Plate IV.55 · Publications
Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers
Article in Cell Reports Medicine, January 2026.
Abstract
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.
Cite
@article{fradrich2026multimodal,
title = {{Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers}},
author = {Frädrich, Julian and Reyes, Carmen Mota and Hendel, Michel and Brunner, Vanessa and Toledo, Batu and Manevski, Damjan and Sommer, Alexander and Häußler, Daniel and Beck, Dominik and Lucarelli, Daniele and Martínez de Villareal, Jaime and Halle, Lennard and Kfuri-Rubens, Raphael and Çifcibaşı, Kaan and Hirschberger, Anna and Öllinger, Rupert and Knolle, Percy A. and Steiger, Katja and Rad, Roland and Theis, Fabian J. and Real, Francisco X. and Bärthel, Stefanie and Böttcher, Jan P. and Saur, Dieter and Demir, Ihsan Ekin and Krüger, Achim},
journal = {Cell Reports Medicine},
publisher = {Elsevier BV},
year = {2026},
month = jan,
doi = {10.1016/j.xcrm.2025.102546},
url = {https://doi.org/10.1016/j.xcrm.2025.102546},
pmid = {41564862},
pmcid = {PMC12866174}
}