학술논문
Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer.
Document Type
Academic Journal
Author
Bojmar L; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Zambirinis CP; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.; Hernandez JM; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.; Chakraborty J; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Shaashua L; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Kim J; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.; Johnson KE; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Hanna S; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Askan G; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Burman J; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Ravichandran H; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.; Zheng J; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Jolissaint JS; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Srouji R; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Song Y; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Choubey A; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Kim HS; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Cioffi M; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; van Beek E; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Sigel C; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Jessurun J; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; Velasco Riestra P; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Blomstrand H; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Department of Clinical Pathology, Linköping University, Linköping, Sweden.; Jönsson C; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Jönsson A; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Lauritzen P; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Buehring W; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Ararso Y; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Hernandez D; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Vinagolu-Baur JP; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Friedman M; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Glidden C; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Firmenich L; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Lieberman G; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Mejia DL; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Nasar N; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Mutvei AP; Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.; Paul DM; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.; Bram Y; Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY, USA.; Costa-Silva B; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Basturk O; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Boudreau N; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Zhang H; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Matei IR; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Hoshino A; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA.; Kelsen D; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Sagi I; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.; Scherz A; Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot, Israel.; Scherz-Shouval R; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.; Yarden Y; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.; Oren M; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.; Egeblad M; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Lewis JS; Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Medical College, New York, NY, USA.; Keshari K; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Grandgenett PM; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.; Hollingsworth MA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.; Rajasekhar VK; Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Healey JH; Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Björnsson B; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Simeone DM; Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.; Tuveson DA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Iacobuzio-Donahue CA; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Bromberg J; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.; Vincent CT; Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.; Department of Microbiology, New York University Grossman School of Medicine, New York, NY, USA.; O'Reilly EM; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Medical College, New York, NY, USA.; DeMatteo RP; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Balachandran VP; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; D'Angelica MI; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Kingham TP; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Allen PJ; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Simpson AL; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Elemento O; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.; Sandström P; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Schwartz RE; Division of Gastroenterology & Hepatology, Weill Cornell Medicine, New York, NY, USA.; Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.; Jarnagin WR; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Lyden D; Departments of Pediatrics and Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Drukier Institute for Children's Health, Meyer Cancer Center Weill Cornell Medicine, New York, NY, USA. dcl2001@med.cornell.edu.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. dcl2001@med.cornell.edu.
Source
Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
Subject
Language
English
Abstract
Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B + natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B + NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)