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HomeNatureRadiation-induced amphiregulin drives tumour metastasis

Radiation-induced amphiregulin drives tumour metastasis

  • Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Orth, M. et al. Current concepts in clinical radiation oncology. Radiat. Environ. Biophys. 53, 1–29 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lomax, M. E., Folkes, L. K. & O’Neill, P. Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin. Oncol. 25, 578–585 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Lynch, C., Pitroda, S. P. & Weichselbaum, R. R. Radiotherapy, immunity, and immune checkpoint inhibitors. Lancet Oncol. 25, e352–e362 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liang, H. et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 8, 1736 (2017).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiménez-Cortegana, C., Galassi, C., Klapp, V., Gabrilovich, D. I. & Galluzzi, L. Myeloid-derived suppressor cells and radiotherapy. Cancer Immunol. Res. 10, 545–557 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Pitroda, S. P., Chmura, S. J. & Weichselbaum, R. R. Integration of radiotherapy and immunotherapy for treatment of oligometastases. Lancet Oncol. 20, e434–e442 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pointer, K. B., Pitroda, S. P. & Weichselbaum, R. R. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer 8, 9–20 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, L. et al. RNA m6A methylation and MDSCs: roles and therapeutic implications for radiotherapy. Med 4, 863–874 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shoyab, M., Plowman, G., McDonald, V., Bradley, J. G. & Todaro, G. J. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 243, 1074–1076 (1989).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Shoyab, M., McDonald, V. L., Bradley, J. G. & Todaro, G. J. Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Proc. Natl. Acad. Sci. USA 85, 6528–6532 (1988).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zaiss, D. M. W. et al. Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factor receptor. Immunity 38, 275–284 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zaiss, D. M. W., Gause, W. C., Osborne, L. C. & Artis, D. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42, 216–226 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Minutti, C. M. et al. Epidermal growth factor receptor expression licenses type-2 helper T cells to function in a T cell receptor-independent fashion. Immunity 47, 710–722.e6 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Busser, B., Sancey, L., Brambilla, E., Coll, J. L. & Hurbin, A. The multiple roles of amphiregulin in human cancer. Biochim. Biophys. Acta 1816, 119–131 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • Berasain, C. & Avila, M. A. Amphiregulin. Semin. Cell Dev. Biol. 28, 31–41 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shao, J. & Sheng, H. Amphiregulin promotes intestinal epithelial regeneration: roles of intestinal subepithelial myofibroblasts. Endocrinology 151, 3728–3737 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luke, J. J. et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J. Clin. Oncol. 36, 1611–1618 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900.e5 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Georgiades, P. et al. vavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages. Genesis 34, 251–256 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Johnstone, C. N. et al. Functional and molecular characterisation of EO771.LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer. Dis. Model. Mech. 8, 237–251 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McElrath, C. et al. Critical role of interferons in gastrointestinal injury repair. Nat. Commun. 12, 2624 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gilmore, J. L. et al. Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells. Breast Cancer Res. Treat. 110, 493–505 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Miyawaki, M. et al. Enhanced phosphorylation of the epidermal growth factor receptor at the site of tyrosine 992 in esophageal carcinomas. APMIS 116, 1097–1106 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bestvina, C. M. et al. A phase 1 trial of concurrent or sequential ipilimumab, nivolumab, and stereotactic body radiotherapy in patients with stage IV NSCLC study. J. Thorac. Oncol. 17, 130–140 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Van Der Maaten, L. & Hinton, G. Visualizing Data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008).

    MATH 

    Google Scholar
     

  • Swirski, F. K., Hilgendorf, I. & Robbins, C. S. From proliferation to proliferation: monocyte lineage comes full circle. Semin. Immunopathol. 36, 137–148 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, T. et al. Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs. Nat. Immunol. 24, 423–438 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, L. et al. YTHDF2 inhibition potentiates radiotherapy antitumor efficacy. Cancer Cell 41, 1294–1308 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mack, M. et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J. Immunol. 166, 4697–4704 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lecoultre, M., Dutoit, V. & Walker, P. R. Phagocytic function of tumor-associated macrophages as a key determinant of tumor progression control: a review. J. Immunother. Cancer 8, e001408 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Platen, C., Dreschers, S., Reiss, L. K., Wappler, J. & Orlikowsky, T. W. Amphiregulin regulates phagocytosis-induced cell death in monocytes via EGFR and matrix metalloproteinases. Mediators Inflamm. 2018, 4310419 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hsu, Y.-L. et al. Lung tumor-associated dendritic cell-derived amphiregulin increased cancer progression. J. Immunol. 187, 1733–1744 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ebott, J. et al. Enhanced amphiregulin exposure promotes modulation of the high grade serous ovarian cancer tumor immune microenvironment. Front. Pharmacol. 15, 1375421 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lu, J. et al. Reprogramming of TAMs via the STAT3/CD47-SIRPα axis promotes acquired resistance to EGFR-TKIs in lung cancer. Cancer Lett. 564, 216205 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schust, J., Sperl, B., Hollis, A., Mayer, T. U. & Berg, T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 13, 1235–1242 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oldenborg, P. A., Gresham, H. D. & Lindberg, F. P. CD47-signal regulatory protein α (Sirpα) regulates Fcγ and complement receptor-mediated phagocytosis. J. Exp. Med. 193, 855–862 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tsai, R. K. & Discher, D. E. Inhibition of ‘self’ engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J. Cell Biol. 180, 989–1003 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ready, N. et al. Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: Cancer and Leukemia Group B (CALEB) 30106, a CALGB-stratified phase II trial. J. Thorac. Oncol. 5, 1382–1390 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Kelly, K. et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J. Clin. Oncol. 26, 2450–2456 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wrona, A., Dziadziuszko, R. & Jassem, J. Combining radiotherapy with targeted therapies in non-small cell lung cancer: Focus on anti-EGFR, anti-ALK and anti-angiogenic agents. Transl. Lung Cancer Res. 10, 2032–2047 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ishikawa, N. et al. Increases of amphiregulin and transforming growth factor-α in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancers. Cancer Res. 65, 9176–9184 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kaplan, H. S. & Murphy, E. D. The effect of local roentgen irradiation on the biological behavior of a transplantable mouse carcinoma. i. Increased frequency of pulmonary metastasis. J. Natl Cancer Inst. 9, 407–413 (1949).

