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

Linda Bojmar; Constantinos P. Zambirinis; Jonathan M. Hernandez; Jayasree Chakraborty; Lee Shaashua; Junbum Kim; Kofi Ennu Johnson; Samer Hanna; Gokce Askan; Jonas Burman; Hiranmayi Ravichandran; Jian Zheng; Joshua S. Jolissaint; Rami Srouji; Yi Song; Ankur Choubey; Han Sang Kim; Michele Cioffi; Elke van Beek; Carlie Sigel; Jose Jessurun; Paulina Velasco Riestra; Hakon Blomstrand; Carolin Jönsson; Anette Jönsson; Pernille Lauritzen; Weston Buehring; Yonathan Ararso; Dylanne Hernandez; Jessica P. Vinagolu-Baur; Madison Friedman; Caroline Glidden; Laetitia Firmenich; Grace Lieberman; Dianna L. Mejia; Naaz Nasar; Anders P. Mutvei; Doru M. Paul; Yaron Bram; Bruno Costa-Silva; Olca Basturk; Nancy Boudreau; Haiying Zhang; Irina R. Matei; Ayuko Hoshino; David Kelsen; Irit Sagi; Avigdor Scherz; Ruth Scherz-Shouval; Yosef Yarden; Moshe Oren; Mikala Egeblad; Jason S. Lewis; Kayvan Keshari; Paul M. Grandgenett; Michael A. Hollingsworth; Vinagolu K. Rajasekhar; John H. Healey; Bergthor Björnsson; Diane M. Simeone; David A. Tuveson; Christine A. Iacobuzio-Donahue; Jaqueline Bromberg; C. Theresa Vincent; Eileen M. O’Reilly; Ronald P. DeMatteo; Vinod P. Balachandran; Michael I. D’Angelica; T. Peter Kingham; Peter J. Allen; Amber L. Simpson; Olivier Elemento; Per Sandström; Robert E. Schwartz; William R. Jarnagin; David Lyden

doi:10.1038/s41591-024-03075-7

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

Linda Bojmar, Constantinos P. Zambirinis, Jonathan M. Hernandez, Jayasree Chakraborty, Lee Shaashua, Junbum Kim, Kofi Ennu Johnson, Samer Hanna, Gokce Askan, Jonas Burman, Hiranmayi Ravichandran, Jian Zheng, Joshua S. Jolissaint, Rami Srouji, Yi Song, Ankur Choubey, Han Sang Kim, Michele Cioffi, Elke van Beek, Carlie SigelJose Jessurun, Paulina Velasco Riestra, Hakon Blomstrand, Carolin Jönsson, Anette Jönsson, Pernille Lauritzen, Weston Buehring, Yonathan Ararso, Dylanne Hernandez, Jessica P. Vinagolu-Baur, Madison Friedman, Caroline Glidden, Laetitia Firmenich, Grace Lieberman, Dianna L. Mejia, Naaz Nasar, Anders P. Mutvei, Doru M. Paul, Yaron Bram, Bruno Costa-Silva, Olca Basturk, Nancy Boudreau, Haiying Zhang, Irina R. Matei, Ayuko Hoshino, David Kelsen, Irit Sagi, Avigdor Scherz, Ruth Scherz-Shouval, Yosef Yarden, Moshe Oren, Mikala Egeblad, Jason S. Lewis, Kayvan Keshari, Paul M. Grandgenett, Michael A. Hollingsworth, Vinagolu K. Rajasekhar, John H. Healey, Bergthor Björnsson, Diane M. Simeone, David A. Tuveson, Christine A. Iacobuzio-Donahue, Jaqueline Bromberg, C. Theresa Vincent, Eileen M. O’Reilly, Ronald P. DeMatteo, Vinod P. Balachandran, Michael I. D’Angelica, T. Peter Kingham, Peter J. Allen, Amber L. Simpson, Olivier Elemento, Per Sandström, Robert E. Schwartz, William R. Jarnagin, David Lyden^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2170-2180
Number of pages	29
Journal	Nature Medicine
Volume	30
Issue number	8
DOIs	https://doi.org/10.1038/s41591-024-03075-7
Publication status	Published Online - 28 Jun 2024

Bibliographical note

We thank the patients who participated in our study. We thank the research staff of the MSKCC HPB Service and the Rubenstein Center for Pancreatic Cancer Research; the MSKCC Integrated Genomics Core, the Flow Cytometry Core, the Microscopy and Molecular Cytology Core and the Institutional Core Grant (CCSG P30 CA008748-53); the Hospital for Special Surgery Flow Cytometry Core; the BIDMC Mass Spectrometry Facility, Harvard Medical School; the Epigenomics Core of Weill Cornell Medicine; the WCM Metabolomics Core Facility; and the Linkoeping University Core Facility and Region Ostergoetland, Departments of Surgery and Pathology. The authors gratefully acknowledge support from National Cancer Institute CA224175 (D.L.), CA210240 (D.L.), CA232093 (D.L.), CA163117 and CA207983 (D.L.), CA163120 (D.L.), CA169416 (D.L.), CA169538 (D.L.), CA218513 (D.L. and H.Z.) and AI144301 (D.L.); US Department of Defense W81XWH-13-1-0425 (D.L.), W81XWH-13-1-0427, W81XWH-13-1-0249 (D.L.) and W81XWH-14-1-0199 (D.L.); National Institutes of Health/WCM CTSC (NIH/NCATS (UL1TR00457) (H.Z.); and NIH/NCATS (UL1TR002384) (D.L. and H.Z.)). They also gratefully acknowledge support from the Hartwell Foundation (D.L.); the Thompson Family Foundation (D.L. and D.K); STARR Consortium I9-A9-056 (D.L. and H.Z.) and I8-A8-123 (D.L.); the Pediatric Oncology Experimental Therapeutics Investigator's Consortium (D.L.); Alex's Lemonade Stand Foundation (D.L.); the Breast Cancer Research Foundation (D.L.); the Feldstein Medical Foundation (D.L.); the Tortolani Foundation (D.L.); the Clinical & Translational Science Center (D.L. and H.Z.); the Mary Kay Ash Charitable Foundation (D.L. and I.M.); the Malcolm Hewitt Weiner Foundation; the Manning Foundation (D.L. and A.H.); the Daniel P. and Nancy C. Paduano Family Foundation; the James Paduano Foundation; the Sohn Foundation; the AHEPA Vth District Cancer Research Foundation; the Daedalus Fund Selma and Lawrence Ruben Science to Industry Bridge Award; Atossa Therapeutics; the Children's Cancer and Blood Foundation (all to D.L.); a Swedish Cancer Society project grant (21 1824 Pj 01 H); a Swedish Research Society Starting Grant (2021-02356); the Swedish Society for Medical Research (grant no. S21-0079) (L.B); the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of Memorial Sloan Kettering Cancer Center (C.P.Z.); the Conquer Cancer Foundation of the American Society of Clinical Oncology (J.M.H.); the National Institutes of Health (R01CA234614 and R01DK121072 to R.E.S.); the US Department of Defense (W81XWH-21-1-0978 to R.E.S.); and Paul G. Allen Family Foundation UWSC13448 (to R.E.S.).

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1038/s41591-024-03075-7

Cite this

Bojmar, L., Zambirinis, C. P., Hernandez, J. M., Chakraborty, J., Shaashua, L., Kim, J., Johnson, K. E., Hanna, S., Askan, G., Burman, J., Ravichandran, H., Zheng, J., Jolissaint, J. S., Srouji, R., Song, Y., Choubey, A., Kim, H. S., Cioffi, M., van Beek, E., ... Lyden, D. (2024). Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer. Nature Medicine, 30(8), 2170-2180. Advance online publication. https://doi.org/10.1038/s41591-024-03075-7

