28 Stress signalling in breast cancer cells induces matrix components of stem cell niches that promote chemotherapy-resistant metastasis

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IntroductionCancer progression to metastasis remains a major clinical challenge and is commonly associated with resistance to prevailing therapies such as chemotherapy. Exposure to cytotoxic therapies may cause extensive stress responses in cancer cells. The c-Jun N-terminal kinase (JNK) pathway is induced by stress and can be activated by chemotherapy. However, the cellular outcome of JNK signalling in metastatic cancer is still paradoxical and poorly understood.Material and methodsIn our experiments, we utilised 3D culture systems of primary breast cancer cells, transcriptomic screens and xenograft mouse models of metastasis. We validated our findings using annotated clinically derived material, such as pleural effusions, patient-derived gene expression profiles or tissue microarrays.Results and discussionsWe show that high JNK stress signalling in human breast cancer samples predicts poor overall survival and is enriched in dissected nodules of lung metastases compared to patient-matched primary tumours. In experimental models, we show that JNK signalling, which is active in a subpopulation of cancer cells, induces ECM, wound healing and stem cell network that promotes lung metastasis in breast cancer. We find that two ECM proteins of stem cell niches, osteopontin (SPP1) and tenascin C (TNC), play a major role in the JNK-induced network and are direct targets of the c-Jun transcription factor, downstream of JNK signalling. Both SPP1 and TNC act as essential mediators of metastasis to the lungs. Exposure to multiple chemotherapies further exploits this JNK-mediated axis to confer treatment resistance. Importantly, JNK inhibition, or disruption of SPP1 or TNC expression, sensitises experimental mammary tumours and metastases to chemotherapy and may therefore represent a promising new treatment strategy against metastatic breast cancer.ConclusionOur work provides insight into how cancer cells can benefit from chemotherapy-induced stress signals that counteract cytotoxic responses to the therapy. The identification of SPP1 and TNC as mediators of therapy resistance underscores the significance of the ECM as a valuable source of cancer targets. Moreover, our results provide rationale for using JNK inhibition to repress simultaneously the expression of SPP1 and TNC, and thus sensitise metastatic breast cancer to chemotherapy.