    CAS 
    PubMed 

    Google Scholar
     

  • Sundahl, N., Duprez, F., Ost, P., De Neve, W. & Mareel, M. Effects of radiation on the metastatic process. Mol. Med. 24, 16 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nishiga, Y. et al. Radiotherapy in combination with CD47 blockade elicits a macrophage-mediated abscopal effect. Nat. Cancer 3, 1351–1366 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lanaya, H. et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat. Cell Biol. 16, 972–981 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, X. et al. EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer. Sci. Adv. 8, eabn7983 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nickerson, N. K., Mill, C. P., Wu, H. J., Riese, D. J. & Foley, J. Autocrine-derived epidermal growth factor receptor ligands contribute to recruitment of tumor-associated macrophage and growth of basal breast cancer cells in vivo. Oncol. Res. 20, 303 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chayangsu, C., Khunsri, S., Sriuranpong, V. & Tanasanvimon, S. The correlations between serum amphiregulin and other clinicopathological factors in colorectal cancer. J. Gastrointest. Oncol. 8, 980–984 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, S. A. et al. Amphiregulin can predict treatment resistance to palliative first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS wild-type metastatic colorectal cancer. Sci. Rep. 11, 23803 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, Q. et al. Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression. Aging Cell 18, e13027 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luke, J. J. et al. Improved survival associated with local tumor response following multisite radiotherapy and pembrolizumab: secondary analysis of a phase I trial. Clin. Cancer Res. 26, 6437–6444 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

  • Arpaia, N. et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, T.-C. & Threadgill, D. W. Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor. Genesis 47, 85–92 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Doki, Y. et al. Mediastinal lymph node metastasis model by orthotopic intrapulmonary implantation of Lewis lung carcinoma cells in mice. Br. J. Cancer 79, 1121–1126 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, L. M. et al. Validation of an orthotopic non-small cell lung cancer mouse model, with left or right tumor growths, to use in conformal radiotherapy studies. PLoS ONE 18, e0284282 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stringer, C., Wang, T., Michaelos, M. & Pachitariu, M. Cellpose: a generalist algorithm for cellular segmentation. Nat. Methods 18, 100–106 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pachitariu, M. & Stringer, C. Cellpose 2.0: how to train your own model. Nat. Methods 19, 1634–1641 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Youden, W. J. Index for rating diagnostic tests. Cancer 3, 32–35 (1950).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Otsu, N. A threshold selection method from gray-level histograms. IEEE Trans. Syst. Man Cybern. 9, 62–66 (1979).

    Article 

    Google Scholar
     

  • Levine, J. H. et al. Data-driven phenotypic dissection of aml reveals progenitor-like cells that correlate with prognosis. Cell 162, 184–197 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Van Gassen, S. et al. FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A 87, 636–645 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Li, B. et al. Cumulus provides cloud-based data analysis for large-scale single-cell and single-nucleus RNA-seq. Nat. Methods 17, 793–798 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Traag, V. A., Waltman, L. & van Eck, N. J. From Louvain to Leiden: guaranteeing well-connected communities. Sci. Rep. 9, 5233 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Street, K. et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics 19, 477 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gillespie, M. et al. The reactome pathway knowledgebase 2022. Nucleic Acids Res. 50, D687–D692 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, Y. & Li, B. A streamlined method for signature score calculation. GitHub https://github.com/lilab-bcb/pegasus/blob/master/signature_score.pdf (2025).

  • Goldman, M. J. et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat. Biotechnol. 38, 675–678 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • ldonle & apiffko. apiffko/IF.mono.quantif: IF.mono.quantif (v.1.0.0). Zenodo https://doi.org/10.5281/zenodo.14982760 (2025).

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