Targeting senescence-like fibroblasts radiosensitizes non–small cell lung cancer and reduces radiation-induced pulmonary fibrosis
Jingshu Meng, … , Honglin Jin, Kunyu Yang
Jingshu Meng, … , Honglin Jin, Kunyu Yang
Published December 8, 2021
Citation Information: JCI Insight. 2021;6(23):e146334. https://doi.org/10.1172/jci.insight.146334.
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Research Article Oncology

Targeting senescence-like fibroblasts radiosensitizes non–small cell lung cancer and reduces radiation-induced pulmonary fibrosis

Abstract

Cancer cell radioresistance is the primary cause of the decreased curability of non–small cell lung cancer (NSCLC) observed in patients receiving definitive radiotherapy (RT). Following RT, a set of microenvironmental stress responses is triggered, including cell senescence. However, cell senescence is often ignored in designing effective strategies to resolve cancer cell radioresistance. Herein, we identify the senescence-like characteristics of cancer-associated fibroblasts (CAFs) after RT and clarify the formidable ability of senescence-like CAFs in promoting NSCLC cell proliferation and radioresistance through the JAK/STAT pathway. Specific induction of senescence-like CAF apoptosis using FOXO4-DRI, a FOXO4-p53–interfering peptide, resulted in remarkable effects on radiosensitizing NSCLC cells in vitro and in vivo. In addition, in this study, we also uncovered an obvious therapeutic effect of FOXO4-DRI on alleviating radiation-induced pulmonary fibrosis (RIPF) by targeting senescence-like fibroblasts in vivo. In conclusion, by targeting senescence, we offer a strategy that simultaneously decreases radioresistance of NSCLC and the incidence of RIPF.

Authors

Jingshu Meng, Yan Li, Chao Wan, Yajie Sun, Xiaomeng Dai, Jing Huang, Yan Hu, Yanan Gao, Bian Wu, Zhanjie Zhang, Ke Jiang, Shuangbing Xu, Jonathan F. Lovell, Yu Hu, Gang Wu, Honglin Jin, Kunyu Yang

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Figure 1

Effects of SL-CAFs on NSCLC cells in vitro.

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Effects of SL-CAFs on NSCLC cells in vitro. (A) Cell senescence detected...
(A) Cell senescence detected by SA–β-Gal staining assay. Scale bar: 100 μm. (B) Relative mRNA expression of senescence-associated genes in CAFs 10 days after IR. The indicated results represent the mean ± SEM of 4 independent experiments, analyzed by Student’s t test. (C) Schematic diagram of the CM preparation process. (D) Left panel, Ki67 expression of H292 cells cultured with normal medium, CAF CM, or SL-CAF CM for 48 hours detected by flow cytometry. Right panel, statistical analysis of Ki67 expression. The indicated results represent the mean ± SEM of 3 independent experiments, analyzed by 1-way ANOVA. (E) Representative images of EdU staining of H292 cells cultured with CAF CM, SL-CAF CM, or control medium for 48 hours. Scale bar: 100 μm. (F) Quantification of EdU-positive H292 cells in indicated groups detected by flow cytometry. The indicated results represent the mean ± SEM of 3 independent experiments, analyzed by 1-way ANOVA. (G) Clonogenic survival curves of NSCLC cells pretreated with CAF CM, SL-CAF CM, or control medium for 48 hours and then irradiated with 2, 4, 6 or 8 Gy. Cell survival fractions were normalized to those of the unirradiated control cells. The indicated results represent the mean ± SEM of 3 independent experiments, analyzed by 2-way ANOVA. (H) NSCLC cells pretreated with CAF CM, SL-CAF CM, or control medium for 48 hours and then irradiated with 8 Gy. The apoptosis rates were measured 72 hours after 8 Gy IR detected by flow cytometry, as indicated in different groups. The indicated results represent the mean ± SEM of 3 independent experiments, analyzed by 1-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001; n.s., not statistically significant. SL-CAFs, senescence-like CAFs; zVAD, Z-VAD-FMK.