatic cancer cell state. Proc Natl Acad Sci U S A 2010; 107:3698-703. PubMed
  • Irie HY, Shrestha Y, Selfors LM, Frye F, Iida N, Wang Z, Zou L, Yao J, Lu Y, Epstein CB, Natesan S, Richardson AL, Polyak K, Mills GB, Hahn WC, Brugge JS. PTK6 regulates IGF-1-induced anchorage-independent survival. PLoS ONE 2010; 5:e11729. PubMed
  • Knowlton ML, Selfors LM, Wrobel CN, Gu TL, Ballif BA, Gygi SP, Polakiewicz R, Brugge JS. Profiling Y561-dependent and -independent substrates of CSF-1R in epithelial cells. PLoS ONE 2010; 5:e13587. PubMed
  • Leung CT, Brugge JS. Tumor self-seeding: bidirectional flow of tumor cells. Cell 2010; 139:1226-8. PubMed
  • Muller PA, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S, Lukashchuk N, Gillespie DA, Ludwig RL, Gosselin P, Cromer A, Brugge JS, Sansom OJ, Norman JC, Vousden KH. Mutant p53 drives invasion by promoting integrin recycling. Cell 2010; 139:1327-41. PubMed
  • Ng MR, Brugge JS. A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell 2009; 16:455-7. PubMed
  • Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 2009; 11:1444-50. PubMed
  • Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, Gao S, Puigserver P, Brugge JS. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 2009; 461:109-13. PubMed
  • Mouneimne G,Brugge JS. YB-1 translational control of epithelial-mesenchyme transition. Cancer Cell 2009; 15:357-9. PubMed
  • Xian W,Pappas L,Pandya D,Selfors LM,Derksen PW,de Bruin M,Gray NS,Jonkers J,Rosen JM,Brugge JS. Fibroblast growth factor receptor 1-transformed mammary epithelial cells are dependent on RSK activity for growth and survival. Cancer Res 2009; 69:2244-51. PubMed
  • Iwanicki MP, Brugge JS. Transcriptional regulation of metastatic [Id]entity by KLF17. Genome Biol 2010; 10:244. PubMed
  • Overholtzer M,Brugge JS. The cell biology of cell-in-cell structures. Nat Rev Mol Cell Biol 2008; 9:796-809. PubMed
  • Simpson KJ,Selfors LM,Bui J,Reynolds A,Leake D,Khvorova A,Brugge JS. Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nat Cell Biol 2009; 10:1027-38. PubMed
  • Simpson KJ,Selfors LM,Bui J,Reynolds A,Leake D,Khvorova A,Brugge JS. Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nat Cell Biol 2008. PubMed
  • Melani M, Simpson KJ, Brugge JS, Montell D. Regulation of cell adhesion and collective cell migration by hindsight and its human homolog RREB1. Curr Biol 2008; 18:532-7. PubMed
  • Mailleux AA, Overholtzer M, Brugge JS. [Entosis, a cell death process related to cell cannibalism between tumor cells] Med Sci (Paris) 2008; 24:246-8. PubMed
  • Tamimi RM, Brugge JS, Freedman ML, Miron A, Iglehart JD, Colditz GA, Hankinson SE. Circulating colony stimulating factor-1 and breast cancer risk. Cancer Res 2008; 68:18-21. PubMed
  • Mailleux AA, Overholtzer M, Brugge JS. Lumen formation during mammary epithelial morphogenesis: insights from in vitro and in vivo models. Cell Cycle 2008; 7:57-62. PubMed
  • Schafer ZT, Brugge JS. IL-6 involvement in epithelial cancers. J Clin Invest 2007; 117:3660-3. PubMed
  • Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW, Cibas ES, Brugge JS. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 2007; 131:966-79. PubMed
  • Fischbach C, Chen R, Matsumoto T, Schmelzle T, Brugge JS, Polverini PJ, Mooney DJ. Engineering tumors with 3D scaffolds. Nat Methods 2007; 4:855-60. PubMed
  • Mouneimne G, Brugge JS. Tensins: a new switch in cell migration. Dev Cell 2007; 13:317-9. PubMed
  • Miller-Jensen K, Janes KA, Brugge JS, Lauffenburger DA. Common effector processing mediates cell-specific responses to stimuli. Nature 2007; 448:604-8. PubMed
  • Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell 2007; 12:104-7. PubMed
  • Schmelzle T, Mailleux AA, Overholtzer M, Carroll JS, Solimini NL, Lightcap ES, Veiby OP, Brugge JS. Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc Natl Acad Sci U S A 2007; 104:3787-92. PubMed
  • Carroll DK, Brugge JS, Attardi LD. p63, cell adhesion and survival. Cell Cycle 2007; 6:255-61. PubMed
  • Mailleux AA, Overholtzer M, Schmelzle T, Bouillet P, Strasser A, Brugge JS. BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms. Dev Cell 2007; 12:221-34. PubMed
  • Walker SJ, Brugge JS. SePARating polarity and proliferation in ErbB2 oncogenesis. Nat Cell Biol 2006; 8:1220-2. PubMed
  • Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A 2006; 103:12405-10. PubMed
  • Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW. p63 regulates an adhesion programme and cell survival in epithelial cells. Nat Cell Biol 2006; 8:551-61. PubMed
  • Wilsbacher JL, Moores SL, Brugge JS. An active form of Vav1 induces migration of mammary epithelial cells by stimulating secretion of an epidermal growth factor receptor ligand. Cell Commun Signal 2006; 4:5. PubMed
  • Witt AE, Hines LM, Collins NL, Hu Y, Gunawardane RN, Moreira D, Raphael J, Jepson D, Koundinya M, Rolfs A, Taron B, Isakoff SJ, Brugge JS, LaBaer J. Functional proteomics approach to investigate the biological activities of cDNAs implicated in breast cancer. J Proteome Res 2006; 5:599-610. PubMed
  • Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 2005; 65:10992-1000. PubMed
  • Ma XJ, Wang Z, Ryan PD, Isakoff SJ, Barmettler A, Fuller A, Muir B, Mohapatra G, Salunga R, Tuggle JT, Tran Y, Tran D, Tassin A, Amon P, Wang W, Wang W, Enright E, Stecker K, Estepa-Sabal E, Smith B, Younger J, Balis U, Michaelson J, Bhan A, Habin K, Baer TM, Brugge J, Haber DA, Erlander MG, Sgroi DC. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 2004; 5:607-16. PubMed
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