Senturk Lab. on Functional Cancer Genomics

OVERVIEW

Molecular carcinogenesis studies aim to dissect the molecular aspects of cancer initiation and progression and use this information to develop more effective treatments and prevention strategies. Today, molecular mechanisms associated with different cancers are partly being deciphered by functional genomics strategies, leading to translational research-supported novel discoveries of potential therapeutic stratifications designed to counteract or actually reverse such mechanisms. As a molecular carcinogenesis and functional genomics laboratory, we adapt traditional molecular cancer biology and classical biochemical approaches to next generation technologies (e.g. genome engineering and high-throughput functional screening platforms) and aim to implement an ideal research environment for identification and development of targeted cancer therapies. Our ambition is to advance knowledge on carcinogenesis mechanisms and explore drug targets for cancer.  

RESEARCH INTERESTS

Overall goal is to pursue a research program that utilizes functional genomics approaches and state-of-the-art tools for the understanding and the unraveling of cellular and molecular underpinnings of carcinogenesis and develops effective strategies for the discovery of cancer vulnerabilities, and hence potential future cancer drug targets.  In this context, we are interested in the following research themes: (i) understanding why and how non-small cell lung cancer (NSCLC) cells become resistant to targeted therapies, (ii) mapping out cancer cell essential genes and dependencies across cancer types using functional genomics screens, (iii) understanding and mining of the molecular mechanisms of cancer cell senescence and identifying novel druggable cellular targets in senescence-resistance.

In order to do so, our lab is adopting the most comprehensive tools and relevant models for the examination of biological pathways and disease pathobiology.

  1. Cancer cell plasticity driven by Transforming Growth Factor Beta (TGF-β)-induced Epithelial-Mesenchymal Transition (EMT) reprogramming is a fundamental cell fate determination event in acquired drug resistance to EGFR-Tyrosine Kinase Inhibitors (EGFR-TKi) in NSCLC. Notably, our preliminary studies pointed out that EGFR-TKi resistant cells have a unique EMT-associated secretome which modulates complex and dynamic signaling networks and can be recapitulated by TGF-β treatment. In particular, we showed that autocrine loops between TNF- and TGF-β pathways play a key role in driving the resistance. Within the scope of this research theme, we are harnessing next generation genomic tools and various cellular models to define the molecular aspects of resistance to novel EGFR-TKi, in particular we are focusing on the identification and characterization of signaling factors by which the complex and multifaceted EMT program facilitates cellular communication and governs cell fate decisions in acquired resistance. We hope that our studies will further expand our understanding on the complex network of intracellular effectors and TGF-β pathway dynamics that correspond to drug resistance phenotypes in NSCLC.
  2. Future drug targets are expected to emerge from high-throughput functional genomics screening technologies supported by genome engineering approaches and bioinformatics tools that identify the mechanisms regulating biological processes. Functional studies aimed at defining cancer drug targets are driven by the premise that genetic and/or non-genetic alterations modify the dependencies of cancer cells, making them highly vulnerable to the loss of driving alterations and to addictions that the cancer cell state achieves. Therefore, systematic interrogation of the functional basis of cancer by determining genes essential for growth and related phenotypes in different cancer cells is central to this research theme. Recent advancements in functional genomics screening platforms allow us to designate gene essentiality and dependency and characterize cancer vulnerabilities. Our lab is utilizing CRISPR-Cas9 technology to uncover cancer cell essential genes and delineate vulnerabilities in in vitro cellular models of bladder cancer and malignant pleural mesothelioma. Here, we are performing pooled screens using genome-wide lentivirus-based screening libraries for sgRNA delivery and Cas9 expression.
  3. Previously, we showed that TGF-β pathway could provoke senescence in various in vitro and in vivo cellular models of early stage hepatocellular carcinoma (HCC) via induction of reactive oxygen species by Nox4, suggesting the potential use of pro-senescence therapies as tumor suppressive mechanisms to limit tumor growth and spreading. More importantly, we showed that cells normally undergoing TGF-β-induced senescence were able to generate resistant clones while still preserving an intact signaling state. These new findings allowed us to shed light on the mechanisms of intrinsic/acquired senescence-resistance in late stage HCCs. Currently, we are working to further define and characterize the molecular aspects of this resistance phenomenon using functional genomics approaches such as whole-genome transcriptomic analysis, RNAi and CRISPR-Cas9. Taken together, we strongly believe that such studies will help us uncover novel genes and pathways regulating cellular signaling mechanisms driving senescence-resistance in HCC.

