Center for Molecular Medicine Cologne

Reinhard Büttner / Margarete Odenthal - A 1

The multifaceted function of the lysine-specific histone demethylase 1 in lung cancer

Epigenetic abnormalities play a vital role in the progression of many cancer types including non-small cell lung cancer (NSCLC) which is a leading cause of cancer-related mortality. The lysine-specific demethylase 1 (LSD1/KDM1A) acts as an epigenetic regulator and is overexpressed in a wide variety of cancer types. In our studies, we address the mechanistic links of LSD1 function in NSCLC development using cancer-related cell systems and genetic mouse models.

Introduction 

Deregulation of epigenetic mechanisms is a hallmark of cancer and contributes to cancer development and progression, where it can lead to altered gene function and malignant cell-transformation. Histone methylation mediates transcriptional regulation by switching on or off gene expression. The lysine-specific demethylase 1 (LSD1) catalyzes the demethylation of the histone 3 (H3) subunits, namely H3K4 and H3K9, resulting in gene repression or activation, respectively. 

LSD1 is highly overexpressed in many cancer types including non-small cell lung cancer (NSCLC). NSCLC, representing 80% of all lung cancer types, is a leading cause of cancer-related mortality. Our recent studies proved that LSD1 overexpression is associated with NSCLC malignancy (Lim et al. 2017). 

LSD1 inhibitors as novel therapeutic option

Due to the tumor driving potential, novel efficient LSD1 inhibitors are under development. The recently identified inhibitor HCI-2509 is a very potent LSD1 inhibitor, which reversibly binds to LSD1, but also disables its solubility and blocks its interactions within the chromatin remodeling complex e.g. CoREST complex.

In various NSCLC cell lines, HCI-2509 significantly reduced cell growth with an IC50 of 0.3 to 5 µM (Macheleidt et al. 2018). Most importantly, HCI-2509 mediated growth arrest as well as inhibition of the invasion capacities were independent of the underlying driver mutations such as activating KRAS or EGFR mutations (Figure 1 A,B). These in vitro findings were confirmed by preclinical therapeutic approaches including two transgenic NSCLC mouse models driven by either an activating EGFR or KRAS mutation (Figure 1 C-G) (Macheleidt et al. 2018). 

Hence, our findings suggest LSD1 inhibition as a therapeutic target in novel treatment strategies of combinatorial therapy. 

LSD1 inhibition leads to cell growth arrest by repression of the PLK1 pathway

Expression profiling followed by functional classification and pathway analysis indicated prominent repression of proliferation-associated signaling upon LSD1 inhibition. In particular, the polo-like kinase 1 (PLK1) pathway was downregulated in response to LSD1 inhibition (Figure 2). Notably, using TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. This LSD1/PLK1 linkage was confirmed by immunohistochemical analysis of NSCLC tumor samples (Figure 2D, E), demonstrating the clinical relevance of the LSD1 /PLK1 axis (Dalvi et al. 2019). 

Importantly, whereas the PLK1 pathway is downregulated, the tumor suppressor CDKN1A is upregulated upon LSD1 inhibition. Chromatin immunoprecipation (ChIP) followed by whole genome sequencing or qPCR demonstrated that both are direct targets of LSD1 transcriptional gene regulation (Figure 3). 

Perspectives: 

Nuclear encoded mitochondrial (mt) proteins are markedly LSD1 regulated, leading to impaired mt-respiration and ATP production as well as to immense changes in metabolism. The cancer associated metabolic alterations upon LSD1 inhibition will be subject of further studies.

Selected publications (2017-2019)

1. Dalvi P.S., Macheleidt I.F., Lim S.Y., Meemboor S., et al. Buettner R., Klein S., and Odenthal M. (2019) LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway. Mol Cancer Res. 17(6), 1326-1337. 

2. Mariappan A, Soni K, Macheleidt I, et al, Odenthal M, Büttner R, et  al., and Gopalakrishnan J. (2019) Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J. 38(2).

