Research Summary

Our group works in three areas. In the first, we are studying the mechanisms used by the trophoblast cells of the human placenta to invade the uterus during normal pregnancy. Human fetal development depends on the embryo's ability to rapidly gain access to the maternal circulation. The cytotrophoblasts that form the fetal portion of the human placenta have solved this problem by transiently exhibiting certain invasive, tumor-like properties. Our studies show that, in normal pregnancy, cytotrophoblast invasion, both in vivo and in vitro, is accompanied by a dramatic switch in the cells' expression of matrix-degrading metalloproteinases and adhesion molecules. Function-perturbation experiments suggest that cytotrophoblasts carefully regulate their invasive potential by simultaneously expressing a number of molecules that either promote or inhibit invasion. Additionally, we found that cytotrophoblasts that replace the endothelial lining of uterine blood vessels also have the amazing ability to mimic the adhesion phenotype of vascular cells. This phenomenon is likely to be a critical component of normal placentation. What controls this highly unusual differentiation process? Since cytotrophoblasts target large-bore arterioles for invasion, we reasoned that oxygen tension could play a role. Recently, we showed that oxygen controls whether cells proliferate or exit the cell cycle and differentiate; Eph/ephrin family members, transmembrane ligands and receptors, pattern invasion in terms of arterial bias. Finally, we use information about molecular aspects of cytotrophoblast function in normal pregnancy to search for defects that are associated with pregnancy complications such as preeclampsia (e.g., dangerously high blood pressure). For example, our work shows that this pregnancy complication is characterized by specific aberrations in trophoblast secretion of vasculogenic/angiogenic substances.

In parallel, our lab has begun studying the earliest stages of human development using human embryonic stem cells as a model system. Our work to date has focused on deriving additional lines using feeders formed from human placental cells. We recently made the surprising discovery that the cells exhibit apical-basal type polarization. Currently we are investigating how this highly specialized phenomenon is related to pluripotency. Our recently funded CIRM comprehensive grant is focused on constructing a fate map of the human embryo.

Finally, we are using mass spectrometry-based approaches for proteome analyses. Three projects are under way. The first is compilation of an initial draft of the salivary proteome of healthy individuals as a first step in using this body fluid for diagnosis of common diseases. The second is an analysis of the primary proteome and protein complexes of the soil organism Desulfovibrio vulgaris. The goal of the third and newest project is to formulate novel methods that enable robust mass spectrometry-based platforms for the discovery of biomarkers in body fluid for the early detection of tumors.

Research Funding

  • September 25, 2013 - June 30, 2023 - Dissecting gene dysregulation at the maternal-fetal interface in preeclampsia , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R37HD076253
  • August 5, 1999 - May 31, 2023 - Cancer Center Support Grant , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P30CA082103
  • April 1, 2007 - March 31, 2023 - Center for Research, Innovation and Training in Reproduction and Infertility , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P50HD055764
  • February 1, 2017 - June 30, 2019 - THC effects on human implantation: role of trophoblast CB1 , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21DA042951
  • June 15, 2013 - May 31, 2019 - The UCSF Pregnancy Exposures to Environmental Chemicals (PEEC) Children's Center , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01ES022841
  • September 25, 2013 - June 30, 2018 - Dissecting gene dysregulation at the maternal-fetal interface in preeclampsia , Principal Investigator . Sponsor: NIH/NICHD, Sponsor Award ID: R01HD076253
  • May 1, 2012 - April 30, 2018 - Mass Spectrometry Tools in Pursuit of Salivary Biomarkers of Sjogren's Syndrome , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DE022031
  • April 1, 2011 - March 31, 2017 - Functional Glycomics of Human Saliva , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DE021041
  • May 3, 2007 - March 31, 2017 - Origins and Biological Consequences of Human Infertility , Co-Investigator . Sponsor: NIH, Sponsor Award ID: U54HD055764
  • September 20, 2012 - August 31, 2015 - A Novel Model for Assessing the Effects of BPA Exposures on Human Placentation , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21ES019944
  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001614
  • April 1, 1993 - March 31, 2014 - Mechanisms of Preeclampsia: Impact of Obesity , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01HD030367
  • September 28, 2006 - August 31, 2013 - Targeted and global proteomic strategies for early breast cancer detection , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U24CA126477
  • August 7, 2012 - June 30, 2013 - Fetal Programming and Environmental Exposures: Implications for Prenatal Care and , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13ES021699
  • May 7, 2009 - April 30, 2012 - Molecular Mechanisms of Plasmodium Falciparum Adherence to the Human Placenta , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21AI079329
  • August 1, 2008 - July 31, 2011 - The Immune Paradox of Human Pregnancy: Fetal Trophoblasts and Maternal Leukocytes , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R21HD055638
  • December 15, 2004 - November 30, 2010 - Neuronal Guidance Mechanisms in Placental Development , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HD046744
  • September 24, 2004 - May 31, 2010 - Cataloguing the Human Salivary Proteome , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01DE016274
  • April 1, 1985 - February 28, 2009 - MOLECULAR MECHANISMS--BACTERIAL ADHERENCE TO CEMENTUM , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R37DE007244
  • April 1, 2002 - March 31, 2008 - Trophoblast Selectins and Their Uterine Mucin Ligands , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01HD042283
  • August 1, 1999 - July 31, 2006 - NEW STRATEGIES FOR ENHANCING TISSUE INTEGRITY AND REPAIR , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P60DE013058
  • March 7, 2000 - February 28, 2005 - A NOVEL VASCULOGENESIS PROGRAM IN CYTOTROPHOBLASTS , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL064597
  • April 1, 1985 - March 31, 2004 - MOLECULAR MECHANISMS--BACTERIAL ADHERENCE TO CEMENTUM , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DE007244
  • February 1, 1991 - January 31, 2002 - DEVELOPMENTAL BIOLOGY OF THE IMPLANTING MAMMALIAN EMBRYO , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01HD026732
  • May 1, 2000 - April 30, 2001 - GORDON RESEARCH CONFERENCE ON REPRODUCTIVE TRACT BIOLOGY , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R13HD039168
  • September 30, 1994 - September 29, 1997 - CANDIDA ADHERENCE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DE011350
  • December 31, 1987 - March 31, 1992 - PRENATAL DIAGNOSIS USING FETAL CELLS FROM MATERNAL BLOOD , Principal Investigator . Sponsor: NIH/NICHD, Sponsor Award ID: N01HD082903
  • February 1, 1988 - January 31, 1991 - MECHANISMS OF TROPHOBLAST INVASION DURING PLACENTATION , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HD022518

Education

Hope College, Holland, Michigan, A.B., 1972, Biology, Chemistry
University of Michigan, Ann Arbor, Michigan, 1973, Anatomy
University of Kentucky, Lexington, Kentucky, Ph.D., 1977, Anatomy
University of Kentucky, Lexington, KY, Postdoc, 1977-1982, Mass Spectrometry

Honors & Awards

  • 1972-73
    NIH Training Grant
  • 1978-81
    NIH National Research Service Award HD05687
  • 1987
    UCSF Academic Senate Distinguished Teaching Award
  • 1988
    Pew Foundation Faculty Development Award
  • 1994
    Achievement Award in Women's Health (Warner-Lambert Co., National Health Council, Journal of Women's Health)
  • 2000
    Sadler Award from NICHD
  • 2000
    NIH MERIT Award (DE07244)
  • 2002
    UCSF Graduate Association Outstanding Mentor Award
  • 2004
    UCSF School of Dentistry Faculty Research Award
  • 2006
    Dean's Distinguished Lecturer (U of Colorado)
  • 2013
    Frontiers in Reproduction Research Program Pioneer Award (NIH, MBL and Burroughs Welcome)
  • 2013
    NICHD MERIT Award (HD076253)
  • 2014
    NIH State of the Art Lecture, International Federation of Placenta Associations

Selected Publications

  1. Chen H, Kapidzic M, Gantar D, Aksel S, Levan J, Abrahamsson DP, Jigmeddagva U, Basrai S, San A, Gaw SL, Woodruff TJ, Fisher SJ, Robinson JF. Perfluorooctanoic Acid Induces Transcriptomic Alterations in 2nd Trimester Human Cytotrophoblasts. Toxicol Sci. 2023 Sep 20.  View on PubMed
  2. Chen H, Williams KE, Kwan EY, Kapidzic M, Puckett KA, San A, Fisher SJ, Robinson JF. Proteomic analyses of primary human villous trophoblasts exposed to flame retardant BDE-47 using SWATH-MS. Toxicology. 2023 08 01; 494:153583.  View on PubMed
  3. Williams IM, Albertolle ME, Layden AJ, Tao SY, Fisher SJ, Gandley RE, Roberts JM. Lipidomics Reveals Elevated Plasmalogens in Women with Obesity Who Develop Preeclampsia. J Clin Med. 2023 Apr 19; 12(8).  View on PubMed
  4. Blaisdell A, Zhou Y, Kattah MG, Fisher SJ, Mahadevan U. Vedolizumab Antagonizes MAdCAM-1-Dependent Human Placental Cytotrophoblast Adhesion and Invasion In Vitro. Inflamm Bowel Dis. 2022 08 01; 28(8):1219-1228.  View on PubMed
  5. Marsh B, Zhou Y, Kapidzic M, Fisher S, Blelloch R. Regionally distinct trophoblast regulate barrier function and invasion in the human placenta. Elife. 2022 07 07; 11.  View on PubMed
  6. Winkler J, Liu P, Phong K, Hinrichs JH, Ataii N, Williams K, Hadler-Olsen E, Samson S, Gartner ZJ, Fisher S, Werb Z. Bisphenol A replacement chemicals, BPF and BPS, induce protumorigenic changes in human mammary gland organoid morphology and proteome. Proc Natl Acad Sci U S A. 2022 03 15; 119(11):e2115308119.  View on PubMed
  7. Rizzuto G, Brooks JF, Tuomivaara ST, McIntyre TI, Ma S, Rideaux D, Zikherman J, Fisher SJ, Erlebacher A. Establishment of fetomaternal tolerance through glycan-mediated B cell suppression. Nature. 2022 03; 603(7901):497-502.  View on PubMed
  8. Gormley M, Oliverio O, Kapidzic M, Ona K, Hall S, Fisher SJ. RNA profiling of laser microdissected human trophoblast subtypes at mid-gestation reveals a role for cannabinoid signaling in invasion. Development. 2021 10 15; 148(20).  View on PubMed
  9. Chen H, Williams KE, Kwan EY, Kapidzic M, Puckett KA, Aburajab RK, Robinson JF, Fisher SJ. Global proteomic analyses of human cytotrophoblast differentiation/invasion. Development. 2021 07 01; 148(13).  View on PubMed
  10. Costello JF, Fisher SJ. The Placenta - Fast, Loose, and in Control. N Engl J Med. 2021 Jul 01; 385(1):87-89.  View on PubMed
  11. Varshavsky JR, Robinson JF, Zhou Y, Puckett KA, Kwan E, Buarpung S, Aburajab R, Gaw SL, Sen S, Gao S, Smith SC, Park JS, Zakharevich I, Gerona RR, Fisher SJ, Woodruff TJ. Organophosphate Flame Retardants, Highly Fluorinated Chemicals, and Biomarkers of Placental Development and Disease During Mid-Gestation. Toxicol Sci. 2021 05 27; 181(2):215-228.  View on PubMed
  12. Zhang B, Kim MY, Elliot G, Zhou Y, Zhao G, Li D, Lowdon RF, Gormley M, Kapidzic M, Robinson JF, McMaster MT, Hong C, Mazor T, Hamilton E, Sears RL, Pehrsson EC, Marra MA, Jones SJM, Bilenky M, Hirst M, Wang T, Costello JF, Fisher SJ. Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease. Dev Cell. 2021 05 03; 56(9):1238-1252.e5.  View on PubMed
  13. Taylor SK, Houshdaran S, Robinson JF, Gormley MJ, Kwan EY, Kapidzic M, Schilling B, Giudice LC, Fisher SJ. Cytotrophoblast extracellular vesicles enhance decidual cell secretion of immune modulators via TNFα. Development. 2020 09 08; 147(17).  View on PubMed
  14. Quanquin NM, Barres LG, Aliyari SR, Day NT, Gerami H, Fisher SJ, Kakuru A, Kamya MR, Havlir DV, Feeney M, Dorsey G, Cheng G, Gaw SL. Gravidity-dependent associations between interferon response and birth weight in placental malaria. Malar J. 2020 Aug 05; 19(1):280.  View on PubMed
  15. Varshavsky JR, Sen S, Robinson JF, Smith SC, Frankenfield J, Wang Y, Yeh G, Park JS, Fisher SJ, Woodruff TJ. Racial/ethnic and geographic differences in polybrominated diphenyl ether (PBDE) levels across maternal, placental, and fetal tissues during mid-gestation. Sci Rep. 2020 07 22; 10(1):12247.  View on PubMed
  16. McNally L, Zhou Y, Robinson JF, Zhao G, Chen LM, Chen H, Kim MY, Kapidzic M, Gormley M, Hannibal R, Fisher SJ. Up-regulated cytotrophoblast DOCK4 contributes to over-invasion in placenta accreta spectrum. Proc Natl Acad Sci U S A. 2020 07 07; 117(27):15852-15861.  View on PubMed
  17. Varshavsky JR, Robinson JF, Zhou Y, Puckett KA, Kwan E, Buarpung S, Aburajab R, Gaw SL, Sen S, Smith SC, Frankenfield J, Park JS, Fisher SJ, Woodruff TJ. Association of polybrominated diphenyl ether (PBDE) levels with biomarkers of placental development and disease during mid-gestation. Environ Health. 2020 06 03; 19(1):61.  View on PubMed
  18. Sobhani NC, Avvad-Portari E, Nascimento ACM, Machado HN, Lobato DSS, Pereira JP, Esquivel MS, Vasconcelos ZC, Zin AA, Tsui I, Adachi K, Brickley EB, Fisher SJ, Nielsen-Saines K, Brasil P, Moreira ME, Gaw SL. Discordant Zika Virus Findings in Twin Pregnancies Complicated by Antenatal Zika Virus Exposure: A Prospective Cohort. J Infect Dis. 2020 05 11; 221(11):1838-1845.  View on PubMed
  19. Leon-Martinez D, Robinson JF, Zdravkovic T, Genbacev O, Gormley M, Mcmaster M, Fisher SJ, Bianco K. Trisomy 21 is Associated with Caspase-2 Upregulation in Cytotrophoblasts at the Maternal-Fetal Interface. Reprod Sci. 2020 01; 27(1):100-109.  View on PubMed
  20. Mahadevan U, Fisher S, Riley L, Chambers C, Jain R, Robinson C, co-authors of the AGA Inflammatory Bowel Disease in Pregnancy Clinical Care Pathway. Reply. Gastroenterology. 2019 11; 157(5):1435-1436.  View on PubMed

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