Research Summary

Our lab aims to dissect the molecular and cellular mechanisms regulating stem cells, mammalian development, and cancer progression. We use a combination of genetics, genomics, biochemistry, cell biology, and mammalian models. The lab has a strong history of training graduate students who have gone on to successful careers in the biomedical sciences, both in academics and in industry.

Exosome Regulation of the Antitumor Immune Response
We recently discovered that the immune checkpoint inhibitor PD-L1 can be secreted by cancer cells on the surface of small vesicles called exosomes. These exosomes can than travel to the draining lymph node of the tumor, where they suppress T cell activation, effectively blocking the antitumor immune response. Remarkably, short term or even just local inhibition of exosomal PD-L1 reactivates the anti-tumor immune response, which is then able to block growth of the local and distal tumors. For unclear reasons, exosomal PD-L1 is resistant to therapeutic antibodies both for PD-L1 itself and its receptor PD-1. Furthermore, the amount of exosomal PD-L1 released by cells varies between tumors, which we believe is a major reason for the differential response to current immune checkpoint therapies among patients. The lab is now pursuing multiple avenues directly arising from this work ranging from basic to translational biology. For example, we are interested in the control of PD-L1 packaging into exosomes, existence of other immunomodulators on exosomes, how exosomes interact with immune cells, and how can they be manipulated to produce novel therapeutics.

MicroRNA Regulation of Pluripotency, Early Mammalian Development, and Cancer
Our work in exosomes originated from our long-standing interest on the role of microRNAs (miRNAs) in cell fate regulation. We have largely focused on the role of two miRNA families, the ESCC and let-7 families. We have shown that ESCC miRNAs promote embryonic stem cell (ESC) self-renewal, suppress the G1-S checkpoint of the cell cycle, and can dedifferentiate somatic cells into induced pluripotent stem cells (iPSC). We have also shown that the ESCC miRNAs suppress phasic expression of genes during the different phases of the cell cycle. We have shown the let-7 miRNAs have the opposite effects. That is, they promote ESC differentiation, inhibit dedifferentiation into iPSCs, promote a G1-S checkpoint, and induce phasic expression across the cell cycle. We have also studied the roles of the ESCC miRNAs in vivo. We have shown that the ESCC miRNAs regulate the developmental timing of differentiation of both embryonic and extra-embryonic tissues. We are currently using single cell techniques to carefully dissect these in vivo roles in the developing embryo and placenta. We are also dissecting the mechanisms of action of the miRNAs by focusing on their downstream targets. In prostate cancer, we have been studying the role of miRNAs in disease progression and evaluating their potential utility as diagnostic/prognostic markers.

Transcriptional/Epigenetic of Stem Cell Self-Renewal and Differentiation
We have been using a combination of genetics, genomics, and biochemistry to study the transcription/epigenetic regulation of cell fate during early mammalian embryonic stem cell differentiation. We have been particularly interested in the rewiring of genome as pluripotent cells prepare for lineage diversification. Focusing on changes occurring at enhancers we have been determining how transcription factors and their associated epigenetic factors regulate the surrounding chromatin including the remodeling and post-translational modifications of histones as well as the changing interactions between enhancers and their target gene promoters.

Research Funding

  • September 23, 2019 - August 31, 2024 - Mechanisms of Exosome Driven Immunoregulation of Cancer Progression, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: U01CA244452
  • April 1, 2007 - March 31, 2023 - Center for Research, Innovation and Training in Reproduction and Infertility, Co-Investigator. Sponsor: NIH/NICHD, Sponsor Award ID: P50HD055764
  • September 7, 2017 - July 31, 2021 - Iteratively redefining developmental potential through poised enhancers, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM125089
  • September 7, 2017 - July 31, 2021 - Rewiring of the pluripotency enhancer network during early mammalian development, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM122439

Education

Duke University, Durham, North Carolina, B.S., 5/1989, Zoology
Duke University, Durham, North Carolina, M.A.T., 5/1990, Biology
University of Wisconsin, Madison, Wisconsin, Ph.D., 5/1999, Cell & Molec Biology
University of Wisconsin, Madison, Wisconsin, M.D., 5/2001, Medicine
Brigham and Women’s Hospital, Boston, Massachusetts, Residency, 5/2004, Clinical Pathology
Harvard Joint Program in Transfusion Medicine, Boston, Massachusetts, Clinical Fellowship, 5/2005, Transfusion Medicine
Whitehead Institute at MIT, Cambridge, Massachusets, Post-doctoral Fellowship, 12/2005, Epigenetics, Stem Cells, and Cancer

Honors & Awards

  • 2000-2001
    Rath Wisconsin Distinguished Graduate Fellow
  • 2001
    GATE Pharmaceuticals Outstanding Medical Student Award
  • 2001
    Alpha Omega Alpha (Medical Student Honor Society)
  • 2001
    University of Wisconsin-Madison Commencement Student Speaker
  • 2004
    Paul E. Strandjord Young Investigator Award with Distinction
  • 2006-
    Peter R. Carroll, MD, Endowed Chair
  • 2007-2011
    Pew Scholar
  • 2009
    Kavli Fellow (National Academy of Sciences)
  • 2011
    International Society of Stem Cell Research Outstanding Young Investigator Award.
  • 2015
    Inducted into American Society for Clinical Investigation