3. Macheleidt I.F., Dalvi P.S., Lim SY., Meemboor S.,et al. Buettner R., and Odenthal M. (2018) Growth arrest of non-small cell lung cancer shown by preclinical studies using the LSD1 inhibitor HCI-2509. Molecular Oncology 12(11), 1965-1979. 

4. Grasse S, Lienhard M, et al. Odenthal M, Büttner R, et al., and Schweiger MR. (2018) Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Med. J 10(1):55.

5. Lim S.Y., Macheleidt, I., Dalvi P., et al. Buettner R., and Odenthal M. (2017). LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells. Sci Rep. 7(1), 10292.

6. Meder L, König K, Dietlein F, et al., Odenthal M, Klein F, Büttner R, Schulte JH, Heukamp LC, and Ullrich RT. (2018) LIN28B enhanced tumorigenesis in an autochthonous KRASG12V-driven lung carcinoma mouse model. Oncogene 37:2746-2756.

7. Meder L, Büttner R, and Odenthal M. Notch signaling triggers the tumor heterogeneity of small cell lung cancer. (2017) J Thorac Dis. 9(12):4884-4888.

8. Amer W, Toth C, Vassella E, et al.  Buettner R, Scheel A, Schaefer SC, and Odenthal M. (2017) Evolution analysis of heterogeneous non-small cell lung carcinoma by ultra-deep sequencing of the mitochondrial genome. Sci Rep. 11;7(1):11069.

9. Plenker D., Riedel M., Brägelmann J., et al. Buettner R., Shokat K.M., McDonald N.Q., Kast S.M., Gautschi O., Thomas R.K., and Sos M.L. (2017) Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med. 4(9): 394-405.

Castiglione, R., Alidousty, C., Holz, B., Wagener, S., Baar, T., Heydt, C., Binot, E., Zupp, S., Kron, A., Wolf, J., Merkelbach-Bruse, S., Reinhardt, H.C., Buettner, R., and Schultheis, A.M. (2019). Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies. Mod Pathol 32, 627-38.

Dalvi, P.S., Macheleidt, I.F., Lim, S.Y., Meemboor, S., Muller, M., Eischeid-Scholz, H., Schaefer, S.C., Buettner, R., Klein, S., and Odenthal, M. (2019). LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway. Mol Cancer Res 17, 1326-37.

Dammert, M.A., Bragelmann, J., Olsen, R.R., Bohm, S., Monhasery, N., Whitney, C.P., Chalishazar, M.D., Tumbrink, H.L., Guthrie, M.R., Klein, S., Ireland, A.S., Ryan, J., Schmitt, A., Marx, A., Ozretic, L., Castiglione, R., Lorenz, C., Jachimowicz, R.D., Wolf, E., Thomas, R.K., Poirier, J.T., Buttner, R., Sen, T., Byers, L.A., Reinhardt, H.C., Letai, A., Oliver, T.G., and Sos, M.L. (2019). MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nat Commun 10, 3485.

Grimm, C., Fischer, A., Farrelly, A.M., Kalachand, R., Castiglione, R., Wasserburger, E., Hussong, M., Schultheis, A.M., Altmuller, J., Thiele, H., Reinhardt, H.C., Hauschulz, K., Hennessy, B.T., Herwig, R., Lienhard, M., Buettner, R., and Schweiger, M.R. (2019). Combined Targeted Resequencing of Cytosine DNA Methylation and Mutations of DNA Repair Genes with Potential Use for Poly(ADP-Ribose) Polymerase 1 Inhibitor Sensitivity Testing. J Mol Diagn 21, 198-213.

Howell, J., Atkinson, S.R., Pinato, D.J., Knapp, S., Ward, C., Minisini, R., Burlone, M.E., Leutner, M., Pirisi, M., Buttner, R., Khan, S.A., Thursz, M., Odenthal, M., and Sharma, R. (2019). Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma. Eur J Cancer 116, 56-66.

