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Frädrich, J.* ; Reyes, C.M.* ; Hendel, M.* ; Brunner, V.* ; Toledo, B.* ; Manevski, D.* ; Sommer, A.* ; Häußler, D.* ; Beck, D.* ; Lucarelli, D. ; Martínez de Villareal, J.* ; Halle, L. ; Kfuri-Rubens, R. ; Çifcibaşı, K.* ; Hirschberger, A.* ; Öllinger, R.* ; Knolle, P.A.* ; Steiger, K.* ; Rad, R.* ; Theis, F.J. ; Real, F.X.* ; Bärthel, S.* ; Böttcher, J.P.* ; Saur, D.* ; Demir, I.E.* ; Krüger, A.*

Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers.

Cell Rep. Med. 7:102546 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The immunosuppressive tumor microenvironment (TME) fosters cancer progression, yet overarching determinants of cancer-borne immunoinstruction remain ill-defined. By multimodal integration of single-nucleus and bulk transcriptomics, proteomics, functional approaches, and clinical parameters, we discover a cancer-immunoinstructive secretory signature (CISS) across multiple human cancers-a set of inflammatory proteins correlated with poor prognosis and pro-tumorigenic TMEs. In pancreatic cancer (PC), CISS arises in pre-malignant epithelium, intensifies along transformation toward most malignant basal-like PC, and particularly correlates with suppressed natural killer (NK) cell activity. The CISS is quantitatively dominated by tissue inhibitor of metalloproteinases (TIMP)-1, most prevalent in TIMP-1hi/CISShi basal-like PC, and causal for PC-cell-mediated NK cell suppression, reflected by impaired cytotoxicity, interleukin-2 (IL-2) responses, and mammalian target of rapamycin (mTOR) signaling. In pre-clinical PC, TIMP-1/CISS proves targetable through combined inhibition of upstream kinases with clinically approved drugs trametinib and nintedanib. Collectively, CISS represents a ubiquitous signature of pro-tumor immunoinstruction with actionable diagnostic and therapeutic potential across human cancers.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Timp-1 ; Cancer Heterogeneity ; Cancer Immunosuppression ; Epithelial Heterogeneity ; Natural Killer Cells ; Pan-cancer ; Pancreatic Cancer; Set Enrichment Analysis; Ductal Adenocarcinoma; Tissue Inhibitor; Subtypes; Microenvironment; Immunotherapy; Activation; Cells
ISSN (print) / ISBN 2666-3791
e-ISSN 2666-3791
Zeitschrift Cell Reports Medicine
Quellenangaben Band: 7, Heft: 1, Seiten: , Artikelnummer: 102546 Supplement: ,
Verlag Elsevier
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
Förderungen Klaus Tschira Foundation
German Scholars Organization
Klaus Tschira Boost Fund
Else Kroner Clinician Scientist Professorship for Translational Pancreatic Surgery
Deutsche Forschungsgemeinschaft, Bonn, Germany