Stromal Rigidity Stress Accelerates Pancreatic Intraepithelial Neoplasia Progression and Chromosomal Instability via Nuclear Protein Tyrosine Kinase 2 Localization

Li-Yun Ding; Chia-Jung Chang; Szu-Ying Chen; Kuan-Lin Chen; Yueh-Shan Li; Yun-Chieh Wu; Ting-Yi Hsu; Hsin-Yu Ying; Hsin-Yi Wu; Michael W Hughes; Chia-Yih Wang; Chih-Han Chang; Ming-Jer Tang; Woei-Jer Chuang; Yan-Shen Shan; Chia-Jung Chang; Po-Hsien Huang

doi:10.1016/j.ajpath.2024.02.023

Stromal Rigidity Stress Accelerates Pancreatic Intraepithelial Neoplasia Progression and Chromosomal Instability via Nuclear Protein Tyrosine Kinase 2 Localization

Am J Pathol. 2024 Apr 15:S0002-9440(24)00132-9. doi: 10.1016/j.ajpath.2024.02.023. Online ahead of print.

Authors

Li-Yun Ding¹, Chia-Jung Chang², Szu-Ying Chen¹, Kuan-Lin Chen³, Yueh-Shan Li³, Yun-Chieh Wu³, Ting-Yi Hsu³, Hsin-Yu Ying³, Hsin-Yi Wu⁴, Michael W Hughes⁵, Chia-Yih Wang⁶, Chih-Han Chang⁷, Ming-Jer Tang⁸, Woei-Jer Chuang⁹, Yan-Shen Shan¹⁰, Chia-Jung Chang¹¹, Po-Hsien Huang¹²

Affiliations

¹ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
³ Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Instrumentation Center, College of Science, National Taiwan University, Taipei, Taiwan.
⁵ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.
⁶ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁷ Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan; Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan.
⁸ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Department Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁹ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
¹⁰ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
¹¹ Department of Internal Medicine, Ditmanson Medical Foundation, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
¹² Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: phhuang@mail.ncku.edu.tw.

PMID: 38631549
DOI: 10.1016/j.ajpath.2024.02.023

Abstract

Because 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 Kras^LSL-G12D/+;Trp53^flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-μm micropores. To search for pancreatic cancer cell of origin, analysis of single-cell data sets revealed that the extracellular matrix shapes an alternate route of acinar-ductal transdifferentiation of acinar cells into a central hub of elegantly restrained topoisomerase II α (TOP2A)-overexpressing cancer cells that spread out as unique cancer clusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in patients with The Cancer Genome Atlas-PAAD. 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 α-smooth muscle actin deposition in the CD248 knockout KPC mice remodel the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induces the onset of cells of origin of cancer by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment against cells-of-origin cancer.