Mariappan, A., Soni, K., Schorpp, K., Zhao, F., Minakar, A., Zheng, X., Mandad, S., Macheleidt, I., Ramani, A., Kubelka, T., Dawidowski, M., Golfmann, K., Wason, A., Yang, C., Simons, J., Schmalz, H.G., Hyman, A.A., Aneja, R., Ullrich, R., Urlaub, H., Odenthal, M., Buttner, R., Li, H., Sattler, M., Hadian, K., and Gopalakrishnan, J. (2019). Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J 38.

Rossi, A., Dupaty, L., Aillot, L., Zhang, L., Gallien, C., Hallek, M., Odenthal, M., Adriouch, S., Salvetti, A., and Buning, H. (2019). Vector uncoating limits adeno-associated viral vector-mediated transduction of human dendritic cells and vector immunogenicity. Sci Rep 9, 3631.

Zhang, L., Rossi, A., Lange, L., Meumann, N., Koitzsch, U., Christie, K., Nesbit, A., Moore, T., Hacker, U., Morgan, M.A., Hoffmann, D., Zengel, J.R., Carette, J.E., Schambach, A., Salvetti, A., Odenthal, M., and Buning, H. (2019). Capsid engineering overcomes barriers toward Adeno-associated viral (AAV) vector-mediated transduction of endothelial cells. Hum Gene Ther10.1089/hum.2019.027.

Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A, Bartenhagen C, Walter E, Gecht J, Kerschke L, Volland R, Menon R, Heuckmann JM, Gartlgruber M, Hartlieb S, Henrich KO, Okonechnikov K, Altmuller J, Nurnberg P, Lefever S, de Wilde B, Sand F, Ikram F, Rosswog C, Fischer J, Theissen J, Hertwig F, Singhi AD, Simon T, Vogel W, Perner S, Krug B, Schmidt M, Rahmann S, Achter V, Lang U, Vokuhl C, Ortmann M, Buttner R, Eggert A, Speleman F, O'Sullivan RJ, Thomas RK, Berthold F, Vandesompele J, Schramm A, Westermann F, Schulte JH, Peifer M, and Fischer M (2018). A mechanistic classification of clinical phenotypes in neuroblastoma. Science 362, 1165-1170.

Castiglione R, Alidousty C, Holz B, Wagener S, Baar T, Heydt C, Binot E, Zupp S, Kron A, Wolf J, Merkelbach-Bruse S, Reinhardt HC, Buettner R, and Schultheis AM (2018). Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies. Mod Pathol10.1038/s41379-018-0182-8.

Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zhong J, Igo P, Hazar-Rethinam MH, Licausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Buttner R, Haas S, Sequist LV, Shaw AT, Wong KK, Hata AN, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, and Farago AF (2018). Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts. Cancer Discov 8, 600-615.

Fassunke J, Muller F, Keul M, Michels S, Dammert MA, Schmitt A, Plenker D, Lategahn J, Heydt C, Bragelmann 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, Pusken 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, Buttner R, and Sos ML (2018). Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat Commun 9, 4655.

Frank R, Scheffler M, Merkelbach-Bruse S, Ihle MA, Kron A, Rauer M, Ueckeroth F, Konig K, Michels S, Fischer R, Eisert A, Fassunke J, Heydt C, Serke M, Ko YD, Gerigk U, Geist T, Kaminsky B, Heukamp LC, Clement-Ziza M, Buttner R, and Wolf J (2018). Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). Clin Cancer Res10.1158/1078-0432.CCR-17-3416.

George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Muller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmuller J, Becker C, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland A, Solberg S, Ansen S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sanger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Buttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, and Thomas RK (2018). Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9, 1048.

Golfmann K, Meder L, Koker M, Volz C, Borchmann S, Tharun L, Dietlein F, Malchers F, Florin A, Buttner R, Rosen N, Rodrik-Outmezguine V, Hallek M, and Ullrich RT (2018). Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. Oncogene 37, 5682-5693.

Grasse S, Lienhard M, Frese S, Kerick M, Steinbach A, Grimm C, Hussong M, Rolff J, Becker M, Dreher F, Schirmer U, Boerno S, Ramisch A, Leschber G, Timmermann B, Grohe C, Luders H, Vingron M, Fichtner I, Klein S, Odenthal M, Buttner R, Lehrach H, Sultmann H, Herwig R, and Schweiger MR (2018). Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Med 10, 55.

