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Figure 2 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 <p>Tumor-specific overexpression of ADAMTSL4 is sufficient to drive cancer cachexia. <b>A–U,</b> Mice were subcutaneously inoculated with control MC38-GFP cells (<i>n</i> = 7) or MC38 cells stably overexpressing ADAMTSL4 (MC38-ADAMTSL4; <i>n</i> = 9–12). <b>A,</b> Schematic of the preclinical model used to assess the cachexia-inducing capacity of MC38 tumor-derived ADAMTSL4. <b>B,</b><i>Adamtsl4</i> mRNA levels in tumors. <b>C,</b> Plasma ADAMTSL4 protein levels determined by Western blot analysis. <b>D,</b> Tumor mass. <b>E,</b> Food intake in tumor-bearing mice. Food intake was measured daily by weighing chow pellets at a fixed time point. Mice were housed two per cage, and total cage consumption was calculated as the difference between food provided and food remaining on the following day, with visual inspection to account for potential spillage. Intake was normalized to the number of mice per cage and expressed as grams per mouse per day. No significant differences were observed between groups across the study period. <b>F,</b> Initial and final carcass weight (tumor-free body weight). <b>G,</b> Longitudinal kinetics of relative body weight (BW) change (%) in the days preceding sacrifice. <b>H,</b> Spearman correlation between plasma ADAMTSL4 levels and final relative BW change (<i>n</i> = 18 XY pairs). Relative BW change was calculated from the longitudinal measurements shown in <b>G</b>. <b>I,</b> Relative change in fat mass measured by EchoMRI. <b>J,</b> Fat mass in distinct adipose depots: iWAT, eWAT, and BAT. <b>K,</b> Expression of lipid metabolism-related genes in iWAT assessed by qPCR. <b>L,</b> Relative change in lean mass measured by EchoMRI. <b>M,</b> TA and GC muscle weights. <b>N,</b> Representative images of TA muscle cross-sections stained with WGA Alexa Fluor 488 and DAPI (200× magnification; scale bar, 100 μm). Representative structural features are highlighted by arrows (white, control; red, ADAMTSL4-overexpressing condition). <b>O,</b> Quantification of muscle fiber CSA. <b>P,</b> Frequency distribution of fiber CSA in TA muscle. <b>Q,</b> Absolute grip strength (forelimbs and hindlimbs). <b>N–P,</b> Complementary readouts derived from the same TA muscle cross-section analysis. <b>R,</b> Grip strength normalized to lean mass (g/g). <b>S,</b> Selected GO terms identified by GSEA in GC muscle from MC38-ADAMTSL4 vs. MC38-GFP tumor-bearing mice (see also Supplementary Data S1 and S2 for full GO term analysis results). <b>T,</b> Validation of marker genes associated with proteasomal catabolic processes (<i>Fbxo32</i> and <i>Trim63</i>). <b>U,</b> Validation of macroautophagy-related genes (<i>Becn1</i>, <i>Map1lc3</i>, and <i>Gabarapl1</i>) by qPCR. Data are presented as the mean ± SEM. Each dot represents an individual biological replicate. <i>Statistical analysis</i>: two-tailed unpaired <i>t</i> test (<b>B–D</b>, <b>F</b>, <b>I–M</b>, <b>O</b>, <b>Q</b>, <b>R</b>, <b>T</b>, and <b>U</b>), Spearman rank correlation (<b>H</b>), two-way mixed-effects analysis with Šídák multiple-comparisons test (<b>E</b> and <b>G</b>), and weighted Kolmogorov–Smirnov test for GSEA enrichment scores (<b>S</b>). Significance is denoted as *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001; ****, <i>P</i> < 0.0001; ns, not significant. [<b>A,</b> Created in BioRender. Machado, J. (2026) <a target="_blank" href="https://biorender.com/q1z1l3n">https://BioRender.com/q1z1l3n</a>.]</p> 2026-10-01T00:00:00Z Image Figure 10.1158/2159-8290.34040813 https://figshare.com/articles/figure/Figure_2_from_Tumor-Secreted_ADAMTSL4_Activates_Latent_TGF_1_to_Drive_Cancer_Cachexia/34040813 CC BY