Marsha Rosner

Research Summary
Cancer is the second leading cause of death but, unlike heart disease, it has been a difficult disease to effectively understand or treat. The reason relates to the complexity and heterogeneity of the disease. Most tumors have complicated origins and are driven by rare mutations. Furthermore, different tissues have distinct cancers, individual tissues have multiple cancer subtypes, and tumors are composed of cells that are both genetically and phenotypically diverse. Thus, every tumor is unique and dynamic. The cause of lethality in most solid tumors such as breast cancer is the metastatic dissemination of tumor cells throughout the body. Metastasis is characterized by many distinct properties that are driven by changing stresses in the tumor microenvironment. Underlying all of these events are subcellular signaling pathways within tumor and environmental cells that are ultimately responsible for driving cells to a tumorigenic state. The current focus of my laboratory is to understand fundamental signaling mechanisms leading to the generation of tumor cells and their progression to metastatic disease, particularly in triple-negative breast cancer that lacks targeted therapies. We use systems level approaches including activity-based proteomics, RNAseq, ChIPseq, and mass spectrometry as well as computational, molecular, biophysical, cellular and mouse model-based methodologies to identify and characterize key regulators of tumor growth and metastasis. As an additional tool, we have utilized a specific physiological suppressor of metastasis, Raf Kinase Inhibitory Protein (RKIP or PEBP1), and a downstream target of RKIP in cells, BACH1, to identify both molecular and cellular mediators of metastasis. Our recent studies have shown that regulators of metastasis control multiple processes within the tumor cell microenvironment including metabolism, redox state, extracellular matrix, and recruitment and programming of tumor-associated macrophages. These factors also direct extracellular vesicles (exosomes) secreted by tumor cells to reprogram other cells in the body toward a pro-metastatic phenotype. Correlating omic-generated data from these studies with clinical data from cancer patients led to the identification of novel signaling modules that we used to build gene signatures that predict the metastatic potential of a tumor. More recently, our studies have led us to potential therapeutic treatments based on the concept of targeting key regulators of tumorigenesis, mimicking the action of metastasis suppressors such as RKIP or reprogramming signaling networks in cells to sensitize tumors to therapeutic agents.
Keywords
Cancer, Breast, Signal Transduction Pathways, Metastasis, Exosomes, Macrophages, Phosphorylation, Oxidative Stress, Single Cell Analysis
Education
  • Harvard University, Cambridge, MA, AB Biochemistry 06/1972
  • Massachusetts Institute of Technology, Cambridge, MA, Ph.D. Biochemistry 06/1978
  • Massachusetts Institute of Technology, Cambridge, MA, Postdoctoral Fellow Biochemistry/MolBio 09/1981
  • Massachusetts Institute of Technology , Cambridge, MA, Instructor Biochemistry/MolBio 09/1982
Biosciences Graduate Program Association
Awards & Honors
  • 1972 - 1972 MIT Endowed Fellowship MIT
  • 1973 - 1975 Sloan Research Traineeship (Biophysics) MIT
  • 1975 - 1977 Inst. National Research Service Award MIT
  • 1978 - 1980 American Cancer Society Postdoctoral Fellowship MIT
  • 1986 - 1986 International Life Sciences Institute Research Foundation Award MIT
  • 1991 - 1991 Quantrell Award for Excellence in Undergraduate Teaching, (Cell Biology) University of Chicago
  • 1999 - pres Fellow, Institute of Medicine of Chicago University of Chicago
  • 2001 - 2001 Quantrell Award for Excellence in Undergraduate Teaching (Cancer Biology) University of Chicago
  • 2011 - 2011 Gerald N Wogan Prize Lecture, Massachusetts Institute of Technology University of Chicago
  • 2014 - 2014 Fellow, American Association for the Advancement of Science (AAAS) University of Chicago
Publications
  1. SARS-CoV-2 Diverges from Other Betacoronaviruses in Only Partially Activating the IRE1a/XBP1 Endoplasmic Reticulum Stress Pathway in Human Lung-Derived Cells. mBio. 2022 10 26; 13(5):e0241522. View in: PubMed

  2. SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1a/XBP1 ER stress pathway in human lung-derived cells. bioRxiv. 2022 Jun 13. View in: PubMed

  3. Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop. Proc Natl Acad Sci U S A. 2022 06 21; 119(25):e2121867119. View in: PubMed

  4. Harnessing RKIP to Combat Heart Disease and Cancer. Cancers (Basel). 2022 Feb 09; 14(4). View in: PubMed

  5. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv. 2022 Feb 25; 8(8):eabi6110. View in: PubMed

  6. New strategies for targeting kinase networks in cancer. J Biol Chem. 2021 10; 297(4):101128. View in: PubMed

  7. Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5. Cancers (Basel). 2021 Jul 10; 13(14). View in: PubMed

  8. Limited inhibition of multiple nodes in a driver network blocks metastasis. Elife. 2021 05 11; 10. View in: PubMed

  9. Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response. bioRxiv. 2021 Mar 10. View in: PubMed