Grimm C, Fischer A, Farrelly AM, Kalachand R, Castiglione R, Wasserburger E, Hussong M, Schultheis AM, Altmuller J, Thiele H, Reinhardt HC, Hauschulz K, Hennessy BT, Herwig R, Lienhard M, Buettner R, and Schweiger MR (2018). Combined Targeted Re-Sequencing of Cytosine DNA Methylation and Mutations of DNA Repair Genes with Potential Use for PARP1 Inhibitor Sensitivity Testing. J Mol Diagn10.1016/j.jmoldx.2018.10.007.

Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, Cartolano M, Oberbeck S, Mayer P, Berg V, Thomalla D, Kutsch N, Stiefelhagen M, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmuller J, Nurnberg P, Pallasch C, Achter V, Lang U, Eichhorst B, Castiglione R, Schafer SC, Buttner R, Kreuzer KA, Reinhardt HC, Hallek M, Frenzel LP, and Peifer M (2018). Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun 9, 727.

Macheleidt IF, Dalvi PS, Lim SY, Meemboor S, Meder L, Kasgen O, Muller M, Kleemann K, Wang L, Nurnberg P, Russeler V, Schafer SC, Mahabir E, Buttner R, and Odenthal M (2018). Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations. Mol Oncol 12, 1965-1979.

Mariappan A, Soni K, Schorpp K, Zhao F, Minakar A, Zheng X, Mandad S, Macheleidt I, Ramani A, Kubelka T, Dawidowski M, Golfmann K, Wason A, Yang C, Simons J, Schmalz HG, Hyman AA, Aneja R, Ullrich R, Urlaub H, Odenthal M, Buttner R, Li H, Sattler M, Hadian K, and Gopalakrishnan J (2019). Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J10.15252/embj.201899876.

Meder L, Konig K, Dietlein F, Macheleidt I, Florin A, Ercanoglu MS, Rommerscheidt-Fuss U, Koker M, Schon G, Odenthal M, Klein F, Buttner R, Schulte JH, Heukamp LC, and Ullrich RT (2018). LIN28B enhanced tumorigenesis in an autochthonous KRAS(G12V)-driven lung carcinoma mouse model. Oncogene 37, 2746-2756.

Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, Borchmann S, Wennhold K, Vlasic I, Oberbeck S, Riedel R, Florin A, Golfmann K, Schlosser HA, Odenthal M, Buttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, and Ullrich RT (2018). Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res10.1158/0008-5472.CAN-17-2176.

Meyer MF, Meinrath J, Seehawer J, Lechner A, Odenthal M, Quaas A, Semrau R, Huebbers CU, Marnitz S, Buttner R, and Beutner D (2018). The relevance of the lymph node ratio as predictor of prognosis is higher in HPV-negative than in HPV-positive oropharyngeal squamous cell carcinoma. Clin Otolaryngol 43, 192-198.

Plenker D, Bertrand M, de Langen AJ, Riedel R, Lorenz C, Scheel AH, Muller J, Bragelmann J, Dassler-Plenker J, Kobe C, Persigehl T, Kluge A, Wurdinger T, Schellen P, Hartmann G, Zacherle T, Menon R, Thunnissen E, Buttner R, Griesinger F, Wolf J, Heukamp L, Sos ML, and Heuckmann JM (2018). Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients. Clin Cancer Res 24, 1337-1343.

Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jungst C, Siedek F, Vogel W, Klumper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Kruger M, Schauss A, Perner S, Pasparakis M, Buttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, and Reinhardt HC (2018). The Cdkn1a(SUPER) Mouse as a Tool to Study p53-Mediated Tumor Suppression. Cell Rep 25, 1027-1039 e1026.

Welcker D, Jain M, Khurshid S, Jokic M, Hohne M, Schmitt A, Frommolt P, Niessen CM, Spiro J, Persigehl T, Wittersheim M, Buttner R, Fanciulli M, Schermer B, Reinhardt HC, Benzing T, and Hopker K (2018). AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene 37, 1503-1518.

Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A, Bartenhagen C, Walter E, Gecht J, Kerschke L, Volland R, Menon R, Heuckmann JM, Gartlgruber M, Hartlieb S, Henrich KO, Okonechnikov K, Altmuller J, Nurnberg P, Lefever S, de Wilde B, Sand F, Ikram F, Rosswog C, Fischer J, Theissen J, Hertwig F, Singhi AD, Simon T, Vogel W, Perner S, Krug B, Schmidt M, Rahmann S, Achter V, Lang U, Vokuhl C, Ortmann M, Buttner R, Eggert A, Speleman F, O'Sullivan RJ, Thomas RK, Berthold F, Vandesompele J, Schramm A, Westermann F, Schulte JH, Peifer M, and Fischer M (2018). A mechanistic classification of clinical phenotypes in neuroblastoma. Science 362, 1165-1170.

Castiglione R, Alidousty C, Holz B, Wagener S, Baar T, Heydt C, Binot E, Zupp S, Kron A, Wolf J, Merkelbach-Bruse S, Reinhardt HC, Buettner R, and Schultheis AM (2018). Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies. Mod Pathol10.1038/s41379-018-0182-8.

Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zhong J, Igo P, Hazar-Rethinam MH, Licausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Buttner R, Haas S, Sequist LV, Shaw AT, Wong KK, Hata AN, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, and Farago AF (2018). Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts. Cancer Discov 8, 600-615.

Fassunke J, Muller F, Keul M, Michels S, Dammert MA, Schmitt A, Plenker D, Lategahn J, Heydt C, Bragelmann 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, Pusken 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, Buttner R, and Sos ML (2018). Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat Commun 9, 4655.

Frank R, Scheffler M, Merkelbach-Bruse S, Ihle MA, Kron A, Rauer M, Ueckeroth F, Konig K, Michels S, Fischer R, Eisert A, Fassunke J, Heydt C, Serke M, Ko YD, Gerigk U, Geist T, Kaminsky B, Heukamp LC, Clement-Ziza M, Buttner R, and Wolf J (2018). Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). Clin Cancer Res10.1158/1078-0432.CCR-17-3416.

George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Muller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmuller J, Becker C, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland A, Solberg S, Ansen S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sanger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Buttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, and Thomas RK (2018). Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9, 1048.

Golfmann K, Meder L, Koker M, Volz C, Borchmann S, Tharun L, Dietlein F, Malchers F, Florin A, Buttner R, Rosen N, Rodrik-Outmezguine V, Hallek M, and Ullrich RT (2018). Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. Oncogene 37, 5682-5693.

Grasse S, Lienhard M, Frese S, Kerick M, Steinbach A, Grimm C, Hussong M, Rolff J, Becker M, Dreher F, Schirmer U, Boerno S, Ramisch A, Leschber G, Timmermann B, Grohe C, Luders H, Vingron M, Fichtner I, Klein S, Odenthal M, Buttner R, Lehrach H, Sultmann H, Herwig R, and Schweiger MR (2018). Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Med 10, 55.

Grimm C, Fischer A, Farrelly AM, Kalachand R, Castiglione R, Wasserburger E, Hussong M, Schultheis AM, Altmuller J, Thiele H, Reinhardt HC, Hauschulz K, Hennessy BT, Herwig R, Lienhard M, Buettner R, and Schweiger MR (2018). Combined Targeted Re-Sequencing of Cytosine DNA Methylation and Mutations of DNA Repair Genes with Potential Use for PARP1 Inhibitor Sensitivity Testing. J Mol Diagn10.1016/j.jmoldx.2018.10.007.

Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, Cartolano M, Oberbeck S, Mayer P, Berg V, Thomalla D, Kutsch N, Stiefelhagen M, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmuller J, Nurnberg P, Pallasch C, Achter V, Lang U, Eichhorst B, Castiglione R, Schafer SC, Buttner R, Kreuzer KA, Reinhardt HC, Hallek M, Frenzel LP, and Peifer M (2018). Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun 9, 727.

