University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Scott A. Oakes, MD

Scott A. Oakes, MD

Associate Professor of Pathology, UCSF

Cancer Center Program Memberships

Non-aligned

Research Summary

I am a board-certified pathologist and cell biologist studying how mammalian cells sense and respond to protein-folding stress within the endoplasmic reticulum (ER) through an ancient signaling pathway called the Unfolded Protein Response (UPR), and what goes wrong with this process in diseases of cell loss (e.g., neurodegeneration, diabetes) and cell gain (e.g., cancer). To this end, we have developed rigorous in vitro assays and mouse models to identify and monitor the pro-survival and pro-death signals sent from the master UPR regulator IRE1, an ER transmembrane kinase/RNase. We designed a novel class of IRE1 inhibitors (KIRAs for Kinase Inhibiting RNase Attenuators) that shuts down its RNase allosterically through the adjacent kinase domain, and showed that they have cytoprotective benefits in pre-clinical models of retinal degeneration and diabetes. Using these genetic, chemical-genetic, and pharmacological tools, we are testing the effects of modulating the UPR in models of pancreatic neuroendocrine tumors (PanNETs) and myeloma, highly secretory solid tumors prone to protein-folding stress.

Education

Elmira College, Elmira, NY, B.A., 1993, Biochemistry
University of Connecticut, Farmington, CT, M.D., 1998, Medicine


Professional Experience

  • 1995-1996
    Research Scholar, HHMI, Lymphocyte Cell Biology Section, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD. Advisor: John J. O'Shea, M.D.
  • 1998-2000
    Resident, Anatomic Pathology, Brigham and Women's Hospital, Boston, MA
  • 1998-2002
    Clinical Fellow in Pathology, Harvard Medical School, Boston, MA
  • 2000-2005
    Research Associate, Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA. Advisor: Stanley J. Korsmeyer, M.D.
  • 2002-2005
    Instructor in Pathology, Harvard Medical School, Boston, MA.
  • 2005-2012
    Assistant Professor, Department of Pathology, University of California San Francisco
  • 2012-present
    Associate Professor (tenured), Department of Pathology, University of California San Francisco

Honors & Awards

  • 1989
    Salutatorian Scholarship
  • 1990
    Borden Highest Freshman GPA Prize
  • 1991
    Phi Beta Kappa Prize
  • 1992
    Phi Beta Kappa Prize
  • 1992
    Gorman Prize for Most Scholarly Work in Chemistry
  • 1993
    Outstanding Senior Chemistry Award
  • 1993
    Elmira College Valedictorian
  • 1998
    American Endocrine Society Award
  • 1998
    American Endocrine Society Award
  • 2000-2003
    NIH Pathology Training Grant Recipient
  • 2003-2008
    NIH Mentored Clinical Scientist Development Award (K08)
  • 2006-2007
    American Cancer Society Junior Investigator Award
  • 2007-2011
    HHMI Early Career Physician Scientist Award
  • 2012-2015
    American Cancer Society Research Scholar
  • 2013-2015
    Harrington Discovery Institute Scholar-Innovator Award
  • 2013
    Inductee—American Society for Clinical Investigation (ASCI)

Selected Publications

  1. Moore PC, Oakes SA. CPEB4 links the clock and the UPR to protect the liver. Nat Cell Biol. 2017 Jan 31; 19(2):79-81.
    View on PubMed
  2. Oakes SA. Endoplasmic reticulum proteostasis: a key checkpoint in cancer. Am J Physiol Cell Physiol. 2017 Feb 01; 312(2):C93-C102.
    View on PubMed
  3. 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
  4. Hetz C, Chevet E, Oakes SA. Erratum: Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015 Aug; 17(8):1088.
    View on PubMed
  5. Hetz C, Chevet E, Oakes SA. Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015 Jul; 17(7):829-38.
    View on PubMed
  6. Huskey NE, Guo T, Evason KJ, Momcilovic O, Pardo D, Creasman KJ, Judson RL, Blelloch R, Oakes SA, Hebrok M, Goga A. CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation. Stem Cell Reports. 2015 Mar 10; 4(3):374-89.
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  7. Guo WT, Wang XW, Yan YL, Li YP, Yin X, Zhang Q, Melton C, Shenoy A, Reyes NA, Oakes SA, Blelloch R, Wang Y. Suppression of epithelial-mesenchymal transition and apoptotic pathways by miR-294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells. Cell Death Differ. 2015 Jul; 22(7):1158-69.
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  8. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015; 10:173-94.
    View on PubMed
  9. Crane CA, Austgen K, Haberthur K, Hofmann C, Moyes KW, Avanesyan L, Fong L, Campbell MJ, Cooper S, Oakes SA, Parsa AT, Lanier LL. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci U S A. 2014 Sep 02; 111(35):12823-8.
    View on PubMed
  10. Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, Prado K, Thamsen M, Caswell D, Macias H, Weiberth KF, Gliedt MJ, Alavi MV, Hari SB, Mitra AK, Bhhatarai B, Schürer SC, Snapp EL, Gould DB, German MS, Backes BJ, Maly DJ, Oakes SA, Papa FR. Allosteric inhibition of the IRE1a RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014 Jul 31; 158(3):534-48.
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  11. van Dis V, Kuijpers M, Haasdijk ED, Teuling E, Oakes SA, Hoogenraad CC, Jaarsma D. Golgi fragmentation precedes neuromuscular denervation and is associated with endosome abnormalities in SOD1-ALS mouse motor neurons. Acta Neuropathol Commun. 2014 Apr 07; 2:38.
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  12. Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schürer SC, Oakes SA, Papa FR, Maly DJ. Divergent allosteric control of the IRE1a endoribonuclease using kinase inhibitors. Nat Chem Biol. 2012 Dec; 8(12):982-9.
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  13. Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT, Ruggero D, Goga A, Papa FR, Oakes SA. IRE1a cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science. 2012 Nov 09; 338(6108):818-22.
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  14. Lerner AG, Upton JP, Praveen PV, Ghosh R, Nakagawa Y, Igbaria A, Shen S, Nguyen V, Backes BJ, Heiman M, Heintz N, Greengard P, Hui S, Tang Q, Trusina A, Oakes SA, Papa FR. IRE1a induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 2012 Aug 08; 16(2):250-64.
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  15. Cheng CK, Gustafson WC, Charron E, Houseman BT, Zunder E, Goga A, Gray NS, Pollok B, Oakes SA, James CD, Shokat KM, Weiss WA, Fan QW. Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma. Proc Natl Acad Sci U S A. 2012 Jul 31; 109(31):12722-7.
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  16. Austgen K, Johnson ET, Park TJ, Curran T, Oakes SA. The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress. Nat Cell Biol. 2011 Dec 18; 14(1):87-92.
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  17. Austgen K, Oakes SA, Ganem D. Multiple defects, including premature apoptosis, prevent Kaposi's sarcoma-associated herpesvirus replication in murine cells. J Virol. 2012 Feb; 86(3):1877-82.
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  18. Shore GC, Papa FR, Oakes SA. Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol. 2011 Apr; 23(2):143-9.
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  19. Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, Haas-Kogan D, James CD, Oakes SA, Debnath J, Shokat KM, Weiss WA. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal. 2010 Nov 09; 3(147):ra81.
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  20. Reyes NA, Fisher JK, Austgen K, VandenBerg S, Huang EJ, Oakes SA. Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis. J Clin Invest. 2010 Oct; 120(10):3673-9.
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