Suzie Scales

Senior Scientist, Molecular Biology

POSTDOC MENTOR

"I lead the research program for one of the antibody-drug conjugates, which gratifyingly just entered the clinic this year (2011)."

• 12
  years at Genentech
• 12
  publications (2010-12)

I studied membrane trafficking and fusion in the secretory pathway for my PhD (Kreis lab) and postdoc (Scheller lab) and was recruited to Genentech in 2001 to examine the endocytosis (internalization) of antibodies to cell surface cancer targets as part of the antibody-drug conjugate team. As well as helping to establish the rules for antibody trafficking and linker-drug selection, I lead the research program for one of the antibody-drug conjugates, which gratifyingly just entered the clinic this year (2011).

Once here, I was also recruited to the Hedgehog team to better understand the cell biology and trafficking of various components of this pathway, which led to our discovery that the transcription factors of the pathway (Gli1,2,3) accumulate at the tips of primary cilia (a sort of signaling antenna on the cell surface) upon stimulation by Hedgehog ligand. This naturally led to an interest in primary cilia, which have been implicated in several disparate diseases ("ciliopathies").

• My Focus

  Primary cilia are sensory organelles evolved from the flagella of primitive eukaryotes, with a single cilium protruding from most cell types in vertebrates. Unlike the cilia of brush borders (9+2 cilia), primary cilia have a 9+0 arrangement of microtubules and are therefore non-motile, allowing them instead to sense their environment e.g. the flow of urine in the kidney or the presence of light, hormones and other stimuli, and to transmit signals to the cell. One exception is the nodal cilia, which exhibit a spiraling motion, thought to help diffuse the Hedgehog morphogen in determining left-right body axis formation, and are therefore important in Hedgehog signaling. Indeed, mutants of several proteins transported along cilia (known as IFTs for intraflagellar transport proteins) have similar phenotypes to Hedgehog mutants in mice, including hydrocephalus, polydactyly and situs invertus. In humans, defects in ciliogenesis have been implicated in several diseases, such as polycystic kidney disease, situs invertus, retinal degeneration and Bardet-Biedel syndrome [which encompasses all the above disorders as well as obesity, diabetes, male sterility and hypertension], thus further understanding this process is warranted.

  Although many candidate ciliary genes have been identified by proteomics, comparative genomics of ciliated vs non-ciliated organisms and cilia-specific promoter analyses, few of them have been characterized at the cellular level. We are therefore conducted an siRNA screen to determine whether these genes are involved in ciliogenesis, cilia structure and/or cilia function, using fluorescence microscopy of cilia and transport of different cargoes and Hedgehog signaling assays as readouts (Lai et al, 2011). As expected, knockdown of genes that prevent cilia formation also disrupt Hedgehog signaling and transport. However, others affect cilia length with or without defects in transport or signaling, while another subset affects cargo transport and signaling with no apparent structural defects. We are currently further characterizing the top validated hits to decipher their roles in cilia function. Additionally we are attempting to further dissect the actual role of cilia in the Hedgehog-dependent translocation of pathway components such as Smoothened and Gli3."

• Publications

  • Rer1p maintains ciliary length and signaling by regulating gamma-secretase activity and Foxj1a levels

    Journal of Cell Biology, 2013, ISSN: 0021-9525

    Jurisch-Yaksi, Nathalie; Rose, Applonia J.; Lu, Huiqi; Raemaekers, Tim; Munck, Sebastian; Baatsen, Pieter; Baert, Veerle; Vermeire, Wendy; Scales, Suzie J.; Verleyen, Daphne; Vandepoel, Roel; Tylzanowski, Przemko; Yaksi, Emre; de Ravel, Thomy; Yost, H. Joseph; Froyen, Guy; Arrington, Cammon B.; Annaert, Wim

     View on PubMed

  • The Ciliary G-Protein-Coupled Receptor Gpr161 Negatively Regulates the Sonic Hedgehog Pathway via cAMP Signaling

    Cell, 2013, ISSN: 0092-8674

    Mukhopadhyay, Saikat; Wen, Xiaohui; Ratti, Navneet; Loktev, Alexander; Rangell, Linda; Scales, Suzie J; Jackson, Peter K

     View on PubMed

  • Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates

    Nature Biotechnology, 2012, ISSN: 1087-0156

    Shen, Ben-Quan; Xu, Keyang; Liu, Luna; Raab, Helga; Bhakta, Sunil; Kenrick, Margaret; Parsons-Reponte, Kathryn L; Tien, Janet; Yu, Shang-Fan; Mai, Elaine; Li, Dongwei; Tibbitts, Jay; Baudys, Jakub; Saad, Ola M; Scales, Suzie J; McDonald, Paul J; Hass, Philip E; Eigenbrot, Charles; Nguyen, Trung; Solis, Willy A; Fuji, Reina N; Flagella, Kelly M; Patel, Darshana; Spencer, Susan D; Khawli, Leslie A; Ebens, Allen; Wong, Wai Lee; Vandlen, Richard; Kaur, Surinder; Sliwkowski, Mark X; Scheller, Richard H; Polakis, Paul; Junutula, Jagath R

     View on PubMed

  • Membrane targeting of palmitoylated Wnt and Hedgehog revealed by chemical probes.

