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van Driel MS, Linssen JDG, Flanagan DJ, et al. Caffeine Limits Expansion of Apc-Deficient Clones in the Intestine by NOTUM Inhibition. Cell Mol Gastroenterol Hepatol 2023;16:652-655.
In the above article the figure legends for Supplementary Figures 1-4 are missing from the text. The supplementary figure legends are provided below.
Supplementary Figure 1.(A) Schematic illustration of TOP-GFP Wnt reporter construct. (B) Wnt activation as measured by GFP expression (n=3). (C-E) Representative phase images of wells containing wild-type organoids that have been passaged after 5-day treatment of Apc-/- CM or Apc-/-;NotumKO CM in the absence or presence of caffeine (C), and corresponding measurements of clonogenicity (D-E) (n=4).
Supplementary Figure 2.(A) Phase images of wild-type organoids in the absence and presence of caffeine. (B-D) The size (B) relative clonogenicity (C) and relative Axin2 expression (D) of wild-type organoids in the absence or presence of caffeine (n=4). (E) Schematic illustration of short-term experiment in Lgr5-EGFP-IRES-CreERT2; Rosa26LSL-tdTom mice in the absence or presence of caffeine. (F) Representative image of tdTomato+ clones 14 days after tamoxifen injection. g, Clone fraction distributions over time, (n=#crypts). (H-I) Relative clone fractions (H) and crypt fixation (I) of tdTomato+ clones in the absence or presence of caffeine. (n=3-4 mice per group).
Supplementary Figure 3.(A-B) Size contributions of adenoma size in the distal small intestine of control mice (n=6 mice) (A) and caffeine treated mice (n=8 mice) (B). (C-D) Representative images of Dkk2 expression using RNA-ISH in adenomas of mouse treated with or without caffeine, (C), and corresponding quantification of Dkk2 (D) intensity (n=3 mice, each dot is an ISH-positive region). (E-G), Relative expression of Wnt antagonists Notum (E), Wif1 (F), and Dkk2 (G) in Apc-mutant organoids in the presence or absence of caffeine (n=3). (H) Relative clonogenicity of wild-type organoids cultured in Apc-/- CM without caffeine treatment (control) (n=3), or cultured in Apc-/- CM with caffeine treatment for either 4 days (short-term) (n=3) or 21 days (long-term) (n=4). (I) Schematic illustration of the experiment in VillinCreERT2;ApcMin;Notumfl/fl mice. (J-O), Representative images of Notum (J), Wif1 (L) and Dkk3 (N) expression using RNA-ISH in adenomas of VillinCreERT2;ApcMin;Notumfl/fl mice, and corresponding quantification of Notum (K), Wif1 (M) and Dkk3 (O) intensity (n=3 mice, each dot is an ISH-positive region).
Supplementary Figure 4. Schematic illustration depicting the proposed model of compensatory upregulation of Wnt antagonists secreted by Apc-mutant ISCs (yellow) upon long-term NOTUM inhibition. The bold arrows indicate Apc-mutant cells overtaking normal ISCs (green, blue) and the blunt-ended arrows indicate inhibition.