RESEARCH HIGHLIGHTS

We undertake a wide range of research efforts focused on the following major areas of investigation: (1) identification and characterization of the mechanisms driving cancer; (2) druggable target identification and validation against such mechanisms. The close proximity to basic and translational research for interdisciplinary collaboration is invaluable in the selection and validation of novel cancer drug discovery targets. Our lab is at the center of characterization of cancer-specific vulnerabilities using high-throughput data combined with information on genomic abnormalities in order to increase research opportunities and support improved treatment of such diseases.

Group Members

Senturk Lab. on Functional Cancer Genomics

Research Group Leader

Şerif ŞENTÜRK
serif.senturk@ibg.edu.tr
+90 232 299 41 00 (5111)
+9 0 232 299 41 61

Sude ERİŞ Undergraduate Student  sude.eris@msfr.ibg.edu.tr


Merve UYSAL MSc Student  merve.uysal@msfr.ibg.edu.tr


YUSUF PEKMEZCİ Visiting Researcher  None


Bengisu ULUATA DAYANÇ PhD Student  bengisu.dayanc@msfr.ibg.edu.tr


Ece ÇAKIROĞLU PhD Student  ece.cakiroglu@msfr.ibg.edu.tr


Minenur KALYONCU Researcher  minenur.kalyoncu@ibg.edu.tr

0 (232) 299 _ _

Fatma Aybüke MAZI MSc Student  fatmaaybuke.mazi@msfr.ibg.edu.tr


Zeynep GÜNGÖR MSc Student  zeynep.gungor@msfr.ibg.edu.tr


Mahdi SHEKARI PhD Student  mahdi.shekari@msfr.ibg.edu.tr


Hale GÜLER Visiting Researcher  hale.guler@msfr.ibg.edu.tr


Former Members

Yağmur TOKTAY MSc Student 


Özlem Şilan COŞKUN PhD Student  silan.coskun@msfr.ibg.edu.tr


Aslı KURDEN PEKMEZCİ PhD Student  asli.kurden@msfr.ibg.edu.tr


Dilara DEMİRCİ Researcher  dilara.demirci@ibg.edu.tr


Zehra Zeynep KAPLAN Undergraduate Student  zehrazeynep.kaplan@msfr.ibg.edu.tr


Selected Publications

Dilara Demirci, Bengisu Dayanc, Fatma Aybuke Mazi, Serif Senturk. The Jekyll and Hyde of Cellular Senescence in Cancer. Cells. 2021 January ; 10 (2) : 208. doi:10.3390/cells10020208. Download

Daniel J. Klionsky and Co-authors. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy. 2021 February ; 17 (1) : 1-382. doi:10.1080/15548627.2020.1797280. Download

Hasan Akbaba, Gülşah Erel-Akbaba, Serif Senturk. Recruitment of solid lipid nanoparticles for the delivery of CRISPR/Cas9: primary evaluation of anticancer gene editing. Nanomedicine. 2021 May ; 16 (12) : 963–978. doi:10.2217/nnm-2020-0412. Download

Polona Safaric Tepes, Debjani Pal, Trine Lindsted, Ingrid Ibarra, Amaja Lujambio, Vilma Jimenez Sabinina, Serif Senturk, Madison Miller, Navya Korimerla, Jiahao Huang, Larry Glassman, Paul Lee, David Zeltsman, Kevin Hyman, Michael Esposito, Gregory J. Hannon, Raffaella Sordella. An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKI resistant cells by modulating miR-335 expression. eLife. 2021 July . doi:10.7554/eLife.66109. Download

