Alterations in Wnt- and/or STAT3 signaling pathways and the immune microenvironment during metastatic progression

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  • A Correction to this article was published on 26 September 2019

Abstract

Metastatic breast cancer is an extremely complex disease with limited treatment options due to the lack of information about the major characteristics of metastatic disease. There is an urgent need, therefore, to understand the changes in cellular complexity and dynamics that occur during metastatic progression. In the current study, we analyzed the cellular and molecular differences between primary tumors and paired lung metastases using a syngeneic p53-null mammary tumor model of basal-like breast cancer. Distinct subpopulations driven by the Wnt- and/or STAT3 signaling pathways were detected in vivo using a lentiviral Wnt- and STAT3 signaling reporter system. A significant increase in the overlapping populations driven by both the Wnt- and STAT3 signaling pathways was observed in the lung metastases as compared to the primary tumors. Furthermore, the overlapping populations showed a higher metastatic potential relative to the other populations and pharmacological inhibition of both signaling pathways was shown to markedly reduce the metastatic lesions in established lung metastases. An analysis of the unique molecular features of the lung metastases revealed a significant association with immune response signatures. Specifically, Foxp3 gene expression was markedly increased and elevated levels of Foxp3 + Treg cells were detected in close proximity to lung metastases. Collectively, these studies illustrate the importance of analyzing intratumoral heterogeneity, changes in population dynamics, and the immune microenvironment during metastatic progression.

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  • 26 September 2019

    The original version of this Article incorrectly matched the supplementary files with their titles. This has been corrected. The following information has also been added to the Methods section.

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Acknowledgements

This work was supported by NIH RO1 CA148761 (to JMR and CMP) and by the Susan G. Komen to SGR (PDF17479425). We would like to thank to Dr. Michael T. Lewis for generously providing us with the STAT3-GFP and EFS-GFP reporters. This project was conducted with technical support from the Cytometry and Cell Sorting Core (NIH CA125123 and RR024574) and the expert assistance of Joel M. Sederstrom, the Integrated Microscopy core (NCI CA125123, NIDDK56338, CPRIT RP150578 and John S. Dunn Gulf Coast Consortium for Chemical Genomics), the Lester and Sue Smith Breast Center Pathology Core, and Human Genome Sequencing Center at Baylor College of Medicine. We thank Yiqun Zhang for technical assistance with the gene expression analyses. We would also like to thank to the IHC laboratory at University of Texas MD Anderson Cancer Center for scanning of IHC images. We specially thank Drs. Michael T. Lewis and Kevin P. Roarty for critically reading and editing the manuscript.

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Correspondence to J. M. Rosen.

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CMP is an equity stock holder, consultant, and Board of Director Member, of BioClassifier LLC and GeneCentric Diagnostics. CMP is also listed an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. The other authors declare that they have no conflict of interest.

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Kim, S.J., Garcia-Recio, S., Creighton, C.J. et al. Alterations in Wnt- and/or STAT3 signaling pathways and the immune microenvironment during metastatic progression. Oncogene 38, 5942–5958 (2019) doi:10.1038/s41388-019-0852-0

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