Leader cells promote immunosuppression to drive ovarian cancer progression in vivo.

Autor:	Wilson AL; Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia., Moffitt LR; Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia., Doran BR; Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia., Basri B; Hudson Institute of Medical Research, Clayton, VIC, Australia., Do J; Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia., Jobling TW; Monash Medical Centre, Department of Gynecology Oncology, Monash Health, 823-865 Centre Rd, Bentleigh East, VIC 3165, Australia., Plebanski M; School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia., Stephens AN; Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia., Bilandzic M; Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia. Electronic address: maree.bilandzic@hudson.org.au.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Nov 26; Vol. 43 (11), pp. 114979. Date of Electronic Publication: 2024 Nov 13.
DOI:	10.1016/j.celrep.2024.114979
Abstrakt:	Over 75% of patients with ovarian cancer present with late-stage disease, often accompanied by extensive metastasis. The metastatic cascade is driven by a sub-population of transcriptionally plastic cells known as "leader cells" (LCs), which play a critical role in collective invasion yet remain poorly understood. LCs are marked by the expression of keratin-14 (KRT14), which determines their migratory and invasive capacity in ovarian cancer. This study demonstrates that KRT14+ LCs promote tumor progression through immunosuppression and immune privilege in vivo. In the ID8 syngeneic epithelial ovarian cancer mouse model, tumor-specific loss of KRT14+ LCs impairs tumor progression and metastatic spread without affecting cellular proliferation. Immune profiling shows reduced immunosuppressive regulatory T cells (Tregs) and M2 macrophages and improved CD8 + T cell/Treg ratios in LC knockout (LC KO ) mice. Conversely, forced LC overexpression accelerates metastasis and increases the secretion of immunosuppressive chemokines, such as CCL22 and CCL5, highlighting the role of KRT14+ LCs in immune suppression and metastatic progression. Competing Interests: Declaration of interests The authors declare no competing interests. (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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