Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

George S. Karagiannis, Jessica M. Pastoriza, Yarong Wang, Allison S. Harney, David R. Entenberg, Jeanine Pignatelli, Ved P. Sharma, Emily A. Xue, Esther Cheng, Timothy M. D'Alfonso, Joan G. Jones, Jesus D. Anampa Mesias, Thomas E. Rohan, Joseph A. Sparano, John S. Condeelis, Maja H. Oktay

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Abstract

Breast cancer cells disseminate through TIE2/MENACalc/MENAINV-dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEMscore and itsmechanistically connected MENAINV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.

Original languageEnglish (US)
Article numberaan0026
JournalScience Translational Medicine
Volume9
Issue number397
DOIs
StatePublished - Jul 5 2017

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Tumor Microenvironment
Breast Neoplasms
Neoplasm Metastasis
Drug Therapy
Protein Isoforms
Gene Knockdown Techniques
Neoplasms
Residual Neoplasm
Paclitaxel
Heterografts
Doxorubicin
Cyclophosphamide

ASJC Scopus subject areas

  • Medicine(all)

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Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. / Karagiannis, George S.; Pastoriza, Jessica M.; Wang, Yarong; Harney, Allison S.; Entenberg, David R.; Pignatelli, Jeanine; Sharma, Ved P.; Xue, Emily A.; Cheng, Esther; D'Alfonso, Timothy M.; Jones, Joan G.; Anampa Mesias, Jesus D.; Rohan, Thomas E.; Sparano, Joseph A.; Condeelis, John S.; Oktay, Maja H.

In: Science Translational Medicine, Vol. 9, No. 397, aan0026, 05.07.2017.

Research output: Contribution to journalArticle

Karagiannis, George S. ; Pastoriza, Jessica M. ; Wang, Yarong ; Harney, Allison S. ; Entenberg, David R. ; Pignatelli, Jeanine ; Sharma, Ved P. ; Xue, Emily A. ; Cheng, Esther ; D'Alfonso, Timothy M. ; Jones, Joan G. ; Anampa Mesias, Jesus D. ; Rohan, Thomas E. ; Sparano, Joseph A. ; Condeelis, John S. ; Oktay, Maja H. / Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. In: Science Translational Medicine. 2017 ; Vol. 9, No. 397.
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