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[Preprint]. 2025 May 18:2025.05.14.654046. [Version 1] doi: 10.1101/2025.05.14.654046

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Figure 4: — a-b, Maximum intensity projection of 3D images of CK19 immunostaining in KIC mice treated with anti-Netrin-1 antibody (αNetrin-1) or isotype control antibody (Iso-antibody). CK19 labels both pancreatic ducts and their ramifications (asterisks), and PanIN lesions (arrows). Scale bar: 500 μm.

c, Quantification of the number of PanIN lesions per mm³ in KIC mice treated with Iso-antibody (Iso) or αNetrin-1 (αNet). Data are presented as mean ± SEM. n = 6 ROIs (Iso) and 5 ROIs (αNet) from 3 mice per group. p-values are indicated on the graph (Mann–Whitney test).

d-e, 2D optical sections illustrating low-grade (d) and high-grade (e) PanIN lesions. PanINs were labeled with CK19, and pancreatic tissue was visualized by autofluorescence (AF). The insets show the maximum intensity projections of 3D CK19⁺ signals. Scale bars: 100 μm (d), 200 μm (e).

f, Proportions of low- and high-grade PanIN lesions in KIC mice treated with Iso-antibody (Iso) or αNetrin-1 (αNet). N =20 (Iso) and 41 (αNet) PanINs from 3 mice per group. Data are presented in percentage. p-values are indicated on the graph (Chi-squared test).

g-h, Representative immunohistochemistry staining for Sox9 and KI67 in pancreatic sections through PanIN lesions in KIC mice treated with Iso-antibody (g) or αNetrin-1 (h). DAPI for nuclear staining. Scale bar: 50 μm.

i, Quantification of the proportion of Sox9+ cells expressing KI67 in PanIN lesions in KIC mice treated with Iso-antibody (Iso) or αNetrin-1 (αNet). Data are presented as mean ± SEM.

n = 20 (Iso) and 19 (αNet) ROIs from 3 mice per group. p-value is indicated on the graph (Mann–Whitney test).

j, Summary of findings and proposed model: Reactivation of the neurodevelopmental Netrin-1/DCC signaling pathway promotes hyperinnervation of non-malignant pancreatic lesions by sympathetic nerve terminals. This process may initiate a negative feedback loop that restrains lesion progression to higher grades by limiting cell proliferation.