Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state
Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada
Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada
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Research Article Endocrinology Gastroenterology

Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state

Abstract

Pancreatic stellate cells (PSCs) are the origin of cancer-associated fibroblasts. Type 2 diabetes mellitus (T2D) may promote pancreatic ductal adenocarcinoma (PDAC), eliciting changes in the quiescent PSC (qPSC) population from the precancerous stage. However, the details are unknown. We evaluated the subpopulations of qPSCs and the impact of T2D. PSCs isolated from 8-week-old C57BL/6J mice and diabetic db/db mice were analyzed by single-cell RNA-seq. Sorted qPSCs and PDAC cells were transplanted into allogenic mice. The isolated qPSCs were broadly classified into mesothelial cell and pancreatic fibroblast (Paf) populations by single-cell RNA-seq. Pafs were subclassified into inflammatory Pafs, myofibroblastic Pafs (myPafs) and a small population named tumor immunity- and angiogenesis-promoting Pafs (tapPafs), expressing Cxcl13. In the subcutaneous transplantation model, the tumors transplanted with myPafs were significantly larger than the tumors transplanted with tapPafs. An increase in myPafs and a decrease in tapPafs were observed from the precancerous stage in human T2D, indicating the effects of tumor progression. This study revealed the subpopulation changes in qPSCs in T2D. A therapy that increases the number of tapPafs could be a therapeutic option for patients with PDAC and T2D and even those in a precancerous stage of T2D.

Authors

Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada

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Figure 7

PSC activation score and CXCL13 expression around PanIN lesions in human PDAC samples.

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PSC activation score and CXCL13 expression around PanIN lesions in human...
(A) Representative images of IHC and in situ hybridization illustrating the expression of α-SMA, CXCL13, CD8, and CD20 surrounding PanIN lesions (original magnification, ×20 and ×40 (inset)). (B) PSC activation was evaluated by the PSCa score in individuals who did not have T2D (n = 24) and who did have T2D (n = 21). (C) The presence of CXCL13-positive stromal cells surrounding PanIN lesions evaluated in sections via in situ hybridization in individuals who did not have T2D (n = 24) and who did have T2D (n = 21). (D) The density of CD8- and CD20-positive cells surrounding PanIN lesions quantitatively evaluated in immunostained sections according to the presence of T2D and differences in the PSCa score (n = 24: non-T2D; and n = 21: T2D). Kaplan-Meier analysis was performed according to the presence of T2D and differences in CXCL13-positive stromal cells and PSCa to compare RFS and OS (E and F) in PDAC samples. The data are presented as the means ± SDs. For D, box and whiskers are median and 25% interquartile intervals. Statistical analysis was performed by Fisher’s exact test and Mann-Whitney U test. For multiple comparisons, the Z test with Bonferroni adjustment was used. Survival curves were calculated with Kaplan–Meier analysis. PanIN, pancreatic intraepithelial neoplasia; T2D, type 2 diabetes; PSCs; pancreatic stellate cells; PSCa, pancreatic stellate cell activation; PSCa-L, PSCa-low; PSCa-H, PSCa-high; PDAC, pancreatic ductal adenocarcinoma. * P < 0.05, ** P < 0.01, *** P < 0.001. Scale bar: 100 μm and 25 μm (inset).