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Figure 3 from Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia Juliano Machado (25154222) Vignesh Karthikaisamy (25154225) Hermine Mohr (25154228) Doris Kaltenecker (25154231) Pia Benedikt (25154234) Pauline Morigny (25154237) Amit Mhamane (25154240) Julia Geppert (25154243) Amy Rose Fumo (25154246) Kerstin Haase (14123058) Estefania Simoes (25154249) Joanna D.C.C. Lima (18725115) Anastasia Georgiadi (25154252) Achim Krüger (25154255) José Pinhata Otoch (25154258) Marc E. Martignoni (25154261) Vickie E. Baracos (25154264) Mariam Jamal-Hanjani (15386766) Marilia C.L. Seelaender (25154267) Olga Prokopchuk (25154270) Julia Szendrödi (25154273) Maria Rohm (25154276) Stephan Herzig (25154279) Mauricio Berriel Diaz (15037094) Cancer Molecular and Cellular Biology Gastrointestinal Cancers Colorectal cancer Lung Cancer Metabolism Metabolic pathways Suppression of C26 tumor-derived ADAMTSL4 attenuates cancer cachexia and muscle atrophy in vivo. A–R, Mice were subcutaneously inoculated with PBS (n = 5), control C26 cells (C26-shCtrl, n = 10), or C26 cells with stable ADAMTSL4 knockdown (C26-shAdamtsl4, n = 9). A, Schematic overview of the preclinical model used to investigate the role of C26 tumor-derived ADAMTSL4 in cachexia. B, Adamtsl4 mRNA expression in tumors assessed by qPCR. C, Plasma ADAMTSL4 protein levels measured by Western blot. D, Tumor mass and (E) food intake in tumor-bearing or PBS-injected mice. Food intake measured daily per cage and normalized to grams per mouse per day. Mice were housed two per cage unless otherwise indicated. F, Initial body weight (iBW), final BW (fBW), and tumor-free carcass weight. G, Relative BW loss kinetics during the final days prior to sacrifice. H, Relative change in lean mass determined by EchoMRI. I, GC and TA muscle weights. J, Representative images of TA muscle sections stained with WGA Alexa Fluor 488 and DAPI (200× magnification; scale bar, 100 μm). Representative structural features are highlighted by arrows (white, PBS/control; red, cachectic condition; blue, ADAMTSL4 knockdown). K, Quantification of muscle fiber CSA (n = 3 per group, >500 fibers per mouse) and (L) fiber size distribution in TA. M, Selected GO terms from GSEA of GC muscle from C26-shCtrl vs. PBS-injected mice (see also Supplementary Data S3 and S4 for full GO term analysis results). N, Selected GO terms from GSEA of GC muscle from C26-shAdamtsl4 vs. C26-shCtrl tumor-bearing mice (see also Supplementary Data S5 and S6 for full GO term analysis results). O, Quantification of Western blot analysis of key proteins involved in proteasomal catabolism and autophagy, including p-FOXO3a at T32 and p-STAT3 at Y705. P, mRNA expression of proteasomal catabolic genes (Fbxo32 and Trim63) and (Q) autophagy-related genes (Becn1, Map1lc3, and Gabarapl1) validated by qPCR. R, Quantification of Western blot analysis of autophagy marker LC3, showing LC3-I, LC3-II, and the LC3-II/LC3-I ratio. Data are presented as the mean ± SEM. Each dot represents an individual biological replicate. Statistical analysis: two-tailed unpaired t test with Welch correction (B and D), one-way ANOVA with Tukey multiple-comparisons test (C, F, G–I, K, and O–R), two-way ANOVA with mixed-effects model (REML) followed by Tukey’s test (E and G), and GSEA enrichment scores calculated using weighted Kolmogorov–Smirnov statistics (M and N). Significance is denoted as *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, not significant. [A, Created in BioRender. Machado, J. (2026) <a target="_blank" href="https://BioRender.com/vx8zzgy">https://BioRender.com/vx8zzgy</a>.] 2026-10-01T00:00:00Z Image Figure 10.1158/2159-8290.34040810 https://figshare.com/articles/figure/Figure_3_from_Tumor-Secreted_ADAMTSL4_Activates_Latent_TGF_1_to_Drive_Cancer_Cachexia/34040810 CC BY