Govindarajan and Mejia-Guerrero et al. used enrichment of N-glycosylated surface proteins and mass spectrometry to profile 85 patient-derived xenografts and generated Glyco PDXplorer, an in vivo pan-cancer atlas of tumor cell-surface N-glycoproteins. 290 cancer-enriched surface targets with limited normal tissue expression were identified. FAT2 emerged as a novel HNSC-enriched surface protein, essential for HNSC adhesion, growth, and survival via integrin-PI3K signaling. In the BT530 patient-derived model of brain metastasis with squamous cell histology, intracranial administration of FAT2 CAR-T cells reduced tumor burden and extended survival.
Contributed by Shishir Pant
ABSTRACT: Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central roles in cellular signaling, yet their promise remains largely untapped due to technical challenges inherent to profiling them. Here, we employ N-glycoproteomics to analyze 85 patient-derived xenografts (PDXs), constructing Glyco PDXplorer-an in vivo pan-cancer atlas of cancer-derived surface proteins. We develop a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validate FAT2 as a squamous-cancer-enriched surface protein minimally detected in normal tissue. Functional studies reveal that FAT2 is essential for head and neck squamous cancer (HNSC) cell growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR)-T cells targeting FAT2 demonstrate anti-tumor activity. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal platform to inform therapeutic target discovery across cancers.
Author Info: (1) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (
Author Info: (1) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (2) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (3) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (4) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (5) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (6) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (7) Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. (8) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (9) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (10) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (11) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (12) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (13) Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. (14) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (15) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (16) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (17) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (18) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (19) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (20) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (21) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (22) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (23) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (24) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (25) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (26) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (27) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (28) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (29) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (30) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (31) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (32) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (33) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (34) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (35) Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada. (36) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada. (37) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Otolaryngology-Head & Neck Surgery, University of Toronto, Toronto, ON M5S 3H2, Canada. (38) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (39) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (40) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada. (41) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (42) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (43) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (44) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. Electronic address: thomas.kislinger@utoronto.ca.
