Center for Molecular Medicine Cologne

Meder, Lydia - CAP 23

Deciphering therapeutic targets in the lung cancer metastatic cascade

Introduction

Lung cancers are aggressive malignancies that are often detected at an extensive stage of disease with systemic metastasis to the lymph nodes, liver, adrenal glands, brain, and bone.
Bone metastases cause severe pain due to sensitive neurons in the periosteum and bone marrow. They are accompanied by impaired bone remodeling leading to an osteolytic or osteosclerotic cycle. In this process, osteoblasts, osteoclasts and tumor cells communicate via secreted signal molecules as soon as the tumor cells colonize the bone. Tumor cells capable of osteomimicry have a higher ability to form bone metastases. In this process, tumor cells express osteomarkers and factors that regulate the interplay between tumor cells and bone tumor microenvironment (TME) cells.
Local and systemic interventions are available for the treatment of patients with bone tumors. In cases of pain symptoms or fracture risk, radiation is the treatment of choice. It can be performed with continuous systemic therapy. Surgical treatment is another option.
Systemic measures include causal therapy and administration of bone modifying agents (bisphosphonates, RANKL antibodies). Immune checkpoint blockade in combination with platinum-based chemotherapies has been shown to be effective in the treatment of advanced and metastatic lung cancer. In this context, immune checkpoint blockade is designed to reactivate the host immune system to fight tumor cells. Immune cells of the adaptive and innate immune systems have been shown to be stimulated by immune checkpoint blockade. However, this combined treatment does not specifically target metastasis, which is nevertheless one of the common complications.
The mechanisms underlying the organ-specific metastatic process are still largely unknown. Therefore, there is not only an urgent need for new therapies to treat metastatic lung cancer, but also to explore new treatment options that protect lung cancer patients from metastasis, especially after relapse.

Research Activities

One factor that likely regulates the bone metastasis microenvironment and contributes to tumor progression is Lin28. LIN28A and LIN28B are RNA-binding proteins that mainly regulate miRNA superfamily let-7 and reprogramming stem cell properties. In adult bone marrow hematopoietic progenitors, LIN28B enables multiple lineage reconstitution and fetal-like lymphopoiesis. Moreover, LIN28B regulates bone morphogenic proteins (BMPs) and promotes tumor progression in a TGFβ- and IL-6-dependent manner. Therefore, LIN28B has been shown to promote metastasis, particularly to bone.
We and others have described LIN28B as an independent marker of poor prognosis and an indicator of highgrade progressive carcinoma subsets undergoing epithelial-to-mesenchymal transition (EMT) and exhibiting increased tumor angiogenesis.
An important angiogenic pathway involved in metastasis is the angiopoietin signaling axis. For example, angiopoietin-2/integrin-β1-dependent signaling induces EMT, which triggers tumor cell migration and invasion and thus contributes to lung cancer metastasis. In addition, angiopoietin-2 confers a survival advantage to cancer cells in the bone marrow niche and may play a critical role in systemic formation of pre-metastatic niches.

Clinical relevance

The clinical implementation of preclinical findings benefits from profound in vitro- and in vivo-systems for an efficient translation into personalized medicine for cancer patients. Our expertise comprises inducible genetically engineered cancer models, organ-specific tumor cell injection models, in vivo imaging, patient-derived xenograft transplantation, humanization strategies, serial blood collections and serial different therapy regimens. We are excited by designing ex vivo modified cancer cell lines transferred into orthotopically injected cancer models, to subsequently investigate the effect of previously identified targets in extra-/intravasation, in the tumor-immune-microenvironment and on therapy sensitivity in vivo. It is our pleasure to provide the bridge from bench-to-bedside and from bedside-to-bench to improve therapy outcome for cancer patients.