@article{d57184bffc084a9f9961101c7724360c,

title = "Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer",

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.",

author = "Linda Bojmar and Zambirinis, {Constantinos P.} and Hernandez, {Jonathan M.} and Jayasree Chakraborty and Lee Shaashua and Junbum Kim and Johnson, {Kofi Ennu} and Samer Hanna and Gokce Askan and Jonas Burman and Hiranmayi Ravichandran and Jian Zheng and Jolissaint, {Joshua S.} and Rami Srouji and Yi Song and Ankur Choubey and Kim, {Han Sang} and Michele Cioffi and {van Beek}, Elke and Carlie Sigel and Jose Jessurun and {Velasco Riestra}, Paulina and Hakon Blomstrand and Carolin J{\"o}nsson and Anette J{\"o}nsson and Pernille Lauritzen and Weston Buehring and Yonathan Ararso and Dylanne Hernandez and Vinagolu-Baur, {Jessica P.} and Madison Friedman and Caroline Glidden and Laetitia Firmenich and Grace Lieberman and Mejia, {Dianna L.} and Naaz Nasar and Mutvei, {Anders P.} and Paul, {Doru M.} and Yaron Bram and Bruno Costa-Silva and Olca Basturk and Nancy Boudreau and Haiying Zhang and Matei, {Irina R.} and Ayuko Hoshino and David Kelsen and Irit Sagi and Avigdor Scherz and Ruth Scherz-Shouval and Yosef Yarden and Moshe Oren and Mikala Egeblad and Lewis, {Jason S.} and Kayvan Keshari and Grandgenett, {Paul M.} and Hollingsworth, {Michael A.} and Rajasekhar, {Vinagolu K.} and Healey, {John H.} and Bergthor Bj{\"o}rnsson and Simeone, {Diane M.} and Tuveson, {David A.} and Iacobuzio-Donahue, {Christine A.} and Jaqueline Bromberg and Vincent, {C. Theresa} and O{\textquoteright}Reilly, {Eileen M.} and DeMatteo, {Ronald P.} and Balachandran, {Vinod P.} and D{\textquoteright}Angelica, {Michael I.} and Kingham, {T. Peter} and Allen, {Peter J.} and Simpson, {Amber L.} and Olivier Elemento and Per Sandstr{\"o}m and Schwartz, {Robert E.} and Jarnagin, {William R.} and David Lyden",

note = "We thank the patients who participated in our study. We thank the research staff of the MSKCC HPB Service and the Rubenstein Center for Pancreatic Cancer Research; the MSKCC Integrated Genomics Core, the Flow Cytometry Core, the Microscopy and Molecular Cytology Core and the Institutional Core Grant (CCSG P30 CA008748-53); the Hospital for Special Surgery Flow Cytometry Core; the BIDMC Mass Spectrometry Facility, Harvard Medical School; the Epigenomics Core of Weill Cornell Medicine; the WCM Metabolomics Core Facility; and the Linkoeping University Core Facility and Region Ostergoetland, Departments of Surgery and Pathology. The authors gratefully acknowledge support from National Cancer Institute CA224175 (D.L.), CA210240 (D.L.), CA232093 (D.L.), CA163117 and CA207983 (D.L.), CA163120 (D.L.), CA169416 (D.L.), CA169538 (D.L.), CA218513 (D.L. and H.Z.) and AI144301 (D.L.); US Department of Defense W81XWH-13-1-0425 (D.L.), W81XWH-13-1-0427, W81XWH-13-1-0249 (D.L.) and W81XWH-14-1-0199 (D.L.); National Institutes of Health/WCM CTSC (NIH/NCATS (UL1TR00457) (H.Z.); and NIH/NCATS (UL1TR002384) (D.L. and H.Z.)). They also gratefully acknowledge support from the Hartwell Foundation (D.L.); the Thompson Family Foundation (D.L. and D.K); STARR Consortium I9-A9-056 (D.L. and H.Z.) and I8-A8-123 (D.L.); the Pediatric Oncology Experimental Therapeutics Investigator's Consortium (D.L.); Alex's Lemonade Stand Foundation (D.L.); the Breast Cancer Research Foundation (D.L.); the Feldstein Medical Foundation (D.L.); the Tortolani Foundation (D.L.); the Clinical & Translational Science Center (D.L. and H.Z.); the Mary Kay Ash Charitable Foundation (D.L. and I.M.); the Malcolm Hewitt Weiner Foundation; the Manning Foundation (D.L. and A.H.); the Daniel P. and Nancy C. Paduano Family Foundation; the James Paduano Foundation; the Sohn Foundation; the AHEPA Vth District Cancer Research Foundation; the Daedalus Fund Selma and Lawrence Ruben Science to Industry Bridge Award; Atossa Therapeutics; the Children's Cancer and Blood Foundation (all to D.L.); a Swedish Cancer Society project grant (21 1824 Pj 01 H); a Swedish Research Society Starting Grant (2021-02356); the Swedish Society for Medical Research (grant no. S21-0079) (L.B); the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of Memorial Sloan Kettering Cancer Center (C.P.Z.); the Conquer Cancer Foundation of the American Society of Clinical Oncology (J.M.H.); the National Institutes of Health (R01CA234614 and R01DK121072 to R.E.S.); the US Department of Defense (W81XWH-21-1-0978 to R.E.S.); and Paul G. Allen Family Foundation UWSC13448 (to R.E.S.). Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = jun,

day = "28",

doi = "10.1038/s41591-024-03075-7",

language = "English",

volume = "30",

pages = "2170--2180",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "8",

}

Bojmar, L, Zambirinis, CP, Hernandez, JM, Chakraborty, J, Shaashua, L, Kim, J, Johnson, KE, Hanna, S, Askan, G, Burman, J, Ravichandran, H, Zheng, J, Jolissaint, JS, Srouji, R, Song, Y, Choubey, A, Kim, HS, Cioffi, M, van Beek, E, Sigel, C, Jessurun, J, Velasco Riestra, P, 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, Vincent, CT, O’Reilly, EM, DeMatteo, RP, Balachandran, VP, D’Angelica, MI, Kingham, TP, Allen, PJ, Simpson, AL, Elemento, O, Sandström, P, Schwartz, RE, Jarnagin, WR & Lyden, D 2024, 'Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer', Nature Medicine, vol. 30, no. 8, pp. 2170-2180. https://doi.org/10.1038/s41591-024-03075-7

TY - JOUR

T1 - Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer

AU - Bojmar, Linda

AU - Zambirinis, Constantinos P.

AU - Hernandez, Jonathan M.

AU - Chakraborty, Jayasree

AU - Shaashua, Lee

AU - Kim, Junbum

AU - Johnson, Kofi Ennu

AU - Hanna, Samer

AU - Askan, Gokce

AU - Burman, Jonas

AU - Ravichandran, Hiranmayi

AU - Zheng, Jian

AU - Jolissaint, Joshua S.

AU - Srouji, Rami

AU - Song, Yi

AU - Choubey, Ankur

AU - Kim, Han Sang

AU - Cioffi, Michele

AU - van Beek, Elke

AU - Sigel, Carlie

AU - Jessurun, Jose

AU - Velasco Riestra, Paulina

AU - Blomstrand, Hakon

AU - Jönsson, Carolin

AU - Jönsson, Anette

AU - Lauritzen, Pernille

AU - Buehring, Weston

AU - Ararso, Yonathan

AU - Hernandez, Dylanne

AU - Vinagolu-Baur, Jessica P.

AU - Friedman, Madison

AU - Glidden, Caroline

AU - Firmenich, Laetitia

AU - Lieberman, Grace

AU - Mejia, Dianna L.

AU - Nasar, Naaz

AU - Mutvei, Anders P.

AU - Paul, Doru M.

AU - Bram, Yaron

AU - Costa-Silva, Bruno

AU - Basturk, Olca

AU - Boudreau, Nancy

AU - Zhang, Haiying

AU - Matei, Irina R.

AU - Hoshino, Ayuko

AU - Kelsen, David

AU - Sagi, Irit

AU - Scherz, Avigdor

AU - Scherz-Shouval, Ruth

AU - Yarden, Yosef

AU - Oren, Moshe

AU - Egeblad, Mikala

AU - Lewis, Jason S.

AU - Keshari, Kayvan

AU - Grandgenett, Paul M.

AU - Hollingsworth, Michael A.

AU - Rajasekhar, Vinagolu K.

AU - Healey, John H.

AU - Björnsson, Bergthor

AU - Simeone, Diane M.

