3D histology reveals that immune response to pancreatic precancers is heterogeneous and depends on global pancreas structure

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 6, 2024

SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, part due to its unique stromal and immune microenvironment. intraepithelial neoplasia, or PanIN, the main precursor lesion PDAC. Recently it was discovered that PanINs remarkably abundant grossly normal pancreas, suggesting vast majority will never progress cancer. Here, through construction of 48 samples cm 3 -sized human pancreas tissue, we profiled microenvironment 1,476 3D at single-cell resolution better understand early evolution tumor determine how inflammation may play role progression. We found bulk strongly correlates PanIN cell fraction. response around heterogeneous, with distinct hotspots cold spots appear disappear span tens microns. Immune generally mark locations higher grade dysplasia near acinar atrophy. The composition these dominated by naïve, cytotoxic, regulatory T cells, associated fibroblasts, macrophages, little similarity less-inflamed PanINs. By mapping FOXP3+ cells 3D, present density larger lesions compared smaller PanINs, initiation not exhibit an immunosuppressive response. This analysis demonstrates while common pancreases most individuals, pivotal role, both microscopic scale, demarcating regions significance

Language: Английский

Self organisation of invasive breast cancer driven by the interplay of active and passive nematic dynamics

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

Abstract In invasive breast cancer, cell clusters of varying sizes and shapes are embedded in the fibrous extracellular matrix (ECM). Although prevailing view attributes this structure to increasing disorder resulting from loss function dedifferentiation, our findings reveal that it arises through a process active self-organization driven by cancer motility. Simulations histological analyses tumours over 2,000 patients motile, aligned cells within move as nematic aggregates surrounding highly ECM fibres, which form confining, passive phase. Cellular motion leads cluster splitting coalescence. The degree activity, combined with heterogeneity motility, is reflected specific scaling behaviours for shape, size distribution, distance between boundaries defects alignment. Increased activity estimates correlate tumour progression associated poorer prognosis patients.

Language: Английский