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Chemotherapy-induced collagen IV drives cancer cell invasion through activation of Src/FAK signaling

View ORCID ProfileJackson P. Fatherree, View ORCID ProfileJustinne R. Guarin, View ORCID ProfileRachel A. McGinn, View ORCID ProfileStephen P. Naber, View ORCID ProfileMadeleine J. Oudin
doi: https://doi.org/10.1101/2021.04.01.438074
Jackson P. Fatherree
1Department of Biomedical Engineering, Tufts University, Medford, MA, USA
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Justinne R. Guarin
1Department of Biomedical Engineering, Tufts University, Medford, MA, USA
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Rachel A. McGinn
1Department of Biomedical Engineering, Tufts University, Medford, MA, USA
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Stephen P. Naber
2Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA
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Madeleine J. Oudin
1Department of Biomedical Engineering, Tufts University, Medford, MA, USA
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  • For correspondence: madeleine.oudin@tufts.edu
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Abstract

Triple-negative breast cancer (TNBC) is the most aggressive and deadly subtype of breast cancer, accounting for 30,000 cases annually in the US. While there are several clinical trials ongoing to identify new agents to treat TNBC, the majority of TNBC patients are treated with anthracycline- or taxane-based chemotherapies in the neoadjuvant setting, followed by surgical resection and adjuvant chemotherapy. While many patients respond well to this approach, as many as 25% will suffer local or metastatic recurrence within five years. Understanding the mechanisms that drive recurrence after chemotherapy treatment is critical to improving survival for patients with TNBC. It is well-established that the extracellular matrix, which provides structure and support to tissues, is a major driver of tumor growth, local invasion and dissemination of cancer cells to distant metastatic sites. In the present study, we show that decellularized extracellular matrix (dECM) obtained from chemotherapy-treated mice increases invasion of treatment-naïve breast cancer cells compared to vehicle-treated dECM. Using tandem-mass-tag proteomics, we further demonstrate that anthracycline- and taxane-based chemotherapies induce drug-specific changes in tumor ECM composition. We identify the basement membrane protein collagen IV as significantly upregulated in the ECM of chemotherapy-treated mice and patients treated with neoadjuvant chemotherapy. We show that collagen IV drives invasion via Src/FAK signaling and that inhibiting collagen IV-driven signaling decreases invasion in chemotherapy-treated dECM. These studies provide a novel mechanism by which chemotherapy may induce metastasis via effects on ECM composition.

One Sentence Summary Chemotherapy alters the extracellular matrix of breast tumors leading to increased invasion of residual cancer cells.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 02, 2021.
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Chemotherapy-induced collagen IV drives cancer cell invasion through activation of Src/FAK signaling
Jackson P. Fatherree, Justinne R. Guarin, Rachel A. McGinn, Stephen P. Naber, Madeleine J. Oudin
bioRxiv 2021.04.01.438074; doi: https://doi.org/10.1101/2021.04.01.438074
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Chemotherapy-induced collagen IV drives cancer cell invasion through activation of Src/FAK signaling
Jackson P. Fatherree, Justinne R. Guarin, Rachel A. McGinn, Stephen P. Naber, Madeleine J. Oudin
bioRxiv 2021.04.01.438074; doi: https://doi.org/10.1101/2021.04.01.438074

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