Center for Molecular Medicine Cologne

Sos, Martin - A 13

Exploring epigenetic drivers of EMT during therapeutic stress in lung cancer

Introduction

Lung cancer is one of the most aggressive cancers, and with more than two million deaths worldwide lung cancer is a global threat.

Despite a dramatic development in the ability to precisely inhibit tumor growth with targeted drugs, precision cancer medicine is not capable of curing a single lung cancer patient.

On the molecular level, this clinical observation corresponds to the cellular plasticity that results in the persistence of individual tumor cells. We and others have characterized some of these networks involved in drug tolerance and recent data suggest that epithelial-to-mesenchymal transition (EMT) plays an important role in this process.

However, the epigenetic changes that promote EMT-induced drug tolerance and drug targets that would reverse this phenotype remain elusive.

The project is specifically designed to leverage new CRISPR-based technological advances in combination with our established expertise in the field of applied pharmacology and functional genomics. This way we aim at identifying key molecular drivers of drug tolerance and harness these findings in vivo to improve therapeutic strategies against oncogenically driven tumors.

Our Aims

  1. Establish a CRISPR/Cas9-based model to evaluate the impact of EMT on drug response in NSCLC.
  2. Characterize the transcriptional and epigenetic changes in oncogene-dependent lung cancer during therapeutic stress.
  3. Exploit drug-induced effects to prevent outgrowth of drug resistant tumors.

Previous Work

Our lab is well experienced in dissecting the molecular principles that underlie the evolution of resistance against targeted therapies and the translation of genomic, transcriptomic and proteomic analyses into actionable therapeutic strategies for the treatment of lung cancer patients.

In the last funding period, through the tight collaboration with the clinical department (LCGC) we were able to identify novel drivers of resistance to the EGFR inhibitor osimertinib and potential therapeutic escape routes to overcome resistance in lung cancer patients (Fassunke et al., Nat Comm 2018).

We have recently established a pipeline for efficient CRISPR/Cas9-based activation of transcription factors (Dammert et al., Nat Comm 2019) and more complex genome editing. With these prerequisites we anticipate to have an innovative model that will allow the dissection of EMT signaling and its crosstalk to epigenetic regulation during drug resistance in cancer.