  10. Observation and Control of Gene Expression Noise: Barrier Crossing Analogies Between Drug Resistance and Metastasis. Front Genet. 2020; 11:586726. View in: PubMed

  11. Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer. J Exp Med. 2019 06 03; 216(6):1345-1358. View in: PubMed

  12. Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Nature. 2019 04; 568(7751):254-258. View in: PubMed

  13. Targeting Raf Kinase Inhibitory Protein Regulation and Function. Cancers (Basel). 2018 Sep 04; 10(9). View in: PubMed

  14. Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome. Proc Natl Acad Sci U S A. 2017 12 19; 114(51):13453-13458. View in: PubMed

  15. Raf kinase inhibitor protein: lessons of a better way for ?-adrenergic receptor activation in the heart. J Physiol. 2017 06 15; 595(12):4073-4087. View in: PubMed

  16. Insulin-Degrading Enzyme Does Not Require Peroxisomal Localization for Insulin Degradation. Endocrinology. 1997 Aug 01; 138(8):3444-3451. View in: PubMed

  17. Gene expression in local stroma reflects breast tumor states and predicts patient outcome. Sci Rep. 2016 12 16; 6:39240. View in: PubMed

  18. Interaction of tRNA with MEK2 in pancreatic cancer cells. Sci Rep. 2016 06 15; 6:28260. View in: PubMed

  19. Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages. Cancer Res. 2015 Oct 01; 75(19):4063-73. View in: PubMed

  20. Noise-Driven Phenotypic Heterogeneity with Finite Correlation Time in Clonal Populations. PLoS One. 2015; 10(7):e0132397. View in: PubMed

  21. RKIP structure drives its function: a three-state model for regulation of RKIP. Crit Rev Oncog. 2014; 19(6):483-8. View in: PubMed

  22. Raf kinase inhibitory protein (RKIP) as a metastasis suppressor: regulation of signaling networks in cancer. Crit Rev Oncog. 2014; 19(6):447-54. View in: PubMed

  23. Conceptualizing cancer drugs as classifiers. PLoS One. 2014; 9(9):e106444. View in: PubMed

  24. Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions. Proc Natl Acad Sci U S A. 2014 Jan 21; 111(3):E364-73. View in: PubMed

  25. A prognostic gene signature for metastasis-free survival of triple negative breast cancer patients. PLoS One. 2013; 8(12):e82125. View in: PubMed

  26. RKIP and HMGA2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2. Oncogene. 2014 Jul 03; 33(27):3528-37. View in: PubMed

  27. HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci U S A. 2013 Jun 11; 110(24):9920-5. View in: PubMed

  28. RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy. PLoS One. 2013; 8(3):e59104. View in: PubMed

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  33. Identification of novel metastasis suppressor signaling pathways for breast cancer. Cell Cycle. 2012 Jul 01; 11(13):2452-7. View in: PubMed

  34. Nonheritable cellular variability accelerates the evolutionary processes of cancer. PLoS Biol. 2012; 10(4):e1001296. View in: PubMed

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  41. p70 S6K1 nuclear localization depends on its mTOR-mediated phosphorylation at T389, but not on its kinase activity towards S6. Amino Acids. 2012 Jun; 42(6):2251-6. View in: PubMed

  42. Nucleocytoplasmic localization of p70 S6K1, but not of its isoforms p85 and p31, is regulated by TSC2/mTOR. Oncogene. 2011 Nov 03; 30(44):4509-22. View in: PubMed

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  47. Evidence for cell cycle-dependent, rapamycin-resistant phosphorylation of ribosomal protein S6 at S240/244. Amino Acids. 2010 Nov; 39(5):1487-92. View in: PubMed

  48. Characterization of the Raf kinase inhibitory protein (RKIP) binding pocket: NMR-based screening identifies small-molecule ligands. PLoS One. 2010 May 05; 5(5):e10479. View in: PubMed

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  50. Embryoid body formation of human amniotic fluid stem cells depends on mTOR. Oncogene. 2010 Feb 18; 29(7):966-77. View in: PubMed

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  55. Structural changes in intermediate filament networks alter the activity of insulin-degrading enzyme. FASEB J. 2009 Nov; 23(11):3734-42. View in: PubMed

  56. Raf Kinase Inhibitory Protein protects cells against locostatin-mediated inhibition of migration. PLoS One. 2009 Jun 24; 4(6):e6028. View in: PubMed

  57. Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J. 2009 Feb 18; 28(4):347-58. View in: PubMed

  58. mTOR phosphorylated at S2448 binds to raptor and rictor. Amino Acids. 2010 Jan; 38(1):223-8. View in: PubMed

  59. A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle. Cancer Res. 2009 Jan 01; 69(1):65-74. View in: PubMed

  60. Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism. Mol Cell Biol. 2009 Mar; 29(5):1306-20. View in: PubMed

  61. Expression of metalloprotease insulin-degrading enzyme insulysin in normal and malignant human tissues. Int J Mol Med. 2008 Oct; 22(4):421-31. View in: PubMed

  62. Immunohistochemical evidence of ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines. Biol Chem. 2008 Nov; 389(11):1441-5. View in: PubMed

