Browsing by Author "Gedik, Mustafa Emre"

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Open Access
Targeting LINC00152 activates cAMP/Ca²⁺/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer
(Nature Publishing Group, 2024-06-15) Saatçi, Özge; Alam, Rashedul; Huynh-Dam, Kim-Tuyen; Işık, Aynur; Üner, Meral; Belder, Nevin; Ersan, Pelin Gülizar; Tokat, Ünal Metin; Ulukan, Bürge; Çetin, Metin; Çalışır, Kübra; Gedik, Mustafa Emre; Bal, Hilal; Şener Şahin, Özlem; Riazalhosseini, Yasser; Thieffry, Denis; Gautheret, Daniel; Ogretmen, Besim; Aksoy, Sercan; Üner, Ayşegül; Akyol, Aytekin; Şahin, Özgür
Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca²⁺ channel. This causes cytosolic Ca²⁺ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe²⁺ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death, which are reversed upon chelating Ca²⁺ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca²⁺/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca²⁺ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.
Open Access
Targeting TACC3 induces immunogenic cell death and enhances T-DM1 Response in HER2-positive breast cancer
(American Association for Cancer Research, 2024-05-02) Gedik, Mustafa Emre; Saatçi, Özge; Oberholtzer, Nathaniel; Üner, Meral; Akbulut Çalışkan, Özge; Çetin, Metin; Aras, Mertkaya; İbiş, Kübra; Çalışkan, Burcu; Banoğlu, Erden; Wiemann, Stefan; Üner, Ayşegül; Aksoy, Sercan; Mehrotra, Shikhar; Şahin, Özgür
Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2 alpha phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8(+) T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance.