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

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 KrasLSL-G12D/+;Trp53flox/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.

Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer.

BACKGROUND: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). RESULTS: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. CONCLUSION: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

Comparable progression of spinocerebellar ataxias between Caucasians and Chinese.

INTRODUCTION: The aim of this study is to reappraise the progression of the five most common spinocerebellar ataxias (SCAs) in the Chinese population and to establish a much-needed critical comparison with that in other ethnic groups. There are very few longitudinal cohort studies of SCAs in Asian populations. An intriguing finding in an earlier study demonstrated a faster progression of SCA among Chinese than that among Caucasians. METHODS: Patients with SCA1, SCA2, SCA3, SCA6 or SCA17 were consecutively assessed using the scale for the assessment and rating of ataxia (SARA) for five years. A linear mixed model was used to compare the annual progression rates measured using the SARA among patients with different SCA subtypes. Predictors of the progression rates were analyzed. RESULTS: A total of 199 patients with SCA (10 with SCA1, 37 with SCA2, 118 with SCA3, 25 with SCA6 and 9 with SCA17) were enrolled. The mean annual increase in SARA scores was 1.23 points for SCA1, 1.52 points for SCA2, 1.60 points for SCA3, 0.99 points for SCA6 and 3.26 points for SCA17. A larger CAG repeat length (≥74) was associated with faster progression in SCA3, whereas a lower total SARA score at the first visit (<12) was associated with faster clinical progression in SCA6. CONCLUSION: The results of this study confirm that the annual progression rates of SCA2 and SCA3 are comparable between Han Chinese and other ethnic populations. More studies are warranted to confirm the rapid progression of SCA17 observed in our cohort.

Correction: Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias.

[This corrects the article DOI: 10.1371/journal.pone.0187503.].

Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias.

BACKGROUND: The inositol 1,4,5-triphosphate (IP3) receptor type 1 gene (ITPR1) encodes the IP3 receptor type 1 (IP3R1), which modulates intracellular calcium homeostasis and signaling. Mutations in ITPR1 have been implicated in inherited cerebellar ataxias. The aim of this study was to investigate the role of ITPR1 mutations, including both large segmental deletion and single nucleotide mutations, in a Han Chinese cohort with inherited cerebellar ataxias in Taiwan. METHODOLOGY AND PRINCIPAL FINDINGS: Ninety-three unrelated individuals with molecularly unassigned spinocerebellar ataxia selected from 585 pedigrees with autosomal dominant cerebellar ataxias, were recruited into the study with elaborate clinical evaluations. The quantitative PCR technique was used to survey large segmental deletion of ITPR1 and a targeted sequencing approach was applied to sequence all of the 61 exons and the flanking regions of ITPR1. A novel ITPR1 mutation, c.7721T>C (p.V2574A), was identified in a family with dominantly inherited cerebellar ataxia. The proband has an adult-onset non-progressive pure cerebellar ataxia and her daughter is afflicted with a childhood onset cerebellar ataxia with intellectual sub-normalities. CONCLUSION: ITPR1 mutation is an uncommon cause of inherited cerebellar ataxia, accounting for 0.2% (1/585) of patients with dominantly inherited cerebellar ataxias in Taiwan. This study broadens the mutational spectrum of ITPR1 and also emphasizes the importance of considering ITPR1 mutations as a potential cause of inherited cerebellar ataxias.