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
- Marco Gerling
2025-09-26
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.