AU - Tuveson, David A.

AU - Iacobuzio-Donahue, Christine A.

AU - Bromberg, Jaqueline

AU - Vincent, C. Theresa

AU - O’Reilly, Eileen M.

AU - DeMatteo, Ronald P.

AU - Balachandran, Vinod P.

AU - D’Angelica, Michael I.

AU - Kingham, T. Peter

AU - Allen, Peter J.

AU - Simpson, Amber L.

AU - Elemento, Olivier

AU - Sandström, Per

AU - Schwartz, Robert E.

AU - Jarnagin, William R.

AU - Lyden, David

N1 - We thank the patients who participated in our study. We thank the research staff of the MSKCC HPB Service and the Rubenstein Center for Pancreatic Cancer Research; the MSKCC Integrated Genomics Core, the Flow Cytometry Core, the Microscopy and Molecular Cytology Core and the Institutional Core Grant (CCSG P30 CA008748-53); the Hospital for Special Surgery Flow Cytometry Core; the BIDMC Mass Spectrometry Facility, Harvard Medical School; the Epigenomics Core of Weill Cornell Medicine; the WCM Metabolomics Core Facility; and the Linkoeping University Core Facility and Region Ostergoetland, Departments of Surgery and Pathology. The authors gratefully acknowledge support from National Cancer Institute CA224175 (D.L.), CA210240 (D.L.), CA232093 (D.L.), CA163117 and CA207983 (D.L.), CA163120 (D.L.), CA169416 (D.L.), CA169538 (D.L.), CA218513 (D.L. and H.Z.) and AI144301 (D.L.); US Department of Defense W81XWH-13-1-0425 (D.L.), W81XWH-13-1-0427, W81XWH-13-1-0249 (D.L.) and W81XWH-14-1-0199 (D.L.); National Institutes of Health/WCM CTSC (NIH/NCATS (UL1TR00457) (H.Z.); and NIH/NCATS (UL1TR002384) (D.L. and H.Z.)). They also gratefully acknowledge support from the Hartwell Foundation (D.L.); the Thompson Family Foundation (D.L. and D.K); STARR Consortium I9-A9-056 (D.L. and H.Z.) and I8-A8-123 (D.L.); the Pediatric Oncology Experimental Therapeutics Investigator's Consortium (D.L.); Alex's Lemonade Stand Foundation (D.L.); the Breast Cancer Research Foundation (D.L.); the Feldstein Medical Foundation (D.L.); the Tortolani Foundation (D.L.); the Clinical & Translational Science Center (D.L. and H.Z.); the Mary Kay Ash Charitable Foundation (D.L. and I.M.); the Malcolm Hewitt Weiner Foundation; the Manning Foundation (D.L. and A.H.); the Daniel P. and Nancy C. Paduano Family Foundation; the James Paduano Foundation; the Sohn Foundation; the AHEPA Vth District Cancer Research Foundation; the Daedalus Fund Selma and Lawrence Ruben Science to Industry Bridge Award; Atossa Therapeutics; the Children's Cancer and Blood Foundation (all to D.L.); a Swedish Cancer Society project grant (21 1824 Pj 01 H); a Swedish Research Society Starting Grant (2021-02356); the Swedish Society for Medical Research (grant no. S21-0079) (L.B); the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of Memorial Sloan Kettering Cancer Center (C.P.Z.); the Conquer Cancer Foundation of the American Society of Clinical Oncology (J.M.H.); the National Institutes of Health (R01CA234614 and R01DK121072 to R.E.S.); the US Department of Defense (W81XWH-21-1-0978 to R.E.S.); and Paul G. Allen Family Foundation UWSC13448 (to R.E.S.). Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

PY - 2024/6/28

Y1 - 2024/6/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85197913692&partnerID=8YFLogxK

U2 - 10.1038/s41591-024-03075-7

DO - 10.1038/s41591-024-03075-7

M3 - Article

AN - SCOPUS:85197913692

SN - 1078-8956

VL - 30

SP - 2170

EP - 2180

JO - Nature Medicine

JF - Nature Medicine

IS - 8

ER -

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

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