  63. Raf kinase inhibitory protein (RKIP): a physiological regulator and future therapeutic target. Expert Opin Ther Targets. 2008 Oct; 12(10):1275-87. View in: PubMed

  64. Tuberin, p27 and mTOR in different cells. Amino Acids. 2009 Feb; 36(2):297-302. View in: PubMed

  65. Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor. Cell Res. 2008 Apr; 18(4):452-7. View in: PubMed

  66. Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations. Endocr Relat Cancer. 2007 Dec; 14(4):1053-62. View in: PubMed

  67. Ras mediates cell survival by regulating tuberin. Oncogene. 2008 Mar 27; 27(14):2072-83. View in: PubMed

  68. Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1. J Biol Chem. 2007 Jul 06; 282(27):19781-7. View in: PubMed

  69. Cytoplasmic/nuclear localization of tuberin in different cell lines. Amino Acids. 2007 Nov; 33(4):575-9. View in: PubMed

  70. Nuclear/cytoplasmic localization of Akt activity in the cell cycle. Amino Acids. 2007; 32(3):341-5. View in: PubMed

  71. MAP kinase meets mitosis: a role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation. Cell Div. 2007 Jan 10; 2:1. View in: PubMed

  72. Immunohistochemical demonstration of the zinc metalloprotease insulin-degrading enzyme in normal and malignant human breast: correlation with tissue insulin levels. Int J Oncol. 2007 Jan; 30(1):73-80. View in: PubMed

  73. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature. 2006 Oct 19; 443(7113):870-4. View in: PubMed

  74. Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell. 2006 Aug; 23(4):561-74. View in: PubMed

  75. Akt regulates nuclear/cytoplasmic localization of tuberin. Oncogene. 2007 Jan 25; 26(4):521-31. View in: PubMed

  76. Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase. Cancer Res. 2006 Jun 15; 66(12):6296-303. View in: PubMed

  77. Tuberin negatively affects BCL-2's cell survival function. Amino Acids. 2006 Jun; 30(4):391-6. View in: PubMed

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  79. The C-terminal domain of human insulin degrading enzyme is required for dimerization and substrate recognition. Biochem Biophys Res Commun. 2006 May 19; 343(4):1032-7. View in: PubMed

  80. NF-kappaB is required for UV-induced JNK activation via induction of PKCdelta. Mol Cell. 2006 Feb 17; 21(4):467-80. View in: PubMed

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  88. ERK7 expression and kinase activity is regulated by the ubiquitin-proteosome pathway. J Biol Chem. 2004 May 28; 279(22):23073-81. View in: PubMed

  89. Human bronchial smooth muscle cell lines show a hypertrophic phenotype typical of severe asthma. Am J Respir Crit Care Med. 2004 Mar 15; 169(6):703-11. View in: PubMed

  90. Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. J Neurochem. 2003 Mar; 84(5):982-96. View in: PubMed

  91. Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J Biol Chem. 2003 Apr 11; 278(15):13061-8. View in: PubMed

  92. The absence of NF-kappaB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol. 2002 Dec; 22(24):8571-9. View in: PubMed

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  94. Characterization of a cysteine proteinase inhibitor induced during neuronal cell differentiation. J Neurochem. 2002 Jun; 81(5):922-34. View in: PubMed

  95. ERK8, a new member of the mitogen-activated protein kinase family. J Biol Chem. 2002 May 10; 277(19):16733-43. View in: PubMed

  96. Tuberous sclerosis causing mutants of the TSC2 gene product affect proliferation and p27 expression. Oncogene. 2001 Aug 09; 20(35):4904-9. View in: PubMed

  97. FGF induces a switch in death receptor pathways in neuronal cells. J Neurosci. 2001 Jul 15; 21(14):4996-5006. View in: PubMed

  98. Tuberous sclerosis gene products in proliferation control. Mutat Res. 2001 Jul; 488(3):233-9. View in: PubMed

  99. Cloning and characterization of MST4, a novel Ste20-like kinase. J Biol Chem. 2001 Jun 22; 276(25):22439-45. View in: PubMed

  100. ERK7 is an autoactivated member of the MAPK family. J Biol Chem. 2001 Jun 15; 276(24):21272-9. View in: PubMed

  101. A novel mitogen-activated protein kinase is responsive to Raf and mediates growth factor specificity. Mol Cell Biol. 2001 Mar; 21(6):2235-47. View in: PubMed

  102. Purified recombinant insulin-degrading enzyme degrades amyloid beta-protein but does not promote its oligomerization. Biochem J. 2000 Oct 15; 351 Pt 2:509-16. View in: PubMed

  103. The TSC1 gene product, hamartin, negatively regulates cell proliferation. Hum Mol Genet. 2000 Jul 22; 9(12):1721-7. View in: PubMed

  104. Different protein kinase C isoforms determine growth factor specificity in neuronal cells. Mol Cell Biol. 2000 Aug; 20(15):5392-403. View in: PubMed

  105. Functional human insulin-degrading enzyme can be expressed in bacteria. Protein Expr Purif. 2000 Jun; 19(1):91-8. View in: PubMed

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