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.
Figure 1
Fig. 1 The majority of lung cancer patients develop resistance against the targeted treatment strategy. The epithelial-to-mesenchymal transition (EMT) describes a transient process characterized by increase of mesenchymal cell traits and loss of epithelial features and is thought to play a major role in the evolution of drug resistance.
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
Establish a CRISPR/Cas9-based model to evaluate the impact of EMT on drug response in NSCLC.
Characterize the transcriptional and epigenetic changes in oncogene-dependent lung cancer during therapeutic stress.
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 Commun 2018). As proposed in Aim 2 and Aim 3 we were able to identify EMT and inflammatory signaling as the key transcriptional processes during drug-induced reprogramming across different types of oncogenic drivers and different types of cancer models (Brägelmann et al. Nat Commun 2021). We found that these changes are associated with an increase of infiltrating T cells in the microenvironment of drug-treated tumors. These findings enabled us to rationally combine targeted therapy aiming at oncogenic EGFR signaling with an agonist of the nucleic acid sensor RIG-I to delay the outgrowth of drug resistant tumors in vivo. Our functional analyses of the molecular drivers of EMT during drug-induced reprogramming suggest that TGFß signaling may play a crucial role in this process. Our ongoing analyses will potentially help to understand the mechanistic links between TGFß signaling and the resistance phenotype that ultimately limits the success of currently used targeted kinase inhibitors (Schaufler et al. NPJ Precis Oncol 2021).
Figure 2
A Combined gene set enrichment analysis of RNA seq from PC9, HCC827 and HCC4006 cells treated with 100 nM trametinib for 72 h. B Hyperion imaging mass cytometry false-color image of an osimertinib-treated tumor stained for pan-cytokeratin (CK, cyan), CD8 (green) and Granzyme B (red). Scale bar 100 µm, representative image of n = 6 regions. C Humanized PC9 xenografts treated with osimertinib or vehicle p.o. followed by IVT4 or control IVT-GAC i.t. as shown in the schematic (left, n = 5 mice per arm inoculated with 2 tumors per mouse). Relative tumor volumes are shown on the right (mean ± SEM of tumors treated with osi-IVT4 (n = 9), osi-IVT-GAC (n = 8), veh-IVT4 (n = 6), veh-IVT-GAC (n = 6)). All panels were published in Brägelmann et al., Nature Comm 2021.
Brägelmann 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 Commun 12, 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 Oncol 5, 102. doi:10.1038/s41698-021-00241-9.
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.
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.
Lategahn J, Tumbrink HL, Schultz-Fademrecht C, Heimsoeth A, Werr L, Niggenaber J, Keul M, Parmaksiz F, Baumann M, Menninger S, Zent E, Landel I, Weisner J, Jeyakumar K, Heyden L, Russ N, Muller F, Lorenz C, Bragelmann J, Spille I, Grabe T, Muller MP, Heuckmann JM, Klebl BM, Nussbaumer P, Sos ML, and Rauh D (2022). Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors. J Med Chem65, 6643-6655. doi:10.1021/acs.jmedchem.1c02080.
Werr L, Plenker D, Dammert MA, Lorenz C, Bragelmann J, Tumbrink HL, Klein S, Schmitt A, Buttner R, Persigehl T, Shokat KM, Wunderlich FT, Schram AM, Peifer M, Sos ML, Reinhardt HC, and Thomas RK (2022). CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization. Mol Cancer Ther21, 821-830. doi:10.1158/1535-7163.MCT-21-0820.
French CA, Cheng ML, Hanna GJ, DuBois SG, Chau NG, Hann CL, Storck S, Salgia R, Trucco M, Tseng J, Stathis A, Piekarz R, Lauer UM, Massard C, Bennett K, Coker S, Tontsch-Grunt U, Sos ML, Liao S, Wu CJ, Polyak K, Piha-Paul SA, and Shapiro GI (2022). Report of the First International Symposium on NUT Carcinoma. Clin Cancer Res28, 2493-2505. doi:10.1158/1078-0432.CCR-22-0591.
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
Nogova L, Mattonet C, Scheffler M, Taubert M, Gardizi M, Sos ML, Michels S, Fischer RN, Limburg M, Abdulla DSY, Persigehl T, Kobe C, Merkelbach-Bruse S, Franklin J, Backes H, Schnell R, Behringer D, Kaminsky B, Eichstaedt M, Stelzer C, Kinzig M, Sörgel F, Tian Y, Junge L, Suleiman AA, Frechen S, Rokitta D, Ouyang D, Fuhr U, Buettner R, Wolf J. Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment. Cancer Med. 2020 Jul;9(14):4991-5007.
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
Inst. of General Pathology and Pathological Anatomy & Dept. of Translational Genomics
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