Our aims and further perspectives

Lung cancer is an aggressive malignancy with early systemic metastasis to lymph nodes, liver, ad-renal glands, brain and bone. The presence of metastases correlates negatively with treatment outcomes in patients receiving immunotherapy. Therefore, we aim to interrupt the metastatic cascade of lung cancer with novel therapeutic strategies. In this context, we focus on:

  • Unraveling the molecular mechanisms of tumor cell intravasation and extravasation into blood and lymphatic vessels.
  • Deciphering the interaction of tumor cells with their microenvironment in the process of organ homing and colonization.
  • Develop novel immunomodulatory therapies to suppress metastatic spread and reduce metastatic burden.
  • Borchmann S, Selenz C, Lohmann M, Ludwig H, Gassa A, Brägelmann J, Lohneis P, Meder L, Mattlener J, Breid S, Nill M, Fassunke J, Wisdom AJ, Compes A, Gathof B, Alakus H, Kirsch D, Hekmat K, Büttner R, Reinhardt HC, Hallek M, Ullrich RT.J Immunother Cancer. Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors. 2022 Oct;10(10):e004781. doi: 10.1136/jitc-2022-004781.PMID: 36223955
  • Brägelmann, J., Lorenz, C., Borchmann, S., Nishii, K., Wegner, J., Meder, L., Ostendorp, J., Ast, D.F., Heimsoeth, A., Nakasuka, T., Hirabae, A., Okawa, S., Dammert, M.A., Plenker, D., Klein, S., Lohneis, P., Gu, J., Godfrey, L.K., Forster, J., Trajkovic-Arsic, M., Zillinger, T., Haarmann, M., Quaas, A., Lennartz, S., Schmiel, M., D'Rozario, J., Thomas, E.S., Li, H., Schmitt, C.A., George, J., Thomas, R.K., von Karstedt, S., Hartmann, G., Büttner, R., Ullrich, R.T., Siveke, J.T., Ohashi, K., Schlee, M., Sos, M.L. N MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Nat Commun. 2021 Sep 17;12(1):5505.
  • Kanne, J., Hussong, M., Isensee, J., Muñoz-López, Á., Wolffgramm, J., Heß, F., Grimm, C., Bessonov, S., Meder, L., Wang, J., Reinhardt, H.C., Odenthal, M., Hucho, T., Büttner, R., Summerer, D., Schweiger, M.R. Pericentromeric Satellite III transcripts induce etoposide resistance. Cell Death Dis. 2021 May 24;12(6):530.
  • Meder, L., Florin, A., Ozretić, L., Nill, M., Koker, M., Meemboor, S., Radtke, F., Diehl, F., Ullrich, R.T., Odenthal, M., Büttner, R., Heukamp, L.C. Notch1 deficiency induces tumor cell accumulation inside the bronchiolar lumen and increases TAZ expression in an autochthonous KrasLSL-G12V driven lung cancer mouse model. Pathol Oncol Res. 2021 Apr 16;27:596522.
  • Selenz C, Compes A, Nill M, Borchmann S, Odenthal M, Florin A, Brägelmann J, Büttner R, Meder L, Ullrich RT. EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer.Cancers (Basel). 2022 Aug 16;14(16):3943. doi: 10.3390/cancers14163943.PMID: 36010935 
  • Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C.D., Nieper, P., Feldmann, T., Merkel, O., Lorsy, E., da Palma Guerreiro, A., von Jan, J., Kisis, I., Wasserburger, E., Claasen, J., Faitschuk-Meyer, E., Altmüller, J., Nürnberg, P., Yang, T.P., Lienhard, M., Herwig, R., Kreuzer, K.A., Pallasch, C.P., Buettner, R., Schäfer, S.C., Hartley, J., Abken, H., Peifer, M., Kashkar, H., Knittel, G., Eichhorst, B., Ullrich, R.T., Herling, M., Reinhardt, H.C., Hallek, M., Schweiger, M.R., Frenzel, L.P. Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies. Blood. 2022 Jun 15:blood.2021014304.
  • Yu X, Eischeid-Scholz H, Meder L, Kondylis V, Büttner R, Odenthal M.Hum Cell. SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion.2022 Nov;35(6):1766-1784. doi: 10.1007/s13577-022-00765-7. Epub 2022 Sep 1.PMID: 36050615 Free PMC article.
  • Brägelmann, J., Lorenz, C., Borchmann, S., Nishii, K., Wegner, J., Meder, L., Ostendorp, J., Ast, D.F., Heimsoeth, A., Nakasuka, T., Hirabae, A., Okawa, S., Dammert, M.A., Plenker, D., Klein, S., Lohneis, P., Gu, J., Godfrey, L.K., Forster, J., Trajkovic-Arsic, M., Zillinger, T., Haarmann, M., Quaas, A., Lennartz, S., Schmiel, M., D'Rozario, J., Thomas, E.S., Li, H., Schmitt, C.A., George, J., Thomas, R.K., von Karstedt, S., Hartmann, G., Büttner, R., Ullrich, R.T., Siveke, J.T., Ohashi, K., Schlee, M., Sos, M.L. N MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I. Nat Commun. 2021 Sep 17;12(1):5505.

