/ Scientists

I came to Genentech in 1990 thinking I would be here only for a few years. I loved the work and the culture so much that I've been here ever since.

Over the years I have had many collaborations across the company. Recently, my lab's interest was mostly focused on the characterization of the hedgehog signaling pathway and the development of pathway antagonists for the treatment of various cancer. This project has evolved into a multidisciplinary project that involves many departments across the organization, which has given me the opportunity to interact with fantastic people.

POSTDOCTORAL MENTOR The Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is crucial for proper development. At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. Hh signaling is most active during embryogenesis and aberrant reactivation of the pathway in adult tissue can lead to the development of cancer. Mutations in the Hh receptor components, Patched (PTCH1) or Smoothened (SMOH), result in constitutive pathway activation and have been identified in basal cell carcinoma and medulloblastoma. It has also been observed that Hh ligand production is upregulated in other cancer types such as pancreatic adenocarcinomas. The mechanisms by which the Hh signal is transmitted inside the cell, leading ultimately to the activation of the GLI family of transcription factors also remains poorly understood. The lab is interested in (i) understanding the contribution of Hh signaling in cancer by using genetic mouse models of cancer, (ii) uncovering signaling mechanisms by which the Hh signal is transduced into a cell and potentially novel therapeutic targets for the treatment of cancer and finally (iii) understand the mechanism of resistance to hedgehog pathway inbibitors. More recently my lab has become interested in the role of intestinal stem cells in homeostasis and in tumor development. While developing agents to target stem cells in the gut we have uncovered mechanism(s) of compensations that allows the GI track to tolerate depletion of the stem cell compartment in various challenge situations. However this mechanism probably also reflect a great deal of plasticity in tumors as well and we are studying the signaling mechanisms that underlie this phenomenon.

• My Focus

  We are studying and targeting a number of important developmental signaling pathways such as Wnt, Hedgehog and Notch. These signaling pathways play critical roles during embryogenesis in pretty much every organ of the body where they modulate proliferation or differentiation of numerous cell types. It is however becoming increasingly clear that these pathways are involved in tumorigenesis when reactivated in adult tissues through mutations or overexpression of pathway components.

  This work has led to the development of vismodegib, a hedgehog pathway inhibitor, which targets Smoothened. Vismodegib was approved in 2012 by the FDA for the treatment of basal cell carcinoma (BCC), which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation We are also involved in a number of earlier stage initiatives using genetic mouse models of cancer to better predict drug efficacy, sequencing the genome of various tumor types to better understand how tumor develop and how to target them as well as as well as cancer and functional genome projects to identify novel drug targets in various therapeutic areas.

• Publications

  • Recapitulating human cancer in a mouse

    Nature Biotechnology, 2013, ISSN: 1087-0156

    Chin, Lynda; De Sauvage, Frederic; Egeblad, Mikala; Olive, Kenneth P.; Tuveson, David; Weiss, William

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  • Lgr5-Expressing Cells Are Sufficient And Necessary for Postnatal Mammary Gland Organogenesis

    Cell Reports, 2013, ISSN:

    Plaks, Vicki; Brenot, Audrey; Lawson, Devon A.; Linnemann, Jelena R.; Van Kappel, Eline C.; Wong, Karren C.; de Sauvage, Frederic; Klein, Ophir D.; Werb, Zena

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  • A tumor-specific stem cell

    Nature Genetics, 2012, ISSN: 1061-4036

    Metcalfe, Ciara; de Sauvage, Frederic J

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  • Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

