An injury-associated lobular microniche is associated with the classical tumor cell phenotype in pancreatic cancer
Pancreatic cancer is an aggressive disease with a dense fibrotic stroma and is often accompanied by chronic inflammation. Peritumoral inflammation is typically viewed as a reaction to nearby tumor growth. Here, we report that the inflamed pancreatic lobules are frequently invaded by tumor cells, forming a distinct, non-fibrotic tumor niche. Using a semi-supervised machine learning approach for annotations of clinical samples and multiplex protein profiling, we show that tumor cells at the invasion front are closely associated with acinar cells undergoing damage-induced changes, and with activated fibroblasts expressing markers of injury. The invaded lobules are linked to classical tumor phenotypes, in contrast to fibrotic areas where tumor cells display a more basal profile, highlighting microenvironment-dependent tumor subtype differences. In female mice, lobular invasion similarly aligns with the classical tumor phenotype. Together, our data reveal that pancreatic tumors colonize injured lobules, creating a unique niche that shapes tumor characteristics and contributes to disease biology.
Authors
- Staffan Strömblad (ORCID: https://orcid.org/0000-0002-1236-6339)
- Bernhard Schmierer (ORCID: https://orcid.org/0000-0002-9082-7022)
- Olga Khorosjutina (ORCID: https://orcid.org/0009-0001-0786-0260)
- Yousra Hamidi
- Miao Zhao (ORCID: https://orcid.org/0000-0002-4895-1177)
- Carlos Fernández Moro (ORCID: https://orcid.org/0000-0001-6863-5959)
- Anna‐Lena Keller (ORCID: https://orcid.org/0000-0001-8100-8175)
- Poya Ghorbani (ORCID: https://orcid.org/0000-0003-2102-7168)
- Ernesto Sparrelid (ORCID: https://orcid.org/0000-0003-0259-8328)
- Natalie Geyer (ORCID: https://orcid.org/0000-0003-1026-968X)
- Kseniya Ruksha
- Jennie Engstrand (ORCID: https://orcid.org/0000-0003-1123-7022)
- Béla Bozóky
- Neda Hekmati (ORCID: https://orcid.org/0009-0009-4814-869X)
- Marco Gerling (ORCID: https://orcid.org/0000-0002-1810-0662)
- Carina Strell (ORCID: https://orcid.org/0000-0002-3783-7256)
- Stefina Milanova (ORCID: https://orcid.org/0000-0001-9865-857X)
- Sara Harrizi
- Andrei Niculae (ORCID: https://orcid.org/0000-0003-2866-8806)
- Annika Viljamaa (ORCID: https://orcid.org/0009-0002-8511-8181)
- Argyro Zacharouli
- Caroline Salmén
- Tânia Costa (ORCID: https://orcid.org/0000-0002-6296-5225)
- Sara Söderqvist (ORCID: https://orcid.org/0009-0003-2133-6400)
Institutions
- Uppsala University (SE)
- Karolinska University Hospital (SE)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Integrated Cardio Metabolic Centre (SE)
- University of Bergen (NO)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41467-025-63864-7
- Citations
- 3
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.14