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Figure 4 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 Stable knockdown of tumor-derived ADAMTSL4 attenuates adipose tissue wasting, prolongs cachexia-related survival, and protects against cancer-induced cardiac atrophy. A–R, Mice were subcutaneously injected with PBS, control C26 cells (C26-shCtrl), or ADAMTSL4-depleted C26 cells (C26-shAdamtsl4). A, Schematic overview of the preclinical model used to assess the impact of tumor-derived ADAMTSL4 on adipose wasting, survival, and cardiac atrophy. B, Relative fat mass changes measured by EchoMRI. C, Mass of individual fat depots: iWAT, eWAT, and BAT. D, Plasma glycerol levels normalized to final fat mass. E, Selected GO terms from GSEA of eWAT comparing C26-shAdamtsl4 vs. C26-shCtrl tumor-bearing mice (see also Supplementary Data S7 and S8 for full GO term analysis results). F, mRNA expression of lipolysis-related genes and (G) fatty acid oxidation genes in eWAT, validating GSEA-enriched “fatty acid oxidation” and “lipid oxidation” terms. H, Western blot analysis of ATGL protein levels. I, Western blot analysis of autophagy-related proteins in eWAT, supporting the “autophagy” GO term from GSEA. J–R, Mice were subcutaneously inoculated with PBS (n = 5), C26-shCtrl cells (n = 6–7), or C26-shAdamtsl4 cells (n = 6–9). J, Tumor mRNA expression of Adamtsl4, Mki67, Bbc3, and Pmaip1 assessed by qPCR. K, Plasma ADAMTSL4 protein levels measured by Western blot. L, Kaplan–Meier curve showing percentage of mice developing cachexia over time. M, Percentage of cachexia-free mice at endpoint. N, Representative heart 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). O, CSA quantification of cardiomyocytes (n = 3 per group, >200 cells per mouse). P, Cardiac expression of autophagy-related genes (Bnip3, Map1lc3, and Gabarapl1) by qPCR. Q, Western blot analysis of cardiac autophagy (LC3-I and LC3-II) and (R) apoptosis (BAX) markers. Data are presented as the mean ± SEM. Each dot represents an individual biological replicate. Statistical analysis: one-way ANOVA with Tukey multiple-comparisons test (B–D, F–I, K, and O), multiple two-tailed unpaired t tests with Welch correction (J), two-way ANOVA or mixed-effects model (REML) with Tukey multiple-comparisons test (P–R), and GSEA enrichment scores calculated using weighted Kolmogorov–Smirnov statistics (E). 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/79ygt3l">https://BioRender.com/79ygt3l</a>.] 2026-10-01T00:00:00Z Image Figure 10.1158/2159-8290.34040807 https://figshare.com/articles/figure/Figure_4_from_Tumor-Secreted_ADAMTSL4_Activates_Latent_TGF_1_to_Drive_Cancer_Cachexia/34040807 CC BY