    Genome Research, 2012, ISSN: 1088-9051

    Liu, Jinfeng; Lee, William; Jiang, Zhaoshi; Chen, Zhongqiang; Jhunjhunwala, Suchit; Haverty, Peter M; Gnad, Florian; Guan, Yinghui; Gilbert, Houston; Stinson, Jeremy; Klijn, Christiaan; Guillory, Joseph; Bhatt, Deepali; Vartanian, Steffan; Walter, Kimberly; Chan, Jocelyn; Holcomb, Thomas; Dijkgraaf, Peter; Johnson, Stephanie; Koeman, Julie; Minna, John D; Gazdar, Adi F; Stern, Howard M; Hoeflich, Klaus P; Wu, Thomas D; Settleman, Jeff; de Sauvage, Frederic J; Gentleman, Robert C; Neve, Richard M; Stokoe, David; Modrusan, Zora; Seshagiri, Somasekar; Shames, David S; Zhang, Zemin

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  • Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer

    Nature Genetics, 2012, ISSN: 1061-4036

    Rudin, Charles M.; Durinck, Steffen; Stawiski, Eric W.; Poirier, John T.; Modrusan, Zora; Shames, David S.; Bergbower, Emily A.; Guan, Yinghui; Shin, James; Guillory, Joseph; Rivers, Celina Sanchez; Foo, Catherine K.; Bhatt, Deepali; Stinson, Jeremy; Gnad, Florian; Haverty, Peter M.; Gentleman, Robert; Chaudhuri, Subhra; Janakiraman, Vasantharajan; Jaiswal, Bijay S.; Parikh, Chaitali; Yuan, Wenlin; Zhang, Zemin; Koeppen, Hartmut; Wu, Thomas D.; Stern, Howard M.; Yauch, Robert L.; Huffman, Kenneth E.; Paskulin, Diego D.; Illei, Peter B.; Varella-Garcia, Marileila; Gazdar, Adi F.; De Sauvage, Frederic J.; Bourgon, Richard; Minna, John D.; Brock, Malcolm V.; Seshagiri, Somasekar

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  • Recurrent R-spondin fusions in colon cancer

    Nature, 2012, ISSN: 0028-0836

    Seshagiri, Somasekar; Stawiski, Eric W. ; Durinck, Steffen; Modrusan, Zora; Storm, Elaine E.; Conboy, Caitlin B.; Chaudhuri, Subhra; Guan, Yinghui; Janakiraman, Vasantharajan; Jaiswal, Bijay S.; Guillory, Joseph; Ha, Connie; Dijkgraaf, Gerrit J. P. ;Stinson, Jeremy; Gnad, Florian; Huntley, Melanie A.; Degenhardt, Jeremiah D.; Haverty, Peter M.; Bourgon, Richard; Wang, Weiru ; Koeppen, Hartmut; Gentleman, Robert; Starr, Timothy K.; Zhang, Zemin; Largaespada, David A.; Wu, Thomas D. ; de Sauvage, Frederic J.

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  • The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients

    Genome Research, 2012, ISSN: 1088-9051

    Jiang, Zhaoshi; Jhunjhunwala, Suchit; Liu, Jinfeng; Haverty, Peter M; Kennemer, Michael I; Guan, Yinghui; Lee, William; Carnevali, Paolo; Stinson, Jeremy; Johnson, Stephanie; Diao, Jingyu; Yeung, Stacy; Jubb, Adrian; Ye, Weilan; Wu, Thomas D; Kapadia, Sharookh B; de Sauvage, Frederic J; Gentleman, Robert C; Stern, Howard M; Seshagiri, Somasekar; Pant, Krishna P; Modrusan, Zora; Ballinger, Dennis G; Zhang, Zemin

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  • Signaling: An oxysterol ligand for Smoothened

    Nature Chemical Biology, 2012, ISSN: 1552-4450

    Sharpe, Hayley J.; De Sauvage, Frederic J.

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  • A reserve stem cell population in small intestine renders Lgr5- positive cells dispensable.

    Nature, 18 Sep 2011, ISSN: 1476-4687.

