Analyse der metastatischen Nische während Brustkrebs-Progression: Charakterisierung der Rolle Osteopontins bei Metastasierung und Therapie-Resistenz
Zellbiologie
Zusammenfassung der Projektergebnisse
Metastasis is the dissemination and outgrowth of cancer cells in secondary organs that has been recognized as the primary cause of cancer related deaths. Although intrinsic properties of cancer cells are crucial determinants of metastatic ability, growing evidence suggests that the microenvironment also plays a key role in the process. In secondary organs, disseminated cancer cells often face unfavorable conditions. However, cancer cells that are able to survive and grow under these challenging circumstances often manage to reprogram the microenvironment, generating a metastatic niche that supports malignant growth. Interactions between metastatic cancer cells and numerous cells of the microenvironment can be a determining factor in the development of metastases. Moreover, importance of the extracellular matrix (ECM) in cancer progression and metastasis is becoming increasingly evident. In this regard, a structurally diverse group of ECM associated glycoproteins called matricellular proteins are of high interest. In advanced breast cancer, many proteins of the matricellular family are highly expressed. These ECM glycoproteins serve as important cell regulators and modulators of signaling pathways, rather than to contribute to the matrix structure, and several are functionally important components of the metastatic niche. In this study, we analyzed the regulation and function of the matricellular protein osteopontin (SPP1) in metastasis and therapy resistance. We showed that SPP1 expression is regulated by JNK signaling in breast cancer cells and is associated with poor clinical outcome in breast cancer patients. Chromatin-IP analysis in breast cancer cells showed that SPP1 is a direct target of the JNK-induced transcription factor c-Jun. Notably, the expression of SPP1 and activation of JNK signaling were associated with stem cell properties in oncospheres derived from breast cancer cells. Indeed, the induction of SPP1 in oncospheres was dependent on JNK activity. In mouse models of spontaneous metastasis, SPP1 deficiency significantly repressed initiation and growth of metastatic lesions in the lungs. This suggests that JNK signaling promotes expression of SPP1 as a metastatic niche component during colonization of a secondary organ. Metastatic progression is frequently associated with resistance to therapeutic intervention. Since most cancer patients presenting with metastasis receive chemotherapy at some point in their treatment, we wanted to address whether the JNK-SPP1 axis, that we showed to be an important regulator in metastasis, also plays a role in chemotherapy resistance. Breast cancer cells treated with chemotherapy, such as paclitaxel or doxorubicin activate JNK signaling and upregulate SPP1 in a JNK-dependent manner. Inhibition of JNK or downregulation of SPP1 significantly sensitized primary tumors and metastases to chemotherapeutics in mice. This suggests that, in parallel to cytotoxic effects, chemotherapy induces JNK stress signaling leading to upregulation of niche components such as SPP1 and thus limiting therapeutic efficacy. The interactions between cancer cells and the tumor microenvironment are recognized to play a critical role during cancer progression and can confer resistance to cancer therapies. This study provides insights into the induction and functional role of metastatic niches in response to therapeutic intervention. The results show that repression of an ECM component within the niche can sensitize primary tumors and metastases to chemotherapy. The findings place a focus on the ECM as a potentially attractive source of targets for cancer therapy.
Projektbezogene Publikationen (Auswahl)
- (2017) Stress signaling induces osteopontin and tenascin C in breast cancer cells to promote therapy-resistant metastasis, Clinical & Experimental Metastasis, Vol. 34, Issue 8 Pages 503-504
Jacob Insua-Rodriguez, Maren Pein, Tsunaki Hongu, Jasmin Meier, Arnaud Descot, Camille M Lowy, Etienne De Braekeleer, Hans-Peter Sinn, Saskia Spaich, Marc Suetterlin, Andreas Schneeweiss, Thordur Oskarsson
(Siehe online unter https://doi.org/10.1007/s10585-018-9885-y) - (2018) 28 Stress signalling in breast cancer cells induces matrix components of stem cell niches that promote chemotherapy-resistant metastasis. ESMO Open, Vol. 3, Pages A13
J Insua-Rodríguez, M Pein, T Hongu, J Meier, HP Sinn, S Spaich, M Sütterlin, A Schneeweiss, T Oskarsson
(Siehe online unter https://doi.org/10.1136/esmoopen-2018-EACR25.28) - (2018) Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis. EMBO Mol Med. Oct; 20: e9003
Insua-Rodriguez J, Pein M, Hongu T, Meier J, Descot A, Lowy CM, De Braekeleer E, Sinn HP, Spaich S, Sütterlin M, Schneeweiss A and Oskarsson T
(Siehe online unter https://doi.org/10.15252/emmm.201809003) - (2020) Stress-induced metastatic niches in breast cancer. Molecular & Cellular Oncology. 7(5): 1780105
Oskarsson T
(Siehe online unter https://doi.org/10.1080/23723556.2020.1780105)
