Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis
Abstract Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c‐J...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809003 |
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| author | Jacob Insua‐Rodríguez Maren Pein Tsunaki Hongu Jasmin Meier Arnaud Descot Camille M Lowy Etienne De Braekeleer Hans‐Peter Sinn Saskia Spaich Marc Sütterlin Andreas Schneeweiss Thordur Oskarsson |
| author_facet | Jacob Insua‐Rodríguez Maren Pein Tsunaki Hongu Jasmin Meier Arnaud Descot Camille M Lowy Etienne De Braekeleer Hans‐Peter Sinn Saskia Spaich Marc Sütterlin Andreas Schneeweiss Thordur Oskarsson |
| author_sort | Jacob Insua‐Rodríguez |
| collection | DOAJ |
| description | Abstract Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c‐Jun N‐terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c‐Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK‐mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer. |
| format | Article |
| id | doaj-art-b247d332148a419e955b465ec8e5f91c |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b247d332148a419e955b465ec8e5f91c2025-08-20T03:43:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-09-01101012110.15252/emmm.201809003Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasisJacob Insua‐Rodríguez0Maren Pein1Tsunaki Hongu2Jasmin Meier3Arnaud Descot4Camille M Lowy5Etienne De Braekeleer6Hans‐Peter Sinn7Saskia Spaich8Marc Sütterlin9Andreas Schneeweiss10Thordur Oskarsson11Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Institute of Pathology, University of HeidelbergDepartment of Obstetrics and Gynecology, University Medical Centre Mannheim, Heidelberg UniversityDepartment of Obstetrics and Gynecology, University Medical Centre Mannheim, Heidelberg UniversityNational Center for Tumor Diseases—NCTHeidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)Abstract Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c‐Jun N‐terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c‐Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK‐mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.https://doi.org/10.15252/emmm.201809003breast cancer metastasischemotherapy resistanceextracellular matrixstem cell nichestress |
| spellingShingle | Jacob Insua‐Rodríguez Maren Pein Tsunaki Hongu Jasmin Meier Arnaud Descot Camille M Lowy Etienne De Braekeleer Hans‐Peter Sinn Saskia Spaich Marc Sütterlin Andreas Schneeweiss Thordur Oskarsson Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis EMBO Molecular Medicine breast cancer metastasis chemotherapy resistance extracellular matrix stem cell niche stress |
| title | Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis |
| title_full | Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis |
| title_fullStr | Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis |
| title_full_unstemmed | Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis |
| title_short | Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis |
| title_sort | stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis |
| topic | breast cancer metastasis chemotherapy resistance extracellular matrix stem cell niche stress |
| url | https://doi.org/10.15252/emmm.201809003 |
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