Karabicici M, Azbazdar Y, Ozhan G, Senturk S, Firtina Karagonlar Z, Erdal E. Changes in Wnt and TGF-β Signaling Mediate the Development of Regorafenib Resistance in Hepatocellular Carcinoma Cell Line HuH7.. Frontiers in cell and developmental biology. 2021 August ; 9 : 639779. doi:10.3389/fcell.2021.639779. Download

Zeynep Güngör, Merve Uysal, Mehmet Öztürk, Şerif Şentürk. Systematic Analysis of Cytostatic TGF-Beta Response in Mesenchymal-Like Hepatocellular Carcinoma Cell Lines. Journal of Gastrointestinal Cancer. 2021 August . doi:10.1007/s12029-021-00704-z. Download

Ece Cakiroglu, Serif Senturk. Genomics and Functional Genomics of Malignant Pleural Mesothelioma. International Journal of Molecular Sciences. 2020 September ; 21 (17) : E6342. doi:10.3390/ijms21176342. Download

Ozgun G, Senturk S, Erkek-Ozhan S. Retinoic acid signaling and bladder cancer: Epigenetic deregulation, therapy and beyond.. International journal of cancer. 2020 October . doi:10.1002/ijc.33374. Download

Soheil Akbari, Nur Arslan, Şerif Şentürk, Esra Erdal. Next-Generation Liver Medicine Using Organoid Models. Frontiers in Cell and Developmental Biology-Stem Cell Research. 2019 December ; 7 : 345. doi:10.3389/fcell.2019.00345. Download

Aysim Gunes, Ezgi Bagirsakci, Evin Iscan, Gulcin Cakan-Akdogan, Umut Aykutlu, Serif Senturk, Gunes Ozhan, Esra Erdal, Deniz Nart, Funda Yilmaz Barbet, Nese Atabey. Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma. Oncotarget. 2018 ; 9 (96) : 36849-36866. doi:10.18632/oncotarget.26402. Download

Senturk S, Shirole NH, Nowak DG, Corbo V, Pal D, Vaughan A, Tuveson DA, Trotman LC, Kinney JB, Sordella R. Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization. Nature communications. 2017 February ; 8 : 14370. doi:10.1038/ncomms14370. Download

Shirole NH, Pal D, Kastenhuber ER, Senturk S, Boroda J, Pisterzi P, Miller M, Munoz G, Anderluh M, Ladanyi M, Lowe SW, Sordella R. Correction: TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions. eLife. 2017 February ; 6 . doi:10.7554/eLife.25532. Download

Shirole NH, Pal D, Kastenhuber ER, Senturk S, Boroda J, Pisterzi P, Miller M, Munoz G, Anderluh M, Ladanyi M, Lowe SW, Sordella R. TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions. eLife. 2016 October ; 5 : e17929. doi:10.7554/eLife.25532. Download

Shirole NH, Pal D, Kastenhuber ER, Senturk S, Boroda J, Pisterzi P, Miller M, Munoz G, Anderluh M, Ladanyi M, Lowe SW, Sordella R. TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions. eLife. 2016 October ; 5 . doi:10.7554/eLife.17929. Download

Nowak DG, Cho H, Herzka T, Watrud K, DeMarco DV, Wang VM, Senturk S, Fellmann C, Ding D, Beinortas T, Kleinman D, Chen M, Sordella R, Wilkinson JE, Castillo-Martin M, Cordon-Cardo C, Robinson BD, Trotman LC. MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2.. Cancer discovery. 2015 June ; 5 (6) : 636-51. doi:10.1158/2159-8290.CD-14-1113. Download

Senturk S, Yao Z, Camiolo M, Stiles B, Rathod T, Walsh AM, Nemajerova A, Lazzara MJ, Altorki NK, Krainer A, Moll UM, Lowe SW, Cartegni L, Sordella R. p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.. Proceedings of the National Academy of Sciences of the United States of America. 2014 August ; 111 (32) : E3287-96. doi:10.1073/pnas.1321640111. Download