    Tian, Hua; Biehs, Brian; Warming, Soeren; Leong, Kevin G; Rangell, Linda; Klein, Ophir D; de Sauvage, Frederic J

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  • miR-221/222 Targeting of Trichorhinophalangeal 1 (TRPS1) Promotes Epithelial-to-Mesenchymal Transition in Breast Cancer

    Science signaling, 16 Aug 2011, vol. 4, no. 186, p. pt5, ISSN: 1937-9145.

    Stinson, Susanna; Lackner, Mark R; Adai, Alex T; Yu, Nancy; Kim, Hyo Jin; O, Brien Carol; Spoerke, Jill; Jhunjhunwala, Suchit; Boyd, Zachary; Januario, Thomas; Newman, Robert J; Yue, Peng; Bourgon, Richard; Modrusan, Zora; Stern, Howard M; Warming, Soeren; de Sauvage, Frederic J; Amler, Lukas; Yeh, Ru Fang; Dornan, David

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  • Hedgehog Fights Back: Mechanisms of Acquired Resistance against Smoothened Antagonists.

    Cancer research, {Cancer-Res}, 19 Jul 2011 (epub: 19 7 2011), ISSN: 1538-7445.

    Metcalfe, Ciara; de Sauvage, Frederic J

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  • Pharmacokinetic–Pharmacodynamic Analysis of Vismodegib in Preclinical Models of Mutational and Ligand-Dependent Hedgehog Pathway Activation

    Clinical cancer research : an official journal of the American Association for Cancer Research, {Clin-Cancer-Res}, 15 Jul 2011 (epub: 24 May 2011), vol. 17, no. 14, p. 4682-92, ISSN: 1078-0432.

    Wong, Harvey; Alicke, Bruno; West, Kristina A; Pacheco, Patricia; La, Hank; Januario, Tom; Yauch, Robert L; de Sauvage, Frederic J; Gould, Stephen E

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  • TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer.

    Science Signaling, 2011, ISSN: 1945-0877

    Stinson, Susanna; Lackner, Mark R; Adai, Alex T; Yu, Nancy; Kim, Hyo-Jin; O’Brien, Carol; Spoerke, Jill; Jhunjhunwala, Suchit; Boyd, Zachary; Januario, Thomas; Newman, Robert J; Yue, Peng; Bourgon, Richard; Modrusan, Zora; Stern, Howard M; Warming, Søren; de Sauvage, Frederic J; Amler, Lukas; Yeh, Ru-Fang; Dornan, David

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  • IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells.

    Journal of Experimental Medicine, 2010, ISSN: 1540-9538

    Batten, M.; Ramamoorthi, N.; Kljavin, N.; Ma, C.; Cox, J.; Dengler, H.; Danilenko, D.; Caplazi, P.; Wong, M.; Fulcher, D.; Cook, M.; King, C.; Tangye, S.; de Sauvage, F.; Ghilardi, N.

  • 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.

  • Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor.

    Development, 2010, ISSN: 0950-1991

    Seidel, K.; Ahn, C.; Lyons, D.; Nee, A.; Ting, K.; Brownell, I.; Cao, T.; Carano, R.; Curran, T.; Schober, M.; Fuchs, E.; Joyner, A.; Martin, G.; de Sauvage, F.; Klein, O.

  • Clinical Experience With Hedgehog Pathway Inhibitors.

    Journal of Clinical Oncology, 2010, ISSN: 1527-7755

    Low, J.A.; de Sauvage, F.J.

  • Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway.

    Bioorganic & Medicinal Chemistry Letters, 2010, ISSN: 1464-3405

    Castanedo, G.; Wang, S.; Robarge, K.; Blackwood, E.; Burdick, D.; Chang, C.; Dijkgraaf, G.; Gould, S.; Gunzner, J.; Guichert, O.; Halladay, J.; Khojasteh, C.; Lee, L.; Marsters, J.; Murray, L.; Peterson, D.; Plise, E.; Salphati, L.; de Sauvage, F.; Wong, S.; Sutherlin, D.

  • Frequent PIK3R1 somatic mutations promote oncogenic signaling.

    Proceedings of the American Association for Cancer Research Annual Meeting, 2010, ISSN: 0197-016X

    Jaiswal, B.; Janakiraman, V.; Chaudhuri, S.; Stern, H.; Kljavin, N.; Wang, W.; Kan, Z.; Bowman, K.; Wu, J.; Kaminker, J.; Yue, P.; de Sauvage, F.; Backer, J.; Seshagiri, S.

  • Diverse somatic mutation patterns and pathway alterations in human cancers.

    Nature, 2010, ISSN: 1476-4687

    Kan, Z.; Jaiswal, B.; Stinson, J.; Janakiraman, V.; Bhatt, D.; Stern, H.; Yue, P.; Haverty, P.; Bourgon, R.; Zheng, J.; Moorhead, M.; Chaudhuri, S.; Tomsho, L.; Peters, B.; Pujara, K.; Cordes, S.; Davis, D.; Carlton, V.; Yuan, W.; Li, L.; Wang, W.; Eigenbrot, C.; Kaminker, J.; Eberhard, D.; Waring, P.; Schuster, S.; Modrusan, Z.; Zhang, Z.; Stokoe, D.; de Sauvage, F.; Faham, M.; Seshagiri, S.

  • Long live science! Long live the hedgehog! (Vive la science! Vive le herisson!)

    EMBO Reports, 2010, ISSN: 1469-221X

    Reiter, J.; de Sauvage, F.

  • A mouse knockout library for secreted and transmembrane proteins.

    Nature Biotechnology, 2010, ISSN: 1546-1696

    Tang, T.; Li, L.; Tang, J.; Li, Y.; Lin, W.Y.; Martin, F.; Grant, D.; Solloway, M.; Parker, L.; Ye, W.; Forrest, W.; Ghilardi, N.; Oravecz, T.; Platt, K.; Rice, D.; Hansen, G.; Abuin, A.; Eberhart, D.; Godowski, P.; Holt, K.; Peterson, A.; Zambrowicz, B.; de Sauvage, F.

  • 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.

  • The mutation spectrum revealed by paired genome sequences from a lung cancer patient.

    Nature, 2010, ISSN: 1476-4687

    Lee, W.; Jiang, Z.; Liu, J.; Haverty, P.; Guan, Y.; Stinson, J.; Yue, P.; Zhang, Y.; Pant, K.; Bhatt, D.; Ha, C.; Johnson, S.; Kennemer ,M.; Mohan, S.; Nazarenko, I.; Watanabe, C.; Sparks, A.; Shames, D.; Gentleman, R.; de Sauvage, F.; Stern, H.; Pandita, A.; Ballinger, D.; Drmanac, R.; Modrusan, Z.; Seshagiri, S.; Zhang, Z.

  • 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.

  • Somatic mutations in p85alpha promote tumorigenesis through Class IA PI3K activation.

    Cancer Cell, 2009, ISSN: 1878-3686

    Jaiswal, B.S.; Janakiraman, V.; Kljavin, N.M.; Chaudhuri, S.; Stern, H.M.; Wang, W.; Kan, Z.; Dbouk, H.A.; Peters, B.A.; Waring, P.; Dela Vega, T.; Kenski, D.M.; Bowman, K.K.; Lorenzo, M.; Li, H.; Wu, J.; Modrusan, Z.; Stinson, J.; Eby, M.; Yue, P.; Kaminker, J.S.; de Sauvage, F.J.; Backer, J.M.; Seshagiri, S.

  • Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma.

    Science, 2009, ISSN: 0036-8075

    Yauch, R.L.; Dijkgraaf, G.J.P.; Alicke, B.; Januario,T.; Ahn, C.P.; Holcomb, T.; Pujara, K.; Stinson, J.; Callahan, C.A.; Tang, T.; Bazan, J.F.; Kan, Z.; Seshagiri, S.; Hann, C.L.; Gould, S.E.; Low, J.A.; Rudin, C.M.; de Sauvage, F.J.