  1. Dammert MA, Brägelmann J, Olsen RR, Böhm S, Monhasery N, Whitney CP, Chalishazar MD, Tumbrink HL, Guthrie MR, Klein S, Ireland AS, Ryan J, Schmitt A,  Marx A, Ozretić L, Castiglione R, Lorenz C, Jachimowicz RD, Wolf E, Thomas RK, Poirier JT, Büttner R, Sen T, Byers LA, Reinhardt HC, Letai A, Oliver TG, Sos ML. MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nat Commun. 2019 Aug 2;10(1):3485.
  2. Fassunke J, Müller F, Keul M, Michels S, Dammert MA, Schmitt A, Plenker D, Lategahn J, Heydt C, Brägelmann J, Tumbrink HL, Alber Y, Klein S, Heimsoeth A, Dahmen I, Fischer RN, Scheffler M, Ihle MA, Priesner V, Scheel AH, Wagener S, Kron A, Frank K, Garbert K, Persigehl T, Püsken M, Haneder S, Schaaf B, Rodermann E, Engel-Riedel W, Felip E, Smit EF, Merkelbach-Bruse S, Reinhardt HC, Kast SM, Wolf J, Rauh D, Büttner R, Sos ML. Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat Commun. 2018 Nov 7;9(1):4655.
  • Bebber CM, Thomas ES, Stroh J, Chen Z, Androulidaki A, Schmitt A, Hohne MN, Stuker L, de Padua Alves C, Khonsari A, Dammert MA, Parmaksiz F, Tumbrink HL, Beleggia F, Sos ML, Riemer J, George J, Brodesser S, Thomas RK, Reinhardt HC, and von Karstedt S (2021). Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nat Commun12, 2048. doi:10.1038/s41467-021-22336-4.
                          • Bragelmann J, Lorenz C, Borchmann S, Nishii K, Wegner J, Meder L, Ostendorp J, Ast DF, Heimsoeth A, Nakasuka T, Hirabae A, Okawa S, Dammert MA, Plenker D, Klein S, Lohneis P, Gu J, Godfrey LK, Forster J, Trajkovic-Arsic M, Zillinger T, Haarmann M, Quaas A, Lennartz S, Schmiel M, D'Rozario J, Thomas ES, Li H, Schmitt CA, George J, Thomas RK, von Karstedt S, Hartmann G, Buttner R,Ullrich RT, Siveke JT, Ohashi K, Schlee M, and Sos ML (2021). MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Nat Commun12, 5505. doi:10.1038/s41467-021-25728-8.
                                                                                                                                                                                                                                                                                                            • Schaufler D, Ast DF, Tumbrink HL, Abedpour N, Maas L, Schwabe AE, Spille I, Lennartz S, Fassunke J, Aldea M, Besse B, Planchard D, Nogova L, Michels S, Kobe C, Persigehl T, Westphal T, Koleczko S, Fischer R, Weber JP, Altmuller J, Thomas RK, Merkelbach-Bruse S, Gautschi O, Mezquita L, Buttner R, Wolf J, Peifer M, Bragelmann J, Scheffler M, and Sos ML (2021). Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer. NPJ Precis Oncol5, 102. doi:10.1038/s41698-021-00241-9.
                                                                                                                                                                                                                                                                                                            • Tumbrink HL, Heimsoeth A, Sos ML. The next tier of EGFR resistance mutations in lung cancer. Oncogene. 2021 Jan;40(1):1-11.
                                                                                                                                                                                                                                                                                                            • Poirier JT, George J, Owonikoko TK, Berns A, Brambilla E, Byers LA, Carbone D, Chen HJ, Christensen CL, Dive C, Farago AF, Govindan R, Hann C, Hellmann MD, Horn L, Johnson JE, Ju YS, Kang S, Krasnow M, Lee J, Lee SH, Lehman J, Lok B, Lovly C, MacPherson D, McFadden D, Minna J, Oser M, Park K, Park KS, Pommier Y, Quaranta V, Ready N, Sage J, Scagliotti G, Sos ML, Sutherland KD, Travis WD, Vakoc CR, Wait SJ, Wistuba I, Wong KK, Zhang H, Daigneault J, Wiens J, Rudin CM, and Oliver TG (2020). New Approaches to SCLC Therapy: From the Laboratory to the Clinic. J Thorac Oncol 15, 520-40.
                                                                                                                                                                                                                                                                                                            Prof. Dr. Martin Sos CMMC Cologne
                                                                                                                                                                                                                                                                                                            Prof. Dr. Martin Sos

                                                                                                                                                                                                                                                                                                            Inst. of General Pathology and Pathological Anatomy & Dept. of Translational Genomics

                                                                                                                                                                                                                                                                                                            CMMC - PI - A 13

                                                                                                                                                                                                                                                                                                            +49 221 478 96175

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                                                                                                                                                                                                                                                                                                            Inst. of General Pathology and Pathological Anatomy & Dept. of Translational Genomics

                                                                                                                                                                                                                                                                                                            Weyertal 115b

                                                                                                                                                                                                                                                                                                            50931 Cologne

                                                                                                                                                                                                                                                                                                            https://pathologie.uk-koeln.de/forschung/molekulare-pathologie-ag-sos/

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                                                                                                                                                                                                                                                                                                            Curriculum Vitae (CV)

                                                                                                                                                                                                                                                                                                            Publications on PubMed

                                                                                                                                                                                                                                                                                                            Publications - Martin Sos

                                                                                                                                                                                                                                                                                                            Link to PubMed

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                                                                                                                                                                                                                                                                                                            Group Members

                                                                                                                                                                                                                                                                                                            Katia Garbert
                                                                                                                                                                                                                                                                                                            Dr. Johannes Brägelmann
                                                                                                                                                                                                                                                                                                            Jenny Ostendorp