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. 2022 Apr 15;72(2):345–359. doi: 10.1136/gutjnl-2021-325564

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© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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Overexpression of Loxl2 worsens overall survival and increases tumour burden. (A) Scheme of the KPC-based Loxl2 overexpression genetic mouse model. The colour code green, KPCL2^KI, is used for all results. (B) Light and EGFP tumour images (left). Loxl2 expression in tumour homogenates from the indicated KPC genotypes (right). Gapdh, loading control. Positive (+) control=cell lysate from murine Loxl2-overexpressing 293 T cells. (C) Mean relative mRNA levels ±SEM of indicated genes in tumour-derived cells from the indicated genotypes (***p<0.001; ns, not significant; one-way analysis of variance (ANOVA) with Dunnett’s post-test). (D) Survival of KPC wild type (+/+), KPC; R26L2^+/KI and KPC; R26L2^KI/KI mice. All mice died of PDAC associated disease at the indicated times (p value is shown; ns, not significant; log-rank (Mantel-Cox) test). Calculated median survivals are: wild type (+/+): 20 weeks; KPC; R26L2^+/KI: 18 weeks; and KPC; R26L2^KI/KI: 17 weeks. (E) Percent tumour incidence in KPC wild type (+/+), KPC; R26L2^+/KI and KPC; R26L2^KI/KI mice at 17–18 weeks post birth. (****P<0.0001; ns, not significant; contingency analysis; two-sided Fisher’s exact test). Tumour incidence was determined as positive if a macroscopic tumour was visible on necropsy. (F) Mean pancreas weight ±SEM in KPC wild type (+/+), KPC; R26L2^+/KI and KPC; R26L2^KI/KI mice at 17–18 weeks post birth. (*P<0.05, **p<0.01; ns, not significant; one-way ANOVA with Tukey post-test). (G) Representative images of PDAC tumours/genotype at 17–18 weeks post birth. (H) Quantification of tissue area in mouse pancreata from wild type (+/+) KPC mice (blue, n=7) and KPCL2^KI (KPC; R26L2^+/KI and KPC; R26L2^KI/KI) mice (green, n=12) determined at 17–18 weeks post birth, categorised as severely altered tissue, PanINs I–III, PDAC or normal acinar tissue (*p<0.05, **p<0.01, contingency analysis, two-sided Fisher’s exact test). (I) Representative H&E-stained sections for the grading of the respective tumours: wild type (+/+) KPC (blue, n=6), KPC; R26L2^+/KI (dark green, n=6) and KPC; R26L2^KI/KI mice (light green, n=6). Pie chart insets=percent of differentiated (blue) vs poorly differentiated (yellow) tumours the indicated genotypes. Scale bar=250 µm. ADM, acinar-to-ductal metaplasia; KI, knock-in; Loxl2, lysyl oxidase-like protein 2; PanINS, pancreatic intraepithelial neoplasias; PDAC, pancreatic ductal adenocarcinoma; wt, wild type.