An injury-associated lobular microniche is associated with the classical tumor cell phenotype in pancreatic cancer

Sara Söderqvist, Annika Viljamaa, Natalie Geyer, Anna-Lena Keller, Kseniya Ruksha, Carina Strell, Neda Hekmati, Alexandra Niculae, Jennie Engstrand, Ernesto Sparrelid, Caroline Salmén, Tânia D. F. Costa, Miao Zhao, Staffan Strömblad, Argyro Zacharouli, Poya Ghorbani, Sara Harrizi, Yousra Hamidi, Olga Khorosjutina, Stefina Milanova, Bernhard Schmierer, Béla Bozóky, Carlos Fernández Moro and Marco Gerling ()
Additional contact information
Sara Söderqvist: Karolinska Institutet
Annika Viljamaa: Karolinska Institutet
Natalie Geyer: Karolinska Institutet
Anna-Lena Keller: Karolinska Institutet
Kseniya Ruksha: Karolinska Institutet
Carina Strell: University of Bergen
Neda Hekmati: Uppsala University
Alexandra Niculae: Karolinska Institutet
Jennie Engstrand: Karolinska Institutet
Ernesto Sparrelid: Karolinska Institutet
Caroline Salmén: Karolinska Institutet
Tânia D. F. Costa: Karolinska Institutet
Miao Zhao: Uppsala University
Staffan Strömblad: Karolinska Institutet
Argyro Zacharouli: Karolinska University Hospital
Poya Ghorbani: Karolinska Institutet
Sara Harrizi: Karolinska Institutet
Yousra Hamidi: Karolinska Institutet
Olga Khorosjutina: Karolinska Institutet
Stefina Milanova: Karolinska Institutet
Bernhard Schmierer: Karolinska Institutet
Béla Bozóky: Karolinska University Hospital
Carlos Fernández Moro: Karolinska Institutet
Marco Gerling: Karolinska Institutet

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63864-7

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