    FEBS letters, {FEBS-Lett}, 5 Jul 2011 (epub: 5 7 2011), ISSN: 1873-3468.

    Gao, Xinxin; Arenas-Ramirez, Natalia; Scales, Suzie J; Hannoush, Rami N

     View on PubMed

  • Mechanisms of Hedgehog pathway activation in cancer and implications for therapy.

    Trends in pharmacological sciences, 2009, ISSN: 1873-3735

    Scales-Suzie-J, de-Sauvage-Frederic-J.;

  • Small molecule inhibition of GDC-0449 refractory Smoothened mutants and downstream mechanisms of drug resistance.

    Cancer Research, 2010, ISSN: 1538-7445

    Dijkgraaf, G.J.P.; Alicke, B.; Weinmann, L.; Januario, T.; West, K.; Modrusan, Z.; Burdick, D.; Goldsmith, R.; Robarge, K.; Sutherlin, D.; Scales, S.J.; Gould, S.E.; Yauch, R.L.; de Sauvage, F.J.

  • FcRL5 as a Target of Antibody-Drug Conjugates for the Treatment of Multiple Myeloma.

    Blood, 2009, ISSN: 0006-4971

    Polson, A.G.; Zheng, B.; Elkins, K.; Lau, J.; Go, M.A.; Scales, S.J.; Yu, S.F.; Chesi, M.; Bergsagel, P.L.; Ebens, A.J.

  • Hedgehog Pathway Antagonist 5E1 Binds Hedgehog at the Pseudo-active Site.

    The Journal of Biological Chemistry, 2010, ISSN: 1083-351X

    Maun, H.; Wen, X.; Lingel, A.; de Sauvage, F.; Lazarus, R.; Scales, S.; Hymowitz, S.

  • Kinetics of Hedgehog-Dependent Full-Length Gli3 Accumulation in Primary Cilia and Subsequent Degradation.

    Molecular & Cellular Biology, 2010, ISSN: 1098-5549

    Wen, X.; Lai, C.K.; Evangelista, M.; Hongo, J.A.; de Sauvage, F.J.; Scales, S.J.

  • The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development.

    Current Biology, 2009, ISSN: 1879-0445

    Endoh-Yamagami, S.; Evangelista, M.; Wilson, D.; Wen, X.; Theunissen, J.-W.; Phamluong, K.; Davis, M.; Scales, S.J.; Solloway, M.J.; de Sauvage, F.J.; Peterson, A.S.

  • The structure of SHH in complex with HHIP reveals a recognition role for the SHH pseudo-active site in signaling.

    Nature Structural & Molecular Biology, 2009, ISSN: 1545-9985

    Bosanac, I.; Maun, H.R.; Scales, S.J.; Wen, X.; Lingel, A.; Bazan, J.F.; de Sauvage, F.J.; Hymowitz, S.G.; Lazarus, R.A.

  • Antibody-drug conjugates for the treatment of Non-Hodgkin's Lymphoma: target and linker-drug selection.

    Cancer Research, 2009, ISSN: 1538-7445

    Polson, A.G.; Calemine-Fenaux, J.; Chan, P.; Chang. W.; Christensen, E.; Clark, S.; de Sauvage, F.J.; Eaton, D.; Elkins, K.; Elliott, M.; Frantz, G.; Fuji, R.N.; Gray, A.; Harden, K.; Ingle, G.S.; Kljavin, N.M.; Koeppen, H.; Nelson, C.; Prabhu, S.; Raab, H.; Ross, S.; Stephan, J.-P.; Scales, S.J.; Spencer, S.D.; Vandlen, R.; Wranik, B.; Yu, S.-F.; Zheng, B.; Ebens, A.

• Education
  • Stanford University, Postdoctoral Fellow – 2001
  • University of Geneva, Ph.D. – 1998
  • University of Cambridge, UK, M.A. – 1995
  • University of Cambridge, UK, B.A. – 1992