Nathalie Scholler, MD, PhD.

faculty photo
Adjunct Assistant Professor of Obstetrics and Gynecology
Department: Obstetrics and Gynecology

Contact information
SRI International Biosciences Division
Cancer & Metabolism Center, #100-51
333 Ravenswood Avenue
Menlo Park, CA 94025
Office: 650-859-3248
Fax: (215) 573 5129
Lab: 650-859-3153
Education:
MD (General Medicine)
School of Medicine, Marseille, France, 1988.
MS (Immunology)
Centre d'Immunologie de Marseille-Luminy (CIML), University of Aix-Marseille II, France, 1991.
PhD (Immunology)
Centre d'Immunologie de Marseille-Luminy (CIML), University of Aix-Marseille II, France, 1995.
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Description of Research Expertise

Research Interests:
Study of B-cell response to tumors and B-cell interactions with innate immunity in the tumor microenvironment; development and evaluation of affinity reagents for diagnostic and targeted-imaging of cancer and therapy for ovarian cancer.

Key words:
Tumor microenvironment, ovarian cancer, innate and humoral immunity, recombinant antibodies, yeast-display scFv, targeted-nanoparticles.

Research Summary:
A/ Study of B-cell responses to tumors and B-cell interactions with innate immunity in the tumor microenvironment

The central hypothesis of my work is that B-cells play a pivotal, yet underappreciated, role in tumor formation and progression, and thus offer unique therapeutic opportunities for ovarian cancer. In my lab we have used a transgenic mouse model of ovarian cancer to better understand the role of B-cells and characterize the underlying mechanisms. We have observed that these tumors are infiltrated early on by B lymphocytes (TIL-B) and by macrophages. My lab is currently focused on understanding the role of different subsets of TIL-B and determining their relative frequency in ovarian cancer, and designing stimulation therapies that are able to activate all classes of TIL-B toward tumor rejection.
In the past year we also investigated the link between B-cell infiltration in tumors and innate immunity and the complement system. We have discovered that complement activation in tumors is critical for TIL-B function. This finding generates important opportunities to understand the role of B-cells but also to develop therapeutic tools.
Given the role of macrophages in tumor growth and their temporal association with B-cell infiltration in tumors, we are investigating whether macrophage depletion or repolarization could prevent some of the effects of TIL-B on tumor growth and are developing tools to repolarize tumor macrophages. Given my expertise in developing antibodies, we developed functional recombinant antibodies (scFv) against MR and showed that these novel anti-MR scFv could abrogate macrophage phenotype shift. My lab is now conducting in vivo experiments with MR knock-out mice which could lead to a novel therapeutic strategy able to redirect the tumor microenvironment toward an anti-tumor response by stabilizing the phenotype of M1 macrophages.

B/ Development and evaluation of affinity reagents for diagnostic and targeted-imaging and therapy of cancer

I have a long-standing expertise in the field of antibody development. The ELISA assay I developed against Mesothelin and published in 1999 in PNAS is now commercialized by Fujirebio, Inc as MesomarkTM. The scFv assays developed for diagnostic and functional tests directed to Mesothelin and its binding partner, CA125, as well as HE4 and other candidate biomarkers, are central to several epidemiological studies. My work in this area continues and I am exploring the potential of a combination of anti-Mesothelin and anti-CA125 mAbs to prevent peritoneal micrometastases.
Capitalizing on my expertise in antibody engineering, I have established a team at the University of Pennsylvania to create and screen novel yeast-display recombinant antibody (scFv) libraries derived from patients. My lab has created two new libraries of yeast-display scFv and identified several target-specific scFv. We are pursuing these important newly developed tools in different clinically relevant applications in various collaborative works at Penn and extramurally, ranging from functionalizing nanoparticles for organ-specific delivery of nucleic acids and contrast imaging agents and/or cytotoxic reagents, to physically active nanoparticles such as nanorods. ScFv are also being tested for direct radiolabelling and to engineer T-cells redirected to target through scFv. My lab is currently invested in deriving additional scFv against critical tumor-associated targets and to test their application in concrete disease models, including ovarian and breast cancers.

Rotation projects:
Study the mechanisms involved in early events in the genesis of ovarian cancer and specifically the role of B-cells and innate immunity.
Identify novel recombinant antibodies of translational interest for targeted-imaging and therapy in preclinical models of ovarian cancer.

