Molecular mechanisms of cancer resistance against anti-angiogenic therapy
Zusammenfassung der Projektergebnisse
Our project addressed several important aspects of the mechanisms related to the development of tumor resistance against anti-angiogenic therapy, as well as other therapies, e.g. against EGFR inhibitors. We could demonstrate in several different tumor models that angiogenesis inhibitors elicit enhanced invasion and metastasis. These processes are linked to the hypoxia and HIF activation, induced by the suppression of blood vessel growth and the concomitant reduction in oxygen supply. One key HIF downstream target that is involved in anti-angiogenesis/hypoxia-induced invasion is ZEB2, a central transcriptional regulator of the process of epithelial-mesenchymal transition (EMT). Our project uncovered novel ZEB2 targets with key roles in tumor growth, invasion and therapy resistance. We found that hypoxia-induced ZEB2 can repress the expression of the cell guidance molecule ephrinB2, which in turn controls glioma cell invasion. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Thus, the ZEB2-ephrinB2 axis represents an attractive therapeutic target to inhibit tumor invasion and counteract tumor resistance mechanisms induced by anti-angiogenic treatment. A second factor that is prominently regulated by hypoxia and ZEB2 is the oxygen sensor PHD3. Our work revealed that PHD3 is a tumor suppressor, whose loss plays an important role in tumor growth, metastasis and therapy resistance in different tumor types. PHD3 silencing in human gliomas or genetic deletion in a mouse tumor models markedly promotes the ability of tumors to continue growing under unfavorable conditions. The growth inhibitory function of PHD3 was dependent on EGFR, with PHD3 loss leading to EGFR activation through inhibition of EGFR internalization and its retention at the plasma membrane, enabling prolonged EGFR signaling. Interestingly, (epi)genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification, indicating that PHD3 inactivation provides an alternative route of EGFR activation, through which tumor cells sustain proliferative signaling even under conditions of limited oxygen availability. We further found that PHD3 is potently repressed by microenvironmental cues that induce EMT and acts as a negative regulator of EMT, metastasis and therapeutic resistance in lung cancer. PHD3 depletion can be elicited by EMT inducers such as TGFβ or by promoter methylation in tumors, and it enhances EMT and spontaneous metastasis via HIF- dependent upregulation of the EGFR ligand TGFα. TGFα, in turn, stimulates EGFR, which potentiates SMAD signaling to promote EMT and metastasis. Furthermore, reduced PHD3 expression is linked to poor prognosis in lung cancer patients and to therapeutic resistance against EGFR inhibitors, such as erlotinib. Importantly, PHD3 re-expression suppresses EMT and metastasis, and restores erlotinib sensitivity. These findings uncover a key novel function of PHD3 in metastasis and drug resistance and suggest opportunities for improved patient treatment by interfering with the signaling mechanisms activated upon PHD3 silencing.
Projektbezogene Publikationen (Auswahl)
- The cancer stem cell niche(s): the crosstalk between glioma stem cells and their microenvironment. Biochim Biophys Acta. 2013;1830(2):2496-508
Filatova A, Acker T, Garvalov BK
(Siehe online unter https://doi.org/10.1016/j.bbagen.2012.10.008) - Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR. Nature Commun.2014;5:5582
Henze AT, Garvalov BK, Seidel S, Cuesta AM, Ritter M, Filatova A, Foss F, Dopeso H, Essmann CL, Maxwell PH, Reifenberger G, Carmeliet P, Acker-Palmer A, Acker T
(Siehe online unter https://doi.org/10.1038/ncomms6582) - PHD3 regulates EGFR internalization and signalling in tumours. Nature Commun. 2014; 5:5577
Garvalov BK, Foss F, Henze AT, Bethani I, Gräf-Höchst S, Singh D, Filatova A, Dopeso H, Seidel S, Damm M, Acker-Palmer A, Acker T
(Siehe online unter https://doi.org/10.1038/ncomms6577) - Isolation and culture of primary glioblastoma cells from human tumor specimens. Methods Mol Biol. 2015;1235:263-75
Seidel S, Garvalov BK, Acker T
(Siehe online unter https://doi.org/10.1007/978-1-4939-1785-3_19) - Acidosis Acts through HSP90 in a PHD/VHL-Independent Manner to Promote HIF Function and Stem Cell Maintenance in Glioma. Cancer Res. 2016; 76(19):5845-5856
Filatova A, Seidel S, Böğürcü N, Gräf S, Garvalov BK, Acker T
(Siehe online unter https://doi.org/10.1158/0008-5472.can-15-2630) - EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nature Commun. 2016;7:12329
Depner C, Zum Buttel H, Böğürcü N, Cuesta AM, Aburto MR, Seidel S, Finkelmeier F, Foss F, Hofmann J, Kaulich K, Barbus S, Segarra M, Reifenberger G, Garvalov BK, Acker T, Acker-Palmer A
(Siehe online unter https://doi.org/10.1038/ncomms12329) - Implications of Oxygen Homeostasis for Tumor Biology and Treatment. Adv Exp Med Biol. 2016; 903:169-85
Garvalov BK, Acker T
(Siehe online unter https://doi.org/10.1007/978-1-4899-7678-9_12)
