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HAPLN1 potentiates peritoneal metastasis in pancreatic cancer

Author

Listed:
  • Lena Wiedmann

    (German Cancer Research Center (DKFZ)
    University of Heidelberg)

  • Francesca De Angelis Rigotti

    (German Cancer Research Center (DKFZ)
    Centro de Investigación Príncipe Felipe)

  • Nuria Vaquero-Siguero

    (German Cancer Research Center (DKFZ))

  • Elisa Donato

    (German Cancer Research Center (DKFZ)
    HI-STEM - Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH)

  • Elisa Espinet

    (German Cancer Research Center (DKFZ)
    HI-STEM - Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH
    University of Barcelona (UB), L’Hospitalet de Llobregat
    L’Hospitalet de Llobregat)

  • Iris Moll

    (German Cancer Research Center (DKFZ))

  • Elisenda Alsina-Sanchis

    (German Cancer Research Center (DKFZ)
    University Medical Center Göttingen)

  • Hanibal Bohnenberger

    (University Medical Center Göttingen, Georg-August-University)

  • Elena Fernandez-Florido

    (German Cancer Research Center (DKFZ))

  • Ronja Mülfarth

    (German Cancer Research Center (DKFZ)
    University of Heidelberg)

  • Margherita Vacca

    (German Cancer Research Center (DKFZ))

  • Jennifer Gerwing

    (German Cancer Research Center (DKFZ))

  • Lena-Christin Conradi

    (University Medical Center Göttingen)

  • Philipp Ströbel

    (University Medical Center Göttingen, Georg-August-University)

  • Andreas Trumpp

    (German Cancer Research Center (DKFZ)
    HI-STEM - Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH)

  • Carolin Mogler

    (Technical University of Munich)

  • Andreas Fischer

    (German Cancer Research Center (DKFZ)
    University Medical Center Göttingen
    German Center for Cardiovascular Research (DZHK))

  • Juan Rodriguez-Vita

    (German Cancer Research Center (DKFZ)
    Centro de Investigación Príncipe Felipe)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here, we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favors a more permissive microenvironment, which accelerates the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promotes TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modifies cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identify HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.

Suggested Citation

  • Lena Wiedmann & Francesca De Angelis Rigotti & Nuria Vaquero-Siguero & Elisa Donato & Elisa Espinet & Iris Moll & Elisenda Alsina-Sanchis & Hanibal Bohnenberger & Elena Fernandez-Florido & Ronja Mülfa, 2023. "HAPLN1 potentiates peritoneal metastasis in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38064-w
    DOI: 10.1038/s41467-023-38064-w
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    References listed on IDEAS

    as
    1. Irene Ischenko & Stephen D’Amico & Manisha Rao & Jinyu Li & Michael J. Hayman & Scott Powers & Oleksi Petrenko & Nancy C. Reich, 2021. "KRAS drives immune evasion in a genetic model of pancreatic cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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