Abstract LB177: Visualization and targeting of CD133+ cancer stem cells in MASLD-related hepatocellular carcinoma
Year: 2025
Type: conference-abstract
Abstract: Metabolic dysfunction-associated steatotic liver disease related hepatocellular carcinoma (MASLD-HCC) is an emerging malignancy. However, the identity and function of cancer stem cells (CSCs) in MASLD-HCC are largely unclear. Here, we aim to investigate the function, mechanism, and targeted therapy of CSCs in MASLD-HCC. Intravital genetic lineage tracing in mice demonstrated that CD133+ cells from high-fat high cholesterol diet (HFHC)-induced MASLD-HCC possess the characteristics of CSCs, including superior self-renewal capacity in vitro and tumorigenicity in vivo compared to CD133- counterparts. ScRNA-seq of CD133+ progenies revealed their clonal expansion into multiple lineages during tumor progression, highlighting the role of CD133+ CSCs in contributing to cellular plasticity in MASLD-HCC. Further, we showed that CD133 functionally drives CSC phenotypes in MASLD-HCC and that hepatocyte-specific Cd133 overexpression in mice accelerated MASLD-HCC formation driven by diethylnitrosamine plus choline-deficient, high-fat (CDHF) diet. Mechanistically, CD133 interacts with myosin heavy chain 9 (MYH9) to promote the stabilization of active β-catenin, thereby propagating Wnt/β-catenin signaling critical for CSC phenotypes as well as pro-tumorigenic potential. Accordingly, MYH9 knockdown abrogated the induction of Wnt/β-catenin by CD133. In terms of translational relevance, targeted ablation of CD133+ cells using a selective diphtheria toxin receptor system (DTRlslCd133-CreER) in mice sensitizes MASLD-HCC to multikinase inhibitors (Sorafenib and Lenvatinib). Moreover, targeting of CD133 by nanoparticle-siRNA in combination with Sorafenib synergized to induce regression of tumors in subcutaneous and orthotopic MASLD-HCC. In summary, our results indicate that CD133+ CSCs potentiate MASLD-HCC by activating Wnt/β-catenin signaling through MYH9 and is a therapeutic target, especially in combination with multikinase inhibitors. Citation Format: Yasi Pan, Xiang Zhang, Chi Chun Wong, Huarong Chen, Kai Yuan, Jun Yu. Visualization and targeting of CD133+ cancer stem cells in MASLD-related hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB177.
Source: Cancer Research
Authors: Yasi Pan, Xiang Zhang, Chi Chun Wong, Huarong Chen, Kai Yuan, Jun Yu
Institution: Chinese University of Hong Kong
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4409821252