Macheleidt IF, Dalvi PS, Lim SY, Meemboor S, Meder L, Kasgen O, Muller M, Kleemann K, Wang L, Nurnberg P, Russeler V, Schafer SC, Mahabir E, Buttner R, and Odenthal M (2018). Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations. Mol Oncol 12, 1965-1979.

Mariappan A, Soni K, Schorpp K, Zhao F, Minakar A, Zheng X, Mandad S, Macheleidt I, Ramani A, Kubelka T, Dawidowski M, Golfmann K, Wason A, Yang C, Simons J, Schmalz HG, Hyman AA, Aneja R, Ullrich R, Urlaub H, Odenthal M, Buttner R, Li H, Sattler M, Hadian K, and Gopalakrishnan J (2019). Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J10.15252/embj.201899876.

Meder L, Konig K, Dietlein F, Macheleidt I, Florin A, Ercanoglu MS, Rommerscheidt-Fuss U, Koker M, Schon G, Odenthal M, Klein F, Buttner R, Schulte JH, Heukamp LC, and Ullrich RT (2018). LIN28B enhanced tumorigenesis in an autochthonous KRAS(G12V)-driven lung carcinoma mouse model. Oncogene 37, 2746-2756.

Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, Borchmann S, Wennhold K, Vlasic I, Oberbeck S, Riedel R, Florin A, Golfmann K, Schlosser HA, Odenthal M, Buttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, and Ullrich RT (2018). Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res10.1158/0008-5472.CAN-17-2176.

Meyer MF, Meinrath J, Seehawer J, Lechner A, Odenthal M, Quaas A, Semrau R, Huebbers CU, Marnitz S, Buttner R, and Beutner D (2018). The relevance of the lymph node ratio as predictor of prognosis is higher in HPV-negative than in HPV-positive oropharyngeal squamous cell carcinoma. Clin Otolaryngol 43, 192-198.

Plenker D, Bertrand M, de Langen AJ, Riedel R, Lorenz C, Scheel AH, Muller J, Bragelmann J, Dassler-Plenker J, Kobe C, Persigehl T, Kluge A, Wurdinger T, Schellen P, Hartmann G, Zacherle T, Menon R, Thunnissen E, Buttner R, Griesinger F, Wolf J, Heukamp L, Sos ML, and Heuckmann JM (2018). Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients. Clin Cancer Res 24, 1337-1343.

Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jungst C, Siedek F, Vogel W, Klumper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Kruger M, Schauss A, Perner S, Pasparakis M, Buttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, and Reinhardt HC (2018). The Cdkn1a(SUPER) Mouse as a Tool to Study p53-Mediated Tumor Suppression. Cell Rep 25, 1027-1039 e1026.

Welcker D, Jain M, Khurshid S, Jokic M, Hohne M, Schmitt A, Frommolt P, Niessen CM, Spiro J, Persigehl T, Wittersheim M, Buttner R, Fanciulli M, Schermer B, Reinhardt HC, Benzing T, and Hopker K (2018). AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene 37, 1503-1518.

 

Amer W, Toth C, Vassella E, Meinrath J, Koitzsch U, Arens A, Huang J, Eischeid H, Adam A, Buettner R, Scheel A, Schaefer SC, and Odenthal M (2017). Evolution analysis of heterogeneous non-small cell lung carcinoma by ultra-deep sequencing of the mitochondrial genome. Sci Rep 7, 11069.

Bragelmann J, Dammert MA, Dietlein F, Heuckmann JM, Choidas A, Bohm S, Richters A, Basu D, Tischler V, Lorenz C, Habenberger P, Fang Z, Ortiz-Cuaran S, Leenders F, Eickhoff J, Koch U, Getlik M, Termathe M, Sallouh M, Greff Z, Varga Z, Balke-Want H, French CA, Peifer M, Reinhardt HC, Orfi L, Keri G, Ansen S, Heukamp LC, Buttner R, Rauh D, Klebl BM, Thomas RK, and Sos ML (2017). Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma. Cell Rep 20, 2833-45.

