Stromal rigidity stress accelerates pancreatic intraepithelial neoplasia progression and chromosomal instability via nuclear PTK2 localization

Am J Pathol. 2024 Apr 15:S0002-9440(24)00132-9. doi: 10.1016/j.ajpath.2024.02.023. Online ahead of print.ABSTRACTSince the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and γH2AX foci links to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3μm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell datasets revealed that the ECM shapes an alternate route of acinar-ductal transdifferentiation of acinar cells into a central hub of elegantly restrained TOP2A-overexpressing cancer cells that spread out as unique cancer clusters with copy number amplifications in MYC-PTK2 locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in TCGA-PAAD patients. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased VAV1 expression, and prolonged overall survival in the KPC mice. Decreases of αSMA deposition in the CD248 knockout KPC mice remodel the tissue stroma and downregulated TOP2A expression in the epithelium. In summary, stromal stiffness...
Source: The American Journal of Pathology - Category: Pathology Authors: Source Type: research