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

Söderqvist S, Viljamaa A, Geyer N, Keller AL, Ruksha K, Strell C, Hekmati N, Niculae A, Engstrand J, Sparrelid E, Salmén C, Costa TDF, Zhao M, Strömblad S, Zacharouli A, Ghorbani P, Harrizi S, Hamidi Y, Khorosjutina O, Milanova S, Schmierer B, Bozóky B, Fernández Moro C, Gerling M

Nat Commun 16 (1) 8307 [2025-09-26; online 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.

CRISPR Functional Genomics [Service]

PubMed 41006303

DOI 10.1038/s41467-025-63864-7

Crossref 10.1038/s41467-025-63864-7

pmc: PMC12475445
pii: 10.1038/s41467-025-63864-7