SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.
Date
2022-03
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Abstract
Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.
Type
Department
Description
Provenance
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Xu, Chuan, Guoxiang Jin, Hong Wu, Wei Cui, Yu-Hui Wang, Rajesh Kumar Manne, Guihua Wang, Weina Zhang, et al. (2022). SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling. The Journal of clinical investigation, 132(5). p. e141797. 10.1172/jci141797 Retrieved from https://hdl.handle.net/10161/31158.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
RAJESHKUMAR MANNE
Che-Chia Hsu
My research has focused on mitochondrial functions in cancer metabolism and understand the role of mitochondrial dynamics in cellular function and human diseases including cancers. Additionally, I also continuously dissect cancer metabolism and identifying potential metabolic vulnerabilities of cancer initiation, progression and metastasis using several in vitro, ex vivo and in vivo genetical approaches such as CRISPR/Cas9 knockout, mouse/ human organoid cultures and genetically engineered mouse models, thereby characterizing molecular mechanisms regulated by metabolic pathways and developing potential metabolic interventions for targeting cancers.
Hui-Kuan Lin
The research interest in Dr. Lin lab is to understand oncogenic networks between oncogenes and tumor suppressor genes, dissect the regulatory mechanisms underlying the crosstalk between ageing and cancer, to unravel the role of posttranslational modifications (PTMs) such as ubiquitination and metabolism in diverse molecular and biological processes important for cancer progression and metastasis, cancer stem regulation, cancer immunity and drug resistance by using biochemical and molecular approaches along with and genetic mouse models, and finally to develop small molecule inhibitors and antibodies targeting critical oncogenic signaling and metabolic vulnerabilities for cancer treatment. His research goals aim to not only reveal fundamental insights and concepts for cancer biology and cancer immunity, but also develop novel paradigms and therapeutic strategies for targeting human cancer and overcoming drug resistance.
Research interests include:
- Crosstalk between oncogenic and tumor suppressor networks
- Posttranslational modifications in signaling and cancer
- Cancer progression and metastasis
- Biology of normal and cancer stem cells
- Metabolism in cancer and ageing
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.