Researcher: Özcan, Selahattin Can
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Özcan, Selahattin Can
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Publication Metadata only Prolonged overexpression of PLK4 leads to formation of centriole rosette clusters that are connected via canonical centrosome linker proteins(Nature Portfolio, 2024) Özcan, Selahattin Can; Kalkan, Batuhan Mert; Çiçek, Enes; Canbaz, Ata Alpay; Ayhan, Ceyda Açılan; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of MedicineCentrosome amplification is a hallmark of cancer and PLK4 is one of the responsible factors for cancer associated centrosome amplification. Increased PLK4 levels was also shown to contribute to generation of cells with centriole amplification in mammalian tissues as olfactory neuron progenitor cells. PLK4 overexpression generates centriole rosette (CR) structures which harbor more than two centrioles each. Long term PLK4 overexpression results with centrosome amplification, but the maturation of amplified centrioles in CRs and linking of PLK4 induced amplified centrosomes has not yet been investigated in detail. Here, we show evidence for generation of large clustered centrosomes which have more than 2 centriole rosettes and define these structures as centriole rosette clusters (CRCs) in cells that have high PLK4 levels for 2 consecutive cell cycles. In addition, we show that PLK4 induced CRs follow normal centrosomal maturation processes and generate CRC structures that are inter-connected with canonical centrosomal linker proteins as C-Nap1, Rootletin and Cep68 in the second cell cycle after PLK4 induction. Increased PLK4 levels in cells with C-Nap1 and Rootletin knock-out resulted with distanced CRs and CRCs in interphase, while Nek2 knock-out inhibited separation of CRCs in prometaphase, providing functional evidence for the binding of CRC structures with centrosomal linker proteins. Taken together, these results suggest a cell cycle dependent model for PLK4 induced centrosome amplification which occurs in 2 consecutive cell cycles: (i) CR state in the first cell cycle, and (ii) CRC state in the second cell cycle.Publication Metadata only Nek2A prevents centrosome clustering and induces cell death in cancer cells via KIF2C interaction(Springernature, 2024) Department of Industrial Engineering; Department of Industrial Engineering; Kalkan, Batuhan Mert; Özcan, Selahattin Can; Çiçek, Enes; Gönen, Mehmet; Ayhan, Ceyda Açılan; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; College of Engineering; School of MedicineUnlike normal cells, cancer cells frequently exhibit supernumerary centrosomes, leading to formation of multipolar spindles that can trigger cell death. Nevertheless, cancer cells with supernumerary centrosomes escape the deadly consequences of unequal segregation of genomic material by coalescing their centrosomes into two poles. This unique trait of cancer cells presents a promising target for cancer therapy, focusing on selectively attacking cells with supernumerary centrosomes. Nek2A is a kinase involved in mitotic regulation, including the centrosome cycle, where it phosphorylates linker proteins to separate centrosomes. In this study, we investigated if Nek2A also prevents clustering of supernumerary centrosomes, akin to its separation function. Reduction of Nek2A activity, achieved through knockout, silencing, or inhibition, promotes centrosome clustering, whereas its overexpression results in inhibition of clustering. Significantly, prevention of centrosome clustering induces cell death, but only in cancer cells with supernumerary centrosomes, both in vitro and in vivo. Notably, none of the known centrosomal (e.g., CNAP1, Rootletin, Gas2L1) or non-centrosomal (e.g., TRF1, HEC1) Nek2A targets were implicated in this machinery. Additionally, Nek2A operated via a pathway distinct from other proteins involved in centrosome clustering mechanisms, like HSET and NuMA. Through TurboID proximity labeling analysis, we identified novel proteins associated with the centrosome or microtubules, expanding the known interaction partners of Nek2A. KIF2C, in particular, emerged as a novel interactor, confirmed through coimmunoprecipitation and localization analysis. The silencing of KIF2C diminished the impact of Nek2A on centrosome clustering and rescued cell viability. Additionally, elevated Nek2A levels were indicative of better patient outcomes, specifically in those predicted to have excess centrosomes. Therefore, while Nek2A is a proposed target, its use must be specifically adapted to the broader cellular context, especially considering centrosome amplification. Discovering partners such as KIF2C offers fresh insights into cancer biology and new possibilities for targeted treatment.Publication Metadata only Unclustering centrosomes and induction of multipolarity: selective killing method to cancer cells(Elsevier