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1.
Figure 7

Figure 7. β-catenin acts as a gatekeeper of Kras-induced reprogramming of acini into ductal PanINs.. From: ?-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.

Pattern of β-catenin signaling activity during acinar regeneration versus Kras-induced ADM/PanIN. β-catenin levels are kept below a critical threshold during the initiation of Kras-induced ductal reprogramming but increase as PanIN lesions form. Therefore, β-catenin antagonizes specification of a ductal state capable of forming PanINs, but likely contributes to PanIN progression and tumor growth.

John P. Morris, et al. J Clin Invest. 2010 February 1;120(2):508-520.
2.
Figure 6

Figure 6. β-catenin signaling inhibits Kras-induced reprogramming of acini into PanINs.. From: ?-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.

(A, E, and I) H&E staining of tamoxifen-stimulated, caerulein- or PBS-treated ElaCreERT;β-cateninexon3/+;LSL-KrasG12D or ElaCreERT;LSL-KrasG12D mice. (B, F, and J) CK19/Alcian blue staining. Note that normal ducts in PBS-treated ElaCreERT;β-cateninexon3/+;LSL-KrasG12D mice are strongly CK19 positive but Alcian blue negative (B). (C, G, and K) β-catenin (green), DAPI (blue) immunofluorescent labeling. β-catenin accumulation is rare in PBS-treated ElaCreERT;β-cateninexon3/+;LSL-KrasG12D mice (asterisk, C). Nuclear localization is noted by cyan overlap of green/blue channels (K). (D, H, and L) phospho-p42/p44 staining. Original magnification, ×400 (A, B, DF, HJ, and L). Scale bars: 50 μm (C, G, and K).

John P. Morris, et al. J Clin Invest. 2010 February 1;120(2):508-520.
3.
Figure 5

Figure 5. Stabilized β-catenin antagonizes Kras-induced ADM.. From: ?-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.

(AL) Characterization of 6-week-old PBS- and caerulein-treated p48Cre;β-cateninexon3/+;LSL-KrasG12D mice and caerulein-treated p48Cre;LSL-KrasG12D mice. (A, E, and I) H&E staining. Yellow lines separate areas of cells with acinar morphology (a), and ductal morphology (d). (B, F, and J) Amylase staining. (C, G, and K) Sox9 staining. (D, H, and L) Clusterin staining. (M) Quantification of relative amylase area 7 days following caerulein in p48Cre;β-cateninExon3/+;LSL-KrasG12D (red bars) and control p48Cre;LSL-KrasG12D (blue bars) mice. Bars represent mean ± SD. 7 indicates days after caerulein treatment. *P < 0.05; **P < 0.01; ***P < 0.001. Original magnification, ×400 (AL).

John P. Morris, et al. J Clin Invest. 2010 February 1;120(2):508-520.
4.
Figure 4

Figure 4. β-catenin is required for efficient acinar regeneration.. From: ?-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.

(AF) H&E staining of regenerating control (p48Cre;β-cateninF/+) versus p48Cre;β-cateninF/F pancreas following caerulein treatment. f, fat accumulation (DF). Rare acini following caerulein treatment are marked with arrowheads (E and F). (GL) β-catenin (green), amylase (blue), and CK19 (red) immunofluorescent labeling. Acini in p48Cre;β-cateninF/F mice lack membrane β-catenin staining (compare insets in G and J). Arrowheads mark rare acini (K and L). Both β-catenin–negative (arrows) and –positive (hatch marks) CK19-labeled ducts are observed. i, islets. (M) Quantification of relative amylase area in control (blue bars) and p48Cre;β-cateninF/F (red bars) following caerulein pancreatitis. Bars represent mean ± SD. P, PBS treatment. 3 and 5 indicate days after caerulein treatment. *P < 0.05; **P < 0.01; ***P < 0.001. Original magnification, ×400 (AL, insets).

John P. Morris, et al. J Clin Invest. 2010 February 1;120(2):508-520.
5.
Figure 2

Figure 2. Mutant Kras blocks acinar regeneration in favor of a persistently dedifferentiated state.. From: ?-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.

(AH) Clusterin and Sox9 (IP) expression during regeneration and Kras-induced ADM. (A and I) Clusterin expression is limited to some normal ducts in PBS-treated Pdx1-CreEarly mice, while Sox9 is restricted to ducts and centroacinar cells (arrowheads). (E and M) Acini in PBS-treated Pdx1-CreEarly;LSL-KrasG12D mice are negative for Clusterin and Sox9, while normal ducts and spontaneous PanINs are positive (asterisks). (B, F, J, and N) Damaged duct-like cells of both genotypes display clusterin- and Sox9-positive cells (insets). (C, D, K, and L) Clusterin and Sox9 are mainly restricted to duct cells (arrowheads) following regeneration in Pdx1-CreEarly pancreata. Rare clusterin-positive cells were observed 7 days following caerulein treatment (arrow, C). (G, H, O, and P) Clusterin and Sox9 remain strongly expressed in ADM and PanINs in Pdx1-CreEarly;LSL-KrasG12D mice. (Q) Schematic of failed regeneration of acini possessing mutant Kras (acini*) versus WT. WT acini transiently dedifferentiate and rapidly regenerate, while acini possessing mutant Kras are sensitized to persistent dedifferentiation and ADM/PanIN formation. Original magnification, ×400 (AP; insets).

John P. Morris, et al. J Clin Invest. 2010 February 1;120(2):508-520.
6.
Figure 3

Figure 3. Regeneration-associated reactivation of β-catenin signaling is inhibited during Kras-induced ductal reprogramming.. From: ?-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.

(AH) β-catenin (above dashed line, gray; below dashed line, green) and amylase (above dashed line, not shown; below dashed line, blue) immunofluorescent staining. (AD) Pdx1-CreEarly mice; (EH) Pdx1-CreEarly;LSL-KrasG12D mice. Asterisk in E marks spontaneous PanIN lesions. (I and J) Western blot analysis of β-catenin 2 days following caerulein treatment. Intensity, normalized to GAPDH, is quantified in J (bars represent mean ± SD). (K and L) Quantitative PCR for β-catenin target genes during WT acinar regeneration (blue bars) and ADM/PanIN (red bars). Values are relative to PBS-treated Pdx1-CreEarly mice and are presented as mean ± SD (n = 3). P, PBS treatment; 2, 7, 21 indicate days after caerulein treatment. *P < 0.05; ***P < 0.001. Original magnification, ×630 (AH).

John P. Morris, et al. J Clin Invest. 2010 February 1;120(2):508-520.
7.
Figure 1

Figure 1. Mutant Kras blocks acinar regeneration and promotes ADM/PanIN formation.. From: ?-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.

(AH) H&E staining of regeneration time course in Pdx1-CreEarly (AD) and Pdx1-CreEarly;LSL-KrasG12D (EH) mice. (E and M) Asterisks indicate spontaneous PanIN lesions in PBS-treated Pdx1-CreEarly;LSL-KrasG12D animals. Insets in B and F show morphologically similar duct-like cells 2 days after induction of acute pancreatitis. (IP) Amylase (red)/CK19 (green) immunofluorescent labeling. Note CK19 expression in spontaneous PanIN lesions in Pdx1-CreEarly;LSL-KrasG12D mice (asterisk, M). (J and N) Amylase is downregulated and CK19 is weakly expressed in transient duct-like cells in Pdx1-CreEarly mice (inset, J) while strongly expressed in duct-like cells in Pdx1-CreEarly;LSL-KrasG12D mice (inset, N). Rare amylase-positive cells are found in metaplastic epithelium (arrowheads, O). (QT) Amylase (red), CK19 (blue), YFP (green) immunofluorescent labeling in Elastase-CreERT;LSL-KrasG12D;R26R-EYFP mice. Without caerulein treatment, YFP expression is restricted to amylase-positive cells and restricted from CK19-positive cells. Arrowheads indicate autofluorescent erythrocytes (Q). Double-CK19/YFP–positive cells (cyan, indicating blue/green overlap) persist following caerulein treatment (RT). Original magnification, ×400 (AP; insets). Scale bars: 50 μm (QT).

John P. Morris, et al. J Clin Invest. 2010 February 1;120(2):508-520.

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