  • Kanne, J., Hussong, M., Isensee, J., Muñoz-López, Á., Wolffgramm, J., Heß, F., Grimm, C., Bessonov, S., Meder, L., Wang, J., Reinhardt, H.C., Odenthal, M., Hucho, T., Büttner, R., Summerer, D., Schweiger, M.R. Pericentromeric Satellite III transcripts induce etoposide resistance. Cell Death Dis. 2021 May 24;12(6):530.
  • Meder, L., Florin, A., Ozretić, L., Nill, M., Koker, M., Meemboor, S., Radtke, F., Diehl, F., Ullrich, R.T., Odenthal, M., Büttner, R., Heukamp, L.C. Notch1 deficiency induces tumor cell accumulation inside the bronchiolar lumen and increases TAZ expression in an autochthonous KrasLSL-G12V driven lung cancer mouse model. Pathol Oncol Res. 2021 Apr 16;27:596522.
  • Mittenbühler, M,J., Saedler, K., Nolte, H., Kern, L., Zhou, J., Qian, S.B., Meder, L., Ullrich, R.T., Brüning, J.C., Wunderlich, F.T. Hepatic FTO is dispensable for the regulation of metabolism but counteracts HCC development in vivo. Mol Metab. 2020 Sep 19:101085.
  • Volz, C., Breid, S., Selenz, C., Zaplatina, A., Golfmann, K., Meder, L., Dietlein, F., Borchmann, S., Chatterjee, S., Siobal, M., Schöttle, J., Florin, A., Koker, M., Nill, M., Ozretić, L., Uhlenbrock, N., Smith, S., Büttner, R., Miao, H., Wang, B., Reinhardt, H.C., Rauh, D., Hallek, M., Acker-Palmer, A., Heukamp, L.C., Ullrich, R.T. Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC. Cell Rep. 2020 Apr 28;31(4):107568.
  • Borchmann, S., Cirillo. M., Goergen, H., Meder, L., Sasse, S., Kreissl, S., Bröckelmann, P.J., von Tresckow, B., Fuchs, M., Ullrich, R.T., Engert, A. Pretreatment Vitamin D Deficiency Is Associated With Impaired Progression-Free and Overall Survival in Hodgkin Lymphoma. J Clin Oncol. 2019 Oct 17:JCO1900985.
  • Macheleidt, I.F., Dalvi, P.S., Lim, S.Y., Meemboor, S., Meder, L., Käsgen, O., Müller, M., Kleemann, K., Wang, L., Nürnberg, P., Rüsseler, V., Schäfer, S.C., Mahabir, E., Büttner, R., Odenthal, M. Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations. Mol Oncol. 2018 Nov;12(11):1965-1979.
  • Golfmann, K.*, Meder, L.*, Koker, M., Volz, C., Borchmann, S., Tharun, L., Dietlein, F., Malchers, F., Florin, A., Büttner, R., Rosen, N., Rodrik-Outmezguine, V., Hallek, M., Ullrich, R.T. Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1 amplified breast cancer. Oncogene. 2018 Oct;37(42):5682-5693.
  • 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, H.A., Odenthal, M., Buttner, R., Wolf, J., Hallek, M., Herling, M., von Bergwelt-Baildon, M., Reinhardt, H.C., Ullrich, R.T. Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res. 2018 Aug 1;78(15):4270-4281.
  • Meder, L., Konig, K., Dietlein, F., Macheleidt, I., Florin, A., Ercanoglu, M.S., Rommerscheidt-Fuss, U., Koker, M., Schon, G., Odenthal, M., Klein, F., Buttner, R., Schulte, J.H., Heukamp, L.C., Ullrich, R.T. LIN28B enhanced tumorigenesis in an autochthonous KRAS(G12V)-driven lung carcinoma mouse model. Oncogene. 2018 May;37(20):2746-2756.
  • Meder, L., Büttner R., Odenthal M. Notch signaling triggers the tumor heterogeneity of small cell lung cancer. J Thorac Dis. 2017 Dec;9(12):4884-4888.