Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer.

TitleMulti-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer.
Publication TypeJournal Article
Year of Publication2024
AuthorsBojmar L, Zambirinis CP, Hernandez JM, Chakraborty J, Shaashua L, Kim J, Johnson KEnnu, Hanna S, Askan G, Burman J, Ravichandran H, Zheng J, Jolissaint JS, Srouji R, Song Y, Choubey A, Kim HSang, Cioffi M, van Beek E, Sigel C, Jessurun J, Riestra PVelasco, Blomstrand H, Jönsson C, Jönsson A, Lauritzen P, Buehring W, Ararso Y, Hernandez D, Vinagolu-Baur JP, Friedman M, Glidden C, Firmenich L, Lieberman G, Mejia DL, Nasar N, Mutvei AP, Paul DM, Bram Y, Costa-Silva B, Basturk O, Boudreau N, Zhang H, Matei IR, Hoshino A, Kelsen D, Sagi I, Scherz A, Scherz-Shouval R, Yarden Y, Oren M, Egeblad M, Lewis JS, Keshari K, Grandgenett PM, Hollingsworth MA, Rajasekhar VK, Healey JH, Björnsson B, Simeone DM, Tuveson DA, Iacobuzio-Donahue CA, Bromberg J, C Vincent T, O'Reilly EM, DeMatteo RP, Balachandran VP, D'Angelica MI, T Kingham P, Allen PJ, Simpson AL, Elemento O, Sandström P, Schwartz RE, Jarnagin WR, Lyden D
JournalNat Med
Volume30
Issue8
Pagination2170-2180
Date Published2024 Aug
ISSN1546-170X
KeywordsAged, Biopsy, Extracellular Traps, Female, Humans, Liver, Liver Neoplasms, Male, Middle Aged, Neoplasm Staging, Pancreatectomy, Pancreatic Neoplasms, Prognosis
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.

DOI10.1038/s41591-024-03075-7
Alternate JournalNat Med
PubMed ID38942992
PubMed Central IDPMC11416063
Grant ListU54 CA163120 / CA / NCI NIH HHS / United States
U54 CA163117 / CA / NCI NIH HHS / United States
2021-600 02356 / / Vetenskapsrådet (Swedish Research Council) /
R01 CA218513 / CA / NCI NIH HHS / United States
grant no. S21-0079 / / Svenska Sällskapet för Medicinsk Forskning (Swedish Society for Medical Research) /
U19 AI144301 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
21 1824 Pj 01 H / / Cancerfonden (Swedish Cancer Society) /
TG-23-0306 / / Svenska Sällskapet för Medicinsk Forskning (Swedish Society for Medical Research) /
UL1 TR002384 / TR / NCATS NIH HHS / United States
U01 CA210240 / CA / NCI NIH HHS / United States
R01 DK121072 / DK / NIDDK NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
R35 CA232093 / CA / NCI NIH HHS / United States
R01 CA207983 / CA / NCI NIH HHS / United States
R01 CA169416 / CA / NCI NIH HHS / United States
R01 CA234614 / CA / NCI NIH HHS / United States
U01 CA169538 / CA / NCI NIH HHS / United States
U01 CA224175 / CA / NCI NIH HHS / United States
Related Faculty: 
Jose Jessurun, M.D.

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