Sci Ltd, 2022) N/A; N/A; Kalkan, Batuhan Mert; Özcan, Selahattin Can; Çiçek, Enes; Ayhan, Ceyda Açılan; PhD Student; Researcher; Master Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; N/A; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; 219658N/APublication Metadata only Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells(Academic Press Inc Elsevier Science, 2021) Mutlu, Aydan; Altunok, Tugba H.; Gurpinar, Yunus; Sarioglu, Aybike; Guler, Sabire; Muchut, Robertino J.; Iglesias, Alberto A.; Celikler, Serap; Campbell, Paul M.; Yalçın, Abdullah; N/A; Özcan, Selahattin Can; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/AActivating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAStransformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.Publication Metadata only PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells(Springer, 2020) Sarioglu, Aybike; Altunok, Tugba H.; Akkoc, Ahmet; Guzel, Saime; Guler, Sabire; Imbert-Fernandez, Yoannis; Muchut, Robertino J.; Iglesias, Alberto A.; Gurpinar, Yunus; Clem, Amy L.; Chesney, Jason A.; Yalçın, Abdullah; N/A; Özcan, Selahattin Can; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/ATumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.Publication Metadata only A deep learning model for automated segmentation of fluorescence cell images(IOP Publishing Ltd, 2022) Aydın, Musa; Kiraz, Berna; Eren, Furkan; N/A; Department of Physics; N/A; N/A; N/A; Department of Physics; Ayhan, Ceyda Açılan; Kiraz, Alper; Uysallı, Yiğit; Morova, Berna; Özcan, Selahattin Can; Faculty Member; Faculty Member; PhD Student; Researcher; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; College of Sciences; Graduate School of Sciences and Engineering; N/A; N/A; 219658; 22542; N/A; N/A; N/ADeep learning techniques bring together key advantages in biomedical image segmentation. They speed up the process, increase the reproducibility, and reduce the workload in segmentation and classifcation. Deep learning techniques can be used for analysing cell concentration, cell viability, as well as the size and form of each cell. In this study, we develop a deep learning model for automated segmentation of fuorescence cell images, and apply it to fuorescence images recorded with a home-built epi-fuorescence microscope. A deep neural network model based on U-Net architecture was built using a publicly available dataset of cell nuclei images [1]. A model accuracy of 97.3% was reached at the end of model training. Fluorescence cell images acquired with our home-built microscope were then segmented using the developed model. 141 of 151 cells in 5 images were successfully segmented, revealing a segmentation success rate of 93.4%. This deep learning model can be extended to the analysis of diferent cell types and cell viability. © 2021 Published under licence by IOP Publishing Ltd.Publication Open Access Keep calm and carry on with extra centrosomes(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Quintyne, Nicholas J.; Reed, Samantha L.; Ayhan, Ceyda Açılan; Kalkan, Batuhan Mert; Özcan, Selahattin Can; Faculty Member; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; 219658; N/A; N/APrecise chromosome segregation during mitosis is a vital event orchestrated by formation of bipolar spindle poles. Supernumerary centrosomes, caused by centrosome amplification, deteriorates mitotic processes, resulting in segregation defects leading to chromosomal instability (CIN). Centrosome amplification is frequently observed in various types of cancer and considered as a significant contributor to destabilization of chromosomes. This review provides a comprehensive overview of causes and consequences of centrosome amplification thoroughly describing molecular mechanisms. Abstract: Aberrations in the centrosome number and structure can readily be detected at all stages of tumor progression and are considered hallmarks of cancer. Centrosome anomalies are closely linked to chromosome instability and, therefore, are proposed to be one of the driving events of tumor formation and progression. This concept, first posited by Boveri over 100 years ago, has been an area of interest to cancer researchers. We have now begun to understand the processes by which these numerical and structural anomalies may lead to cancer, and vice-versa: how key events that occur during carcinogenesis could lead to amplification of centrosomes. Despite the proliferative advantages that having extra centrosomes may confer, their presence can also lead to loss of essential genetic material as a result of segregational errors and cancer cells must deal with these deadly consequences. Here, we review recent advances in the current literature describing the mechanisms by which cancer cells amplify their centrosomes and the methods they employ to tolerate the presence of these anomalies, focusing particularly on centrosomal clustering.