Lab members:
Yi Cheng – Lab Manager (chengyi@mail.med.upenn.edu)
Selene Nunez-Cruz – Research Associate (selene@mail.med.upenn.edu)
Aizhi Zhao – Post-doctoral Fellow (zha@mail.med.upenn.edu)
Andrew Prantner – Post-doctoral Fellow (prantner@mail.med.upenn.edu)
Denarda Dangaj – Graduate Student (ddangaj@mail.med.upenn.edu)

Research Techniques:
Cellular biology: in vitro culture and maturation of human and murine B cells and macrophages, cell functional assays, magnetic and flow sortings, immunohistochemistry.
Molecular biology: engineering and screening of yeast-display scFv libraries, yeast expression of in vivo biotinylated proteins, mammalian expression of recombinant proteins.
Animal models of ovarian cancer in various genetic backgrounds, in vivo tumor imaging, targeted-imaging and therapy.

Selected Publications

Dangaj D, Lanitis E, Zhao A, Joshi S, Cheng Y, Sandaltzopoulos R, Powell Jr. DJ, Scholler N: Novel human anti-B7-H4 recombinant antibodies overcome B7-H4-mediated T-cell inhibition and potentiate T cell anti-tumor responses. Cancer Rsrch 73;4820, 2013.

Prantner A, Chen J, Murray C, Scholler N: Coating Evaluation and Purification of Monodisperse, Water-Soluble, Magnetic Nanoparticles Using Sucrose Density Gradient Ultracentrifugation. Chem of Materials 24(21):4008-10, 2012.

Lanitis E, Poussin M, Hagemann I, Sandaltzopoulos R, Scholler N, Powell, Jr DJ: Redirected anti-tumor activity of primary human lymphocytes transduced with a fully-human anti-mesothelin chimeric receptor. Molecul Ther 20(3):633-43, 2012.

Kalogera E, Scholler N, Powless C, Weaver A, Drapkin R, Li J, Jiang SW, Podratz K, Urban N, Dowdy SC: Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer. Gynecol Oncol 124(2):270-5, 2012.

Urbanska K, Lanitis E, Poussin M, Lynn R, Gavin BP, Kelderman S, Yu J, Scholler N, Powell Jr DJ: A novel immune receptor expressed by T cells for universal targeting of diverse and multiple tumor associated antigens. Cancer Rsrch 72(7):1844-52, 2012.

Li Y, Siegel DL, Scholler N, Kaplan DE: Glypican-3-specific scFv isolation and validation for use in hepatocellular carcinoma. BMC Biotechnology 12:23, 2012.

Lanitis E, Poussin M, Hagemann I, Sandaltzopoulos R, Scholler N, Powell Jr DJ: Redirected anti-tumor activity of primary human lymphocytes transduced with a fully-human anti-mesothelin chimeric receptor. Molecul Ther 20(3):633-43, 2012.

Nunez-Cruz S, Gimotty PA, Guerra MW, Connolly DC, Wu YQ, DeAngelis RA, Lambris JD, Coukos G, Scholler N: Genetic and pharmacologic inhibition of complement impairs endothelial cell function and ablates ovarian cancer neovascularization. Neoplasia (Cover) 14(11):994-1004, 2012.

Zhu CS, Pinsky PF, Cramer DW, Ransohoff DF, Hartge P, Pfeiffer RM, Urban N, Mor G, Bast RC Jr, Moore LE, Lokshin AE, McIntosh MW, Skates SJ, Vitonis A, Zhang Z, Ward DC, Symanowski JT, Lomakin A, Fung ET, Sluss PM, Scholler N, Lu KH, Marrangoni AM, Patriotis C, Srivastava S, Buys SS, Berg CD; PLCO Project Team. : A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer. Cancer Prev Res (Phila) 4(3):375-83, 2011

Cramer DW, Bast RC Jr, Berg CD, Diamandis EP, Godwin AK, Hartge P, Lokshin AE, Lu KH, McIntosh MW, Mor G, Patriotis C, Pinsky PF, Thornquist MD, Scholler N, Skates SJ, Sluss PM, Srivastava S, Ward DC, Zhang Z, Zhu CS, Urban N: Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prev Res (Phila) 4(3):365-74, 2011

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Last updated: 11/18/2013
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