  • Brief Report: treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449.

    New England Journal of Medicine, 2009, ISSN: 0028-4793

    Rudin, C.M.; Hann, C.L.; Laterra, J.; Yauch, R.L.; Callahan, C.A.; Fu, L.; Holcomb, T.; Stinson, J.; Gould, S.E.; Coleman, B.; LoRusso, P.M.; Von Hoff, D.D.; de Sauvage, F.J.; Low, J.A.

  • Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.

    New England Journal of Medicine, 2009, ISSN: 0028-4793

    Von Hoff, D.D.; LoRusso, P.M.; Rudin, C.M.; Reddy, J.C.; Yauch, R.L.; Tibes, R.; Weiss, G.J.; Borad, M.J.; Hann, C.L.; Brahmer, J.R.; Mackey, H.M.; Lum, B.L.; Darbonne, W.C.; Marsters, J.C.; de Sauvage, F.J.; Low J.A.

  • Structural ties between cholesterol transport and morphogen signaling.

    Cell, 2009, ISSN: 1097-4172

    Bazan, J.F.; de Sauvage, F.J.

  • Paracrine hedgehog signaling in cancer.

    Cancer Research, 2009, ISSN: 1538-7445

    Theunissen, J.W.; de Sauvage, F.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.

  • Prostate-specific Klf6 inactivation impairs anterior prostate branching morphogenesis through increased activation of the Shh pathway.

    Journal of Biological Chemistry, 2009, ISSN: 0021-9258

    Leow, C.C.; Wang, B.; Ross, J.; Chan, S.M.; Zha, J.; Carano, R.A.D.; Frantz, G.; Shen, M.M.; deSauvage, F.J.; Gao, W.-Q.

  • Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis.

    Cell Stem Cell, 2009, ISSN: 1934-5909

    Hofmann, I.; Stover, E.H.; Cullen, D.E.; Mao, J.; Morgan, K.J.; Lee, B.H.; Kharas, M.G.; Miller, P.G.; Cornejo, M.G.; Okabe, R.; Armstrong, S.A.; Ghilardi, N.; Gould, S.; de Sauvage, F.J.; McMahon, A.P.; Ghilliland, D.G.

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

    Trends in Pharmacological Sciences, 2009, ISSN: 1873-3735

    Scales, S.J.; de Sauvage, F.J.

  • 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.

  • Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes.

    Blood, 2009, ISSN: 0006-4971

    Tiedt, R.; Coers, J.; Ziegler, S.; Wiestner, A.; Hao-Shen, H.; Bornmann, C.; Schenkel, J.; Karakhanova, S.; de Sauvage, F.J.; Jackson, C.W.; Skoda, R.C.

  • Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction

    Science Signaling, 2008, ISSN: 1937-9145

    Evangelista, M.; Lim, T.Y.; Lee, J.; Parker, L.; Ashique, A.; Peterson, A.S.; Ye, W.; Davis, D.P.; de Sauvage, F.J.

  • Hedgehog signaling in development and disease.

    , 2009, ISSN:

    De Sauvage, F.

  • Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens.

    Nature Medicine, 2008, ISSN: 1546-170X

    Zheng, Y.; Valdez, P.A.; Danilenko, D.M.; Hu, Y.; Sa, S.M.; Gong, Q.; Abbas, A.R.; Modrusan, Z.; Ghilardi, N.; de Sauvage, F.J.; Ouyang W.

  • The magnitude of hedgehog signaling activity defines skin tumor phenotype

    EMBO J., 2003, ISSN:

    Grachtchouk, V.;Grachtchouk, M.;Lowe, L.;Johnson, T.;Wei, L.;Wang, A.;de Sauvage, F.;Dlugosz, A.A.

• Education
  • Catholic University of Louvain, Ph.D. – 1990
  • Catholic University of Louvain, B.S. – 1985