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GPX4-dependent Glutathione (GSH) high consumption drives platinum chemotherapeutic resistance by inhibiting ferroptosis in lung cancer derived brain metastasis

ABSTRACT: Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows limited therapeutic efficacy in patients with brain metastasis (BM). In this study, we utilized a BM model of PC9 lung adenocarcinoma cells and found that the derivative brain metastatic subpopulations (PC9-BrMs) of parental cells PC9 developed obvious resistance to platinum; this suggested that the acquisition of chemo-resistance by brain metastatic cells is attributable to the intrinsic changes in the metastatic cells. Therefore, we performed an integrated profiling of metabolomics and proteomics, and described a radically altered spectrum of BM metabolism and protein expression compared with primary lung cancer cells. We identified a unique metabolite status characterized by high consumption of glutathione (GSH) for antioxidant stress response, both in BM cells and clinical serum samples.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Qi Wang

LAB HEAD: Qi Wang

PROVIDER: PXD019571 | Pride | 2022-02-15

REPOSITORIES: Pride

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Glutathione peroxidase 4-dependent glutathione high-consumption drives acquired platinum chemoresistance in lung cancer-derived brain metastasis.

Liu Wenwen W Zhou Yang Y Duan Wenzhe W Song Jing J Wei Song S Xia Shengkai S Wang Yingyan Y Du Xiaohui X Li Encheng E Ren Caixia C Wang Wei W Zhan Qimin Q Wang Qi Q

Clinical and translational medicine 20210901 9

<h4>Background</h4>Platinum-based chemotherapy is effective in inducing shrinkage of primary lung cancer lesions; however, it shows finite therapeutic efficacy in patients suffering from brain metastasis (BM). The intrinsic changes of BM cells, which contribute to the poor results remain unknown.<h4>Methods</h4>Platinum drug-sensitivity was assessed by utilizing a preclinical BM model of PC9 lung adenocarcinoma cells in vitro and in vivo. High consumption of glutathione (GSH) and two associated ...[more]

PMID: 34586745

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Project description:Background: There is a paucity of non-invasive markers for early detection of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). Secretory proteomic approach based on quantitative tandem mass tag is believed to offer bright prospects for screening potential serum biomarkers for diseases. Methods: We used the secretory proteomics to identify up-regulated proteins in the highly brain metastatic cell line compared to the parental lung cancer cell line. Enzyme linked immunoassay and immunohistochemistry were performed on non-small cell lung cancer patients with brain metastasis and control samples from each cohort to verify the expression levels of candidate proteins. A logistic regression model was used to develop a biomarker panel composed of Cathepsin F (CTSF) and Fibulin-1 (FBLN1), and then an independent validation data set was used for verification. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. Changes in serum CTSF levels of patients were tracked to monitor the effect of treatment, and progression-free survival (PFS) and overall survival (OS) were analyzed to assess their prognostic relevance. Results: CTSF and FBLN1 levels were specifically upregulated in sera and tissues of patients with NSCLC BM. Importantly, the combined diagnostic performance of CTSF and FBLN1 was superior to their individual diagnostic performance (sensitivity and specificity). CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of resistance and progression were detected earlier than the MRI changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS. Moreover, CTSF tissue expression was found to be an independent prognostic factor. Conclusions: CTSF and FBLN1 are potential novel and specific serum markers for early diagnosis of BM in patients with NSCLC. CTSF can also be used as a biomarker for monitoring therapeutic efficacy and prognostic assessment.

Project description:Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45+ cells, T cells and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3+ cells, and to less levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumor of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.

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