Buttner R, Wolf J, Thomas RK, and Sos ML (2017). Resistance Mechanisms to AZD9291 and Rociletinib-Response. Clin Cancer Res 23, 3967-8.

George J, Saito M, Tsuta K, Iwakawa R, Shiraishi K, Scheel AH, Uchida S, Watanabe SI, Nishikawa R, Noguchi M, Peifer M, Jang SJ, Petersen I, Buttner R, Harris CC, Yokota J, Thomas RK, and Kohno T (2017). Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer. Clin Cancer Res 23, 1220-6.

Horpaopan S, Kirfel J, Peters S, Kloth M, Huneburg R, Altmuller J, Drichel D, Odenthal M, Kristiansen G, Strassburg C, Nattermann J, Hoffmann P, Nurnberg P, Buttner R, Thiele H, Kahl P, Spier I, and Aretz S (2017). Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS). Hered Cancer Clin Pract 15, 22.

Koitzsch U, Heydt C, Attig H, Immerschitt I, Merkelbach-Bruse S, Fammartino A, Buttner RH, Kong Y, and Odenthal M (2017). Use of the GeneReader NGS System in a clinical pathology laboratory: a comparative study. J Clin Pathol10.1136/jclinpath-2017-204342.

Lim SY, Macheleidt I, Dalvi P, Schafer SC, Kerick M, Ozretic L, Ortiz-Cuaran S, George J, Merkelbach-Bruse S, Wolf J, Timmermann B, Thomas RK, Schweiger MR, Buettner R, and Odenthal M (2017). LSD1 modulates the non-canonical integrin beta3 signaling pathway in non-small cell lung carcinoma cells. Sci Rep 7, 10292.

Malchers F, Ercanoglu M, Schutte D, Castiglione R, Tischler V, Michels S, Dahmen I, Bragelmann J, Menon R, Heuckmann JM, George J, Ansen S, Sos ML, Soltermann A, Peifer M, Wolf J, Buttner R, and Thomas RK (2017). Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer. Clin Cancer Res 23, 5527-36.

Meyer MF, Meinrath J, Seehawer J, Lechner A, Odenthal M, Quaas A, Semrau R, Huebbers CU, Marnitz S, Buttner R, and Beutner D (2017). The relevance of the lymph node ratio as predictor of prognosis is higher in HPV-negative than in HPV-positive oropharyngeal squamous cell carcinoma. Clin Otolaryngol10.1111/coa.12938.

Schiller J, Klein S, Engels M, Buttner R, Rybniker J, Fatkenheuer G, Scheid C, Wybranski C, Quaas A, Reinhardt HC, and Wassermann R (2017). A Cryptosporidium infection in a patient with relapsed T lymphoblastic lymphoma undergoing allogeneic stem cell transplantation. Eur J Haematol10.1111/ejh.12998.

Schmitt A, Knittel G, Welcker D, Yang TP, George J, Nowak M, Leeser U, Buttner R, Perner S, Peifer M, and Reinhardt HC (2017). ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma. Cancer Res10.1158/0008-5472.CAN-16-3398.

Prof. Dr. Reinhard Büttner CMMC Cologne
Prof. Dr. Reinhard Büttner

Institute for Pathology

Principal Investigator A 1

Executive Board Member

+49 221 478 6320

+49 221 478 6360

Institute for Pathology

Kerpener Str. 62

50937 Cologne

https://pathologie.uk-koeln.de/institut/

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Reinhard Büttner

Link to PubMed

Prof. Dr. Margarete Odenthal CMMC Cologne
Prof. Dr. Margarete Odenthal

Institute for Pathology

Co-Principal Investigator A 1

+49 221 478 6351

+49 221 478 6360

Institute for Pathology

Kerpener Str. 62

50937 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Margarete Odenthal

Link to PubMed

Group Members

Dr. Priya Dalvi (PostDoc) 
Dr. Iris F. Macheleidt (PostDoc)
Marcel Schmiel (Medical student)
Miriam Weiß (Medical student)
Jie Wang (PhD student)
Hannah Eischeidt-Scholz (technician)

Figure 1

Figure 2

Figure 3