Radiation-induced amphiregulin drives tumour metastasis

András Piffkó^#^{1

2

3}, Kaiting Yang^#^{1

2

4}, Arpit Panda^#^{5

6}, Janna Heide⁷, Krystyna Tesak^{1

2

5}, Chuangyu Wen^{1

2}, Katarzyna Zawieracz⁸, Liangliang Wang^{1

2

9}, Emile Z Naccasha^{1

2}, Jason Bugno^{1

2

10}, Yanbin Fu^{1

2

11}, Dapeng Chen^{1

2}, Leonhard Donle⁷, Ernst Lengyel⁷, Douglas G Tilley¹², Matthias Mack¹³, Ronald S Rock⁵, Steven J Chmura^{1

2}, Everett E Vokes¹⁴, Chuan He^{5

6}, Sean P Pitroda^#^{1

2}, Hua Laura Liang^#^{1

2}, Ralph R Weichselbaum^#^{15

16}

Affiliations

¹ Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.
² The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
³ Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴ School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, P. R. China.
⁵ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
⁶ Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
⁷ Department of Obstetrics and Gynecology/Section Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
⁸ Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
⁹ The Laboratory of Microbiome and Microecological Technology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P. R. China.
¹⁰ Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA.
¹¹ Drukier Institute for Children's Health, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
¹² Department of Cardiovascular Sciences, Temple University, Philadelphia, PA, USA.
¹³ Department of Internal Medicine, University of Regensburg, Regensburg, Germany.
¹⁴ Department of Medicine, University of Chicago, Chicago, IL, USA.
¹⁵ Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. ralph.weichselbaum@uchospitals.edu.
¹⁶ The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA. ralph.weichselbaum@uchospitals.edu.

^# Contributed equally.

PMID: 40369065
DOI: 10.1038/s41586-025-08994-0

Radiation-induced amphiregulin drives tumour metastasis

András Piffkó et al. Nature. 2025 Jul.

. 2025 Jul;643(8072):810-819.

doi: 10.1038/s41586-025-08994-0. Epub 2025 May 14.

Authors

Affiliations

¹ Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.
² The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
³ Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴ School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, P. R. China.
⁵ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
⁶ Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
⁷ Department of Obstetrics and Gynecology/Section Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
⁸ Department of Pathology, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
⁹ The Laboratory of Microbiome and Microecological Technology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P. R. China.
¹⁰ Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA.
¹¹ Drukier Institute for Children's Health, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
¹² Department of Cardiovascular Sciences, Temple University, Philadelphia, PA, USA.
¹³ Department of Internal Medicine, University of Regensburg, Regensburg, Germany.
¹⁴ Department of Medicine, University of Chicago, Chicago, IL, USA.
¹⁵ Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA. ralph.weichselbaum@uchospitals.edu.
¹⁶ The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA. ralph.weichselbaum@uchospitals.edu.

^# Contributed equally.

PMID: 40369065
DOI: 10.1038/s41586-025-08994-0

Erratum in

Publisher Correction: Radiation-induced amphiregulin drives tumour metastasis.
Piffkó A, Yang K, Panda A, Heide J, Tesak K, Wen C, Zawieracz K, Wang L, Naccasha EZ, Bugno J, Fu Y, Chen D, Donle L, Lengyel E, Tilley DG, Mack M, Rock RS, Chmura SJ, Vokes EE, He C, Pitroda SP, Liang HL, Weichselbaum RR. Piffkó A, et al. Nature. 2025 Nov 10. doi: 10.1038/s41586-025-09862-7. Online ahead of print. Nature. 2025. PMID: 41214352 No abstract available.

Abstract

The anti-tumour effect of radiotherapy beyond the treatment field-the abscopal effect-has garnered much interest¹. However, the potentially deleterious effect of radiation in promoting metastasis is less well studied. Here we show that radiotherapy induces the expression of the EGFR ligand amphiregulin in tumour cells, which reprogrammes EGFR-expressing myeloid cells toward an immunosuppressive phenotype and reduces phagocytosis. This stimulates distant metastasis growth in human patients and in pre-clinical mouse tumour models. The inhibition of these tumour-promoting factors induced by radiotherapy may represent a novel therapeutic strategy to improve patient outcomes.

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Conflict of interest statement

Competing interests: R.R.W. has stock and other ownership interests with Boost Therapeutics, Immvira, Reflexion Pharmaceuticals, Coordination Pharmaceuticals, Magi Therapeutics and Oncosenescence. He has served in a consulting or advisory role for Aettis, Astrazeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano proteagen, NKMax America and Shuttle Pharmaceuticals. He has a patent pending entitled ‘Methods and Kits for Diagnosis and Triage of Patients with Colorectal Liver Metastases’ (PCT/US2019/028071). He has received research grant funding from Varian and Regeneron. He has received compensation including travel, accommodations, or expense reimbursement from Astrazeneca, Boehringer Ingelheim and Merck Serono S.A. C.H. has stock and other ownership interests with Accent Therapeutics and Aferna Green. C.H. is a scientific advisory board member of Aferna Green and Rona Therapeutics. A. Piffkó has consulted for Related Sciences/Danger Bio and owns equity in Danger Bio. E.L. receives research funding to study the biology of ovarian cancer from AbbVie through The University of Chicago that is unrelated to this work. A patent application has been submitted by A. Piffkó, H.L.L., S.P.P. and R.R.W and is pending at the date of publication. The other authors declare no competing interests.

References

1. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017). - PubMed - DOI
1. Orth, M. et al. Current concepts in clinical radiation oncology. Radiat. Environ. Biophys. 53, 1–29 (2014). - PubMed - DOI
1. 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). - DOI
1. Lynch, C., Pitroda, S. P. & Weichselbaum, R. R. Radiotherapy, immunity, and immune checkpoint inhibitors. Lancet Oncol. 25, e352–e362 (2024). - PubMed - DOI
1. Liang, H. et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 8, 1736 (2017). - PubMed - PMC - DOI

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Radiation-induced amphiregulin drives tumour metastasis

Affiliations

Radiation-induced amphiregulin drives tumour metastasis

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous