TY - JOUR
T1 - PD-L1 interacts with Frizzled 6 to activate β-catenin and form a positive feedback loop to promote cancer stem cell expansion
AU - Fu, Lingchen
AU - Fan, Jia
AU - Maity, Sudipa
AU - McFadden, Grant
AU - Shi, Yixin
AU - Kong, Wei
N1 - Funding Information:
This work was supported by grants National Institutes of Health/National Cancer Institute (CA249517 to WK); Arizona State University (Startup fund 5300 to WK); National Institutes of Health National/Institute of Dental and Craniofacial (DE024607 to YS and WK).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/2/18
Y1 - 2022/2/18
N2 - Cancer stem cells (CSCs) drive tumor initiation, progression, metastasis, and drug resistance. We report here that programmed cell death ligand 1 (PD-L1) is constitutively expressed in cancer cells to maintain and expand CSC through a novel mechanism in addition to promoting cancer cell immune evasion. We discovered that PD-L1 interacts with receptor Frizzled 6 to activate β-catenin signaling and increase β-catenin-targeted gene expression, such as a putative stem cell marker leucine-rich-repeat-containing G-protein-coupled receptor 5. Blockage of PD-L1 function, using a specific small hairpin RNA or a specific antibody, inhibits disease progression by reducing the CSC population in both colorectal and breast tumors. Moreover, β-catenin conversely regulates PD-L1 expression through a β-catenin complex binding site in the PD-L1 promoter. Our discoveries reveal that besides assistant tumor cell immune escaping, PD-L1 and β-catenin signaling form a positive feedback loop to promote cancer progression through CSC maintenance and expansion.
AB - Cancer stem cells (CSCs) drive tumor initiation, progression, metastasis, and drug resistance. We report here that programmed cell death ligand 1 (PD-L1) is constitutively expressed in cancer cells to maintain and expand CSC through a novel mechanism in addition to promoting cancer cell immune evasion. We discovered that PD-L1 interacts with receptor Frizzled 6 to activate β-catenin signaling and increase β-catenin-targeted gene expression, such as a putative stem cell marker leucine-rich-repeat-containing G-protein-coupled receptor 5. Blockage of PD-L1 function, using a specific small hairpin RNA or a specific antibody, inhibits disease progression by reducing the CSC population in both colorectal and breast tumors. Moreover, β-catenin conversely regulates PD-L1 expression through a β-catenin complex binding site in the PD-L1 promoter. Our discoveries reveal that besides assistant tumor cell immune escaping, PD-L1 and β-catenin signaling form a positive feedback loop to promote cancer progression through CSC maintenance and expansion.
UR - http://www.scopus.com/inward/record.url?scp=85122874172&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122874172&partnerID=8YFLogxK
U2 - 10.1038/s41388-021-02144-2
DO - 10.1038/s41388-021-02144-2
M3 - Article
C2 - 35034965
AN - SCOPUS:85122874172
SN - 0950-9232
VL - 41
SP - 1100
EP - 1113
JO - Oncogene
JF - Oncogene
IS - 8
ER -