A glucocorticoid–FAS axis controls immune evasion during metastatic seeding - Nature

The raw data corresponding to bulk RNA-seq datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) repository under accession numbers GSE313249 (tdTomato+ 4T1 tumour cells from NSG versus BALB/c mice across disease stages) and GSE313241 (GFP+ 4T1 DTCs from Jedi versus NSG mice). scRNA-seq raw data have been deposited in the GEO under accession numbers GSE313245 (GFP+ versus Thy1.1+ 4T1 DTCs after Jedi adoptive transfer) and GSE313243 (tdTomato-cTAT-zsGreen niche labelling of shGR versus shControl 4T1 DTCs). CUT&RUN raw data have been deposited in the GEO under accession number GSE313250. Clinical trial data from TBCRC-030 are available on reasonable request. Any additional data reported in this study are available on request. All other datasets reanalysed in this study are publicly available70 (AURORA US, https://cbioportal.org; TCGA, https://xenabrowser.net/ and http://gepia2.cancer-pku.cn/; meta-analysis of patients with TNBC, https://kmplot.com/analysis; Tabula Muris, https://tabula-muris.sf.czbiohub.org/). Source data are provided with this paper.

No custom code was used in the generation of the data in this study. Data analysis using public software packages is described in the Methods.

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Article ADS CAS PubMed PubMed Central Google Scholar

Hosseini, H. et al. Early dissemination seeds metastasis in breast cancer. Nature 540, 552–558 (2016).

Hüsemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).

Goddard, E. T. et al. Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies. Cancer Cell 42, 119–134 (2024).

Michaels, E., Chen, N. & Nanda, R. The role of immunotherapy in triple-negative breast cancer (TNBC). Clin. Breast Cancer 24, 263–270 (2024).

Kroemer, G., Senovilla, L., Galluzzi, L., Andre, F. & Zitvogel, L. Natural and therapy-induced immunosurveillance in breast cancer. Nat. Med. 21, 1128–1138 (2015).

Baldominos, P. et al. Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell 185, 1694–1708 (2022).

Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

Article ADS CAS PubMed Google Scholar

Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).

Baumann, Z., Auf der Maur, P. & Bentires-Alj, M. Feed-forward loops between metastatic cancer cells and their microenvironment-the stage of escalation. EMBO Mol. Med. 14, e14283 (2022).

Massague, J. & Ganesh, K. Metastasis-initiating cells and ecosystems. Cancer Discov. 11, 971–994 (2021).

Hu, J. et al. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature 616, 806–813 (2023).

Agudo, J. et al. GFP-specific CD8 T cells enable targeted cell depletion and visualization of T-cell interactions. Nat. Biotechnol. 33, 1287–1292 (2015).

Falcinelli, M. et al. The role of psychologic stress in cancer initiation: clinical relevance and potential molecular mechanisms. Cancer Res. 81, 5131–5140 (2021).

Abduljabbar, R. et al. Clinical and biological significance of glucocorticoid receptor (GR) expression in breast cancer. Breast Cancer Res. Treat. 150, 335–346 (2015).

Chen, Z. et al. Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer. Nat. Commun. 6, 8323 (2015).

Article ADS PubMed PubMed Central Google Scholar

Pan, D., Kocherginsky, M. & Conzen, S. D. Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res. 71, 6360–6370 (2011).

West, D. C. et al. Discovery of a glucocorticoid receptor (GR) activity signature using selective GR antagonism in ER-negative breast cancer. Clin. Cancer Res. 24, 3433–3446 (2018).

Obradovic, M. M. S. et al. Glucocorticoids promote breast cancer metastasis. Nature 567, 540–544 (2019).

Flaherty, R. L. et al. Stress hormone-mediated acceleration of breast cancer metastasis is halted by inhibition of nitric oxide synthase. Cancer Lett. 459, 59–71 (2019).

Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418 (2017).

Pommier, A. et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science 360, eaao4908 (2018).

Qin, Q. et al. Lisa: inferring transcriptional regulators through integrative modeling of public chromatin accessibility and ChIP-seq data. Genome Biol. 21, 32 (2020).

Garcia-Recio, S. et al. Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis. Nat. Cancer 4, 128–147 (2023).

Mayer, E. L. et al. TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker. Ann. Oncol. 31, 1518–1525 (2020).

Parsons, H. A. et al. Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030. Ann. Oncol. 34, 899–906 (2023).

Ombrato, L. et al. Metastatic-niche labelling reveals parenchymal cells with stem features. Nature 572, 603–608 (2019).

Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).

Gerber, A. N., Newton, R. & Sasse, S. K. Repression of transcription by the glucocorticoid receptor: a parsimonious model for the genomics era. J. Biol. Chem. 296, 100687 (2021).

Hudson, W. H. et al. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements. Nat. Commun. 9, 1337 (2018).