Mender I, Senturk S, Ozgunes N, Akcali KC, Kletsas D, Gryaznov S, Can A, Shay JW, Dikmen ZG. Imetelstat (a telomerase antagonist) exerts off‑target effects on the cytoskeleton.. International journal of oncology. 2013 May ; 42 (5) : 1709-15. doi:10.3892/ijo.2013.1865. Download

Sucularli C, Senturk S, Ozturk M, Konu O. Dose- and time-dependent expression patterns of zebrafish orthologs of selected E2F target genes in response to serum starvation/replenishment.. Molecular biology reports. 2011 August ; 38 (6) : 4111-23. doi:10.1007/s11033-010-0531-2. Download

Buontempo F, Ersahin T, Missiroli S, Senturk S, Etro D, Ozturk M, Capitani S, Cetin-Atalay R, Neri ML. Inhibition of Akt signaling in hepatoma cells induces apoptotic cell death independent of Akt activation status.. Investigational new drugs. 2011 December ; 29 (6) : 1303-13. doi:10.1007/s10637-010-9486-3. Download

Mumcuoglu M, Bagislar S, Yuzugullu H, Alotaibi H, Senturk S, Telkoparan P, Gur-Dedeoglu B, Cingoz B, Bozkurt B, Tazebay UH, Yulug IG, Akcali KC, Ozturk M. The ability to generate senescent progeny as a mechanism underlying breast cancer cell heterogeneity.. PloS one. 2010 June ; 5 (6) : e11288. doi:10.1371/journal.pone.0011288. Download

Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M. Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth.. Hepatology (Baltimore, Md.). 2010 September ; 52 (3) : 966-74. doi:10.1002/hep.23769. Download

Yuzugullu H, Benhaj K, Ozturk N, Senturk S, Celik E, Toylu A, Tasdemir N, Yilmaz M, Erdal E, Akcali KC, Atabey N, Ozturk M. Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells.. Molecular cancer. 2009 October ; 8 : 90. doi:10.1186/1476-4598-8-90. Download

Ozturk M, Arslan-Ergul A, Bagislar S, Senturk S, Yuzugullu H. Senescence and immortality in hepatocellular carcinoma.. Cancer letters. 2009 December ; 286 (1) : 103-13. doi:10.1016/j.canlet.2008.10.048. Download

Ozturk N, Erdal E, Mumcuoglu M, Akcali KC, Yalcin O, Senturk S, Arslan-Ergul A, Gur B, Yulug I, Cetin-Atalay R, Yakicier C, Yagci T, Tez M, Ozturk M. Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells.. Proceedings of the National Academy of Sciences of the United States of America. 2006 February ; 103 (7) : 2178-83. doi:10.1073/pnas.0510877103. Download

Total : 24

Selected Book Chapters

CRISPR/Cas9 Gene Editing in Mammalian Cells Using LentiCRISPRv2/LentiGuide-Puro Vectors (2021). CRISPR-Cas Methods. Springer Protocols.

Inducible CRISPR-based Genome Editing for the Characterization of Cancer Genes (2018). Genome Editing and Engineering: From TALENs, ZFNs and CRISPRs to Molecular Surgery. Cambridge University Press.

Total : 2

Patents

  • Raffaella Sordella, Serif Senturk, Luca Cartegni, Zhan Yao 2017 , Methods and compositions for inhibiting growth and epithelial to mesenchymal transition (emt) in cancer cells, 10501741

Awards

  • Young Scientist (BAGEP) Award by Science Academy, 2019
  • Young Investigator (GEBİP) Awards by Turkish Academy of Sciences (TÜBA), 2017

Academic Memberships

  • TÜBA-Turkish Academy Of Science, 2017
  • The Science Academy, Turkey, 2019
  • Turkish Society of Biochemistry, 2008

Contact

Senturk Lab. on Functional Cancer Genomics

Research Group Leader

Şerif ŞENTÜRK
serif.senturk@ibg.edu.tr
+90 232 299 41 00 (5111)
+9 0 232 299 41 61