Selected Publications

  1. DeVeale B, Swindlehurst-Chan J, Blelloch R. The roles of microRNAs in mouse development. Nat Rev Genet. 2021 05; 22(5):307-323.  View on PubMed
  2. Marsh B, Blelloch R. Single nuclei RNA-seq of mouse placental labyrinth development. Elife. 2020 11 03; 9.  View on PubMed
  3. Sangokoya C, Blelloch R. MicroRNA-dependent inhibition of PFN2 orchestrates ERK activation and pluripotent state transitions by regulating endocytosis. Proc Natl Acad Sci U S A. 2020 08 25; 117(34):20625-20635.  View on PubMed
  4. Zhou X, Nair GG, Russ HA, Belair CD, Li ML, Shveygert M, Hebrok M, Blelloch R. LIN28B Impairs the Transition of hESC-Derived ß Cells from the Juvenile to Adult State. Stem Cell Reports. 2020 01 14; 14(1):9-20.  View on PubMed
  5. Gökbuget D, Blelloch R. Epigenetic control of transcriptional regulation in pluripotency and early differentiation. Development. 2019 09 25; 146(19).  View on PubMed
  6. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R. Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory. Cell. 2019 04 04; 177(2):414-427.e13.  View on PubMed
  7. Belair CD, Hu T, Chu B, Freimer JW, Cooperberg MR, Blelloch RH. High-throughput, Efficient, and Unbiased Capture of Small RNAs from Low-input Samples for Sequencing. Sci Rep. 2019 02 19; 9(1):2262.  View on PubMed
  8. Krishnakumar R, Chen AF, Pantovich MG, Danial M, Parchem RJ, Labosky PA, Blelloch R. FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity. Cell Stem Cell. 2018 Aug 02; 23(2):306-307.  View on PubMed
  9. Freimer JW, Hu TJ, Blelloch R. Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells. Elife. 2018 07 25; 7.  View on PubMed
  10. Chen AF, Liu AJ, Krishnakumar R, Freimer JW, DeVeale B, Blelloch R. GRHL2-Dependent Enhancer Switching Maintains a Pluripotent Stem Cell Transcriptional Subnetwork after Exit from Naive Pluripotency. Cell Stem Cell. 2018 Aug 02; 23(2):226-238.e4.  View on PubMed
  11. Freimer JW, Krishnakumar R, Cook MS, Blelloch R. Expression of Alternative Ago2 Isoform Associated with Loss of microRNA-Driven Translational Repression in Mouse Oocytes. Curr Biol. 2018 01 22; 28(2):296-302.e3.  View on PubMed
  12. Paikari A, D Belair C, Saw D, Blelloch R. The eutheria-specific miR-290 cluster modulates placental growth and maternal-fetal transport. Development. 2017 10 15; 144(20):3731-3743.  View on PubMed
  13. Ye J, Jin H, Pankov A, Song JS, Blelloch R. NF45 and NF90/NF110 coordinately regulate ESC pluripotency and differentiation. RNA. 2017 08; 23(8):1270-1284.  View on PubMed
  14. Curtis A, Li DJ, DeVeale B, Onishi K, Kim MY, Blelloch R, Laird DJ, Hui EE. Patterning of sharp cellular interfaces with a reconfigurable elastic substrate. Integr Biol (Camb). 2017 01 23; 9(1):50-57.  View on PubMed
  15. Gambardella G, Carissimo A, Chen A, Cutillo L, Nowakowski TJ, di Bernardo D, Blelloch R. The impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells. Nat Commun. 2017 01 19; 8:14126.  View on PubMed
  16. D'Aniello C, Habibi E, Cermola F, Paris D, Russo F, Fiorenzano A, Di Napoli G, Melck DJ, Cobellis G, Angelini C, Fico A, Blelloch R, Motta A, Stunnenberg HG, De Cesare D, Patriarca EJ, Minchiotti G. Vitamin C and l-Proline Antagonistic Effects Capture Alternative States in the Pluripotency Continuum. Stem Cell Reports. 2017 01 10; 8(1):1-10.  View on PubMed
  17. Coffre M, Benhamou D, Rieß D, Blumenberg L, Snetkova V, Hines MJ, Chakraborty T, Bajwa S, Jensen K, Chong MMW, Getu L, Silverman GJ, Blelloch R, Littman DR, Calado D, Melamed D, Skok JA, Rajewsky K, Koralov SB. miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation. Cell Rep. 2016 11 22; 17(9):2271-2285.  View on PubMed
  18. Tran ND, Kissner M, Subramanyam D, Parchem RJ, Laird DJ, Blelloch RH. A miR-372/let-7 Axis Regulates Human Germ Versus Somatic Cell Fates. Stem Cells. 2016 07; 34(7):1985-91.  View on PubMed
  19. Krishnakumar R, Chen AF, Pantovich MG, Danial M, Parchem RJ, Labosky PA, Blelloch R. FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity. Cell Stem Cell. 2016 Jan 07; 18(1):104-17.  View on PubMed
  20. Wang ES, Reyes NA, Melton C, Huskey NE, Momcilovic O, Goga A, Blelloch R, Oakes SA. Fas-Activated Mitochondrial Apoptosis Culls Stalled Embryonic Stem Cells to Promote Differentiation. Curr Biol. 2015 Dec 07; 25(23):3110-8.  View on PubMed

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