Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10

Article Article scientifique Article Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10 eng 2025-08-21 author Delangre Etienne 0000-0003-1804-5680 983567 Département de physiologie cellulaire et métabolisme (PHYME) author Correia De Sousa Marta 910172 Département de physiologie cellulaire et métabolisme (PHYME) author Tuerkal Miranda 402574 Département de physiologie cellulaire et métabolisme (PHYME) author Gjorgjieva Ducros Monika 0000-0001-8553-7525 891816 Département de physiologie cellulaire et métabolisme (PHYME) Monika Gjorgjieva author Chartier Suzanne 429825 author Arnoux Grégoire 674746 author Sobolewski Cyril 819918 author Fournier Margot 134287 Département de physiologie cellulaire et métabolisme (PHYME) author Maeder Garavaglia Christine 22210 Département de physiologie cellulaire et métabolisme (PHYME) author Rubbia-Brandt Laura 31809 Département de pathologie et immunologie (PATIM) author Maechler Pierre 0000-0002-2005-1433 76515 Département de physiologie cellulaire et métabolisme (PHYME) author Foti Michelangelo 0000-0001-7199-4135 28033 633 10.1038/s41419-025-07940-2 40841353 2041-4889 PMC12370981 https://www.nature.com/articles/s41419-025-07940-2 S100 proteins are significantly deregulated in hepatocellular carcinoma (HCC) and metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the impact of hepatocyte downregulation of two closely-related members of the S100 family, S100A10 and S100A11, in complementary mouse models of MASLD and liver cancer. Hepatotropic AAV8 encoding shRNAs targeting S100A10 or S100A11 were used to downregulate these proteins specifically in the liver of mice fed a diet inducing hepatic steatosis, inflammation, and fibrosis and in a genetic mouse model of MASLD bearing hepatocyte-specific deletion of PTEN (LPTENKO). The impact of S100A10 or S100A11 downregulation on liver tumor development was further investigated in aged LPTENKO mice spontaneously developing MASLD-driven HCC and in diethylnitrosamine (DEN)-injected mice fed or not with high fat diet. Finally, the upregulation and downregulations of S100A10 were performed in mice harbouring the over-expression of Myc and constitutively activated β-catenin, two main events occurring in a sub-type of human HCC. Downregulation of S100A10 promoted hepatocarcinogenesis in a fatty liver setting, while reducing steatosis and fibrosis development. S100A11 knock-down consistently reduced MASLD and tumoral growth. However, in vivo S100A11 downregulation triggered concomitant partial loss of endogenous protective S100A10. Overexpression of S100A10 reduced the volume of tumors and might represent a therapeutic option. The results show that both S100A10 and S100A11 play active roles in the development of MASLD. However, these two closely associated proteins present opposite contributions to hepatic cancer, S100A10 being protective and S100A11 deleterious. Animals Annexin A2 Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / metabolism Carcinoma, Hepatocellular / pathology Disease Models, Animal Fatty Liver / genetics Fatty Liver / metabolism Fatty Liver / pathology Humans Liver Neoplasms / genetics Liver Neoplasms / metabolism Liver Neoplasms / pathology Male Mice Mice, Inbred C57BL Mice, Knockout PTEN Phosphohydrolase / deficiency PTEN Phosphohydrolase / genetics PTEN Phosphohydrolase / metabolism S100 Proteins / genetics S100 Proteins / metabolism Dewey 612 Dewey 616.07 Swiss National Science Foundation Elucidating the role of S100A10 and S100A11 in NASH and HCC development 200530 CH Projects 134 Département de physiologie cellulaire et métabolisme 21C 137 Département de pathologie et immunologie 21F false 472 Obésité et syndrome métabolique 803 402 Mitochondries et métabolisme énergétique 671 391 Métastases du foie 657 https://doi.org/10.26037/yareta:msbz7hw3fzc2rpjiqinyqs4jtq Cell death and disease 16 1 d7e562cd-0bac-4f33-9467-2e951fa4bec0 Article (Published version) Public Article_scientifique_from_crossref.pdf 3335625 application/pdf CC BY-4.0 66fa041f13d7c5e85ffc753a47ea7b6e39c29ff2925d20d5af3844f849a28c86 75747abe-518e-42db-acbf-371dddca71f0 Supplemental data Public 41419_2025_7940_MOESM1_ESM.jpg 157555 image/jpeg 83acc3b24222115c86c2b84ea8c7350109c65e2590c711bcf1b32a31749cc7d6 bb903ddd-29f0-467a-b4ed-f3849efaefef Supplemental data Public 41419_2025_7940_MOESM2_ESM.jpg 201961 image/jpeg 74ad35d7320abe4161d52f0361ee9d710db23ebff8af303adc30dc95bcf68b07 303b1407-2ab8-48ca-a9bc-6ff63f3be512 Supplemental data Public 41419_2025_7940_MOESM3_ESM.jpg 247691 image/jpeg f789d407d32ca47cf86206c73634c3e3dd4103cd8c7c18abb44e49a7ec742d30 f0034231-ba7e-4f70-8511-d5b3cd34c562 Supplemental data Public 41419_2025_7940_MOESM4_ESM.jpg 411230 image/jpeg 53c3343606c71e0fb80c6658ae94688a183b2d7b3420c1a8c8f07ddc961a7fe0 f161e0de-292b-4986-85d3-714a46e38402 Supplemental data Public 41419_2025_7940_MOESM5_ESM.jpg 159084 image/jpeg 2eebdf5ec952b236cc5caf38b55ed23b68afcae2bf7341f97e8a473e749e2f36 1e22cab3-2ef3-48b8-b242-53e38a5075b3 Supplemental data Public 41419_2025_7940_MOESM6_ESM.jpg 180393 image/jpeg 75562987ccc3c975914a67bcc71972bfa5864fbf3f0e298b9a5f57978f6492c2 226fede3-7940-4ae6-8fbc-2cc84a32fe22 Supplemental data Public 41419_2025_7940_MOESM7_ESM.jpg 165344 image/jpeg 0f328f6374c154b46a37d3a0a396294aa1c17a2cc0423888677b716e9ce4d75e a8d94651-a910-44ec-acb7-c4699f25b370 Supplemental data Public 41419_2025_7940_MOESM8_ESM.jpg 281296 image/jpeg b9a3eaddebf4e75f59625051d7b9670aef72d678fb8f8bfcf92782fd9f221857 457c1f49-cac2-429c-9520-213e817d8871 Supplemental data Public 41419_2025_7940_MOESM9_ESM.jpg 84446 image/jpeg 87d1dc6c1f0667a0cbbec4b1a4d91d5384679176f6c006fbfe1e6c70c4f5927a a23847a9-9c4d-46c9-9dbd-1dbae863719f Supplemental data Public 41419_2025_7940_MOESM10_ESM.xlsx 19834 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 93e7691e2ca627cdb46dbd1bedb82745963626588049f4cb7ce42e91951d2540 8989a29a-f749-4ee1-a8ab-7bf58fce92a8 Supplemental data Public 41419_2025_7940_MOESM11_ESM.docx 19230 application/vnd.openxmlformats-officedocument.wordprocessingml.document 2f9d8c2798179ac3610a727eb72cf4fdff4262aa67b7ff4c0b8fef65497ae898 a31ca264-dbb0-4f22-a490-6c8dfc4aa45e Supplemental data Public 41419_2025_7940_MOESM12_ESM.pdf 1068182 application/pdf 93c819353e68b938b0149d4cbf1d28d89f09c557ba072d2d7639a4ab0603247d openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10	Cell death and disease	2025	52	22
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