Targeting LGSN restores sensitivity to chemotherapy in gastric cancer stem cells by triggering pyroptosis

Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gas...

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Bibliographic Details
Published in:Cell death & disease 2023-08, Vol.14 (8), p.545-545, Article 545
Main Authors: Li, Yu-Ting, Tan, Xiang-Yu, Ma, Li-Xiang, Li, Hua-Hui, Zhang, Shu-Hong, Zeng, Chui-Mian, Huang, Liu-Na, Xiong, Ji-Xian, Fu, Li
Format: Article
Language:English
Subjects:
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13/2
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5-Fluorouracil
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692/699/67/1504/1829
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Antibodies
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell differentiation
Cell fate
Cell self-renewal
Chemoresistance
Chemotherapy
Gastric cancer
Glutamate-ammonia ligase
Immunology
Life Sciences
Oxaliplatin
Pyroptosis
Stem cells
Treatment resistance
Tumors
Vimentin
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Summary:Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gastric cancer stem cells (GCSCs) remains largely unknown. Here, we present evidence that lengsin, lens protein with glutamine synthetase domain (LGSN), a vital cell fate determinant, is overexpressed in GCSCs and is highly correlated with malignant progression and poor survival in GC patients. Ectopic overexpression of LGSN in GCSC-derived differentiated cells facilitated their dedifferentiation and treatment resistance by interacting with vimentin and inducing an epithelial-to-mesenchymal transition. Notably, genetic interference of LGSN effectively suppressed tumor formation by inhibiting GCSC stemness maintenance and provoking gasdermin-D-mediated pyroptosis through vimentin degradation/NLRP3 signaling. Depletion of LGSN combined with the chemo-drugs 5-fluorouracil and oxaliplatin could offer a unique and promising approach to synergistically rendering this deadly cancer eradicable in vivo. Our data place focus on the role of LGSN in GCSC regeneration and emphasize the critical importance of pyroptosis in battling GCSC.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06081-8