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Figure 6 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>ADAMTSL4 induces skeletal muscle fibrosis via local TGFβ signaling and activates fibrosis-related genes in human myotubes and muscles of patients with cancer cachexia. <b>A</b> and <b>B</b>, GSEA (<b>A</b>) of GC muscle from MC38-GFP vs. MC38-ADAMTSL4 tumor-bearing mice showing enrichment of the “TGFβ receptor signaling” pathway and heatmap (<b>B</b>) of the top 10 DEGs within this pathway. <b>C</b> and <b>D</b>, GSEA (<b>C</b>) of GC muscle from C26-shCtrl vs. C26-shAdamtsl4 tumor-bearing mice showing enrichment of “TGFβ receptor signaling activates SMADs” and heatmap (<b>D</b>) of the top 10 DEGs. <b>E,</b> Representative Sirius Red (top) and collagen-I (bottom) staining in GC muscle sections from PBS-injected, C26-shCtrl, and C26-shAdamtsl4 tumor-bearing mice (scale bar, 100 μm). <b>F–K,</b> Human primary myotubes were treated with rhADAMTSL4-CT (250 ng/mL) in the presence or absence of TGFβ pathway blockade: (<b>F</b>) mRNA levels of fibrosis-related genes (<i>TGFB1</i>, <i>CTGF</i>, and <i>TGFBI</i>); (<b>G</b>) atrophy-related genes (<i>FBXO32</i> and <i>TRIM63</i>) measured by qPCR; (<b>H</b>) quantification of myotube diameter; (<b>I</b>) representative images of myotubes treated with vehicle or rhADAMTSL4-CT ± TGFβ1–neutralizing antibody 1D11 (1.5 μg/mL; scale bar, 100 μm); (<b>J</b>) Western blot analysis of phosphorylated SMAD2 (p-SMAD2); (<b>K</b>) qPCR analysis of CTGF and TGM2 mRNA levels in myotubes treated with vehicle or rhADAMTSL4-CT ± galunisertib (10 μmol/L), a TGFBR1 inhibitor. <b>L</b> and <b>M,</b> Relative body weight change and circulating ADAMTSL4 levels measured by ELISA in an exploratory human cancer subcohort including patients with colorectal cancer and PDAC classified as cachectic (cancer cachexia, <i>n</i> = 15) or noncachectic (non–cancer cachexia, <i>n</i> = 7). <b>N–P,</b> qPCR analysis of <i>TGFB1</i>, <i>TGM2</i>, and <i>FBXO21</i> mRNA expression in rectus abdominis muscle biopsies from non–cancer cachexia patients and those with cancer cachexia with colorectal cancer/PDAC. <b>Q,</b> Schematic model depicting how tumor-derived ADAMTSL4 promotes muscle wasting via local activation of TGFβ signaling through LAP engagement and TGFBR1-dependent transcriptional responses. Data are shown as the mean ± SEM unless indicated otherwise. Each dot represents one biological replicate. Statistical analysis: weighted Kolmogorov–Smirnov test for GSEA enrichment scores (<b>A</b> and <b>C</b>); two-way mixed-effects model with Tukey or Holm–Šídák multiple-comparisons test (<b>F–H</b>, <b>J</b>, and <b>K</b>); for circulating ADAMTSL4 measurements in human plasma (<b>M</b>), ELISA values were log<sub>10</sub>-transformed and analyzed using a two-tailed Mann–Whitney test; human gene expression comparisons (<b>N–P</b>) were analyzed using two-tailed Mann–Whitney tests. 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>Q,</b> Created in BioRender. Machado, J. (2026) <a target="_blank" href="https://biorender.com/4sidioq">https://BioRender.com/4sidioq</a>.]</p>
2026-10-01T00:00:00Z
Image
Figure
10.1158/2159-8290.34040798
https://figshare.com/articles/figure/Figure_6_from_Tumor-Secreted_ADAMTSL4_Activates_Latent_TGF_1_to_Drive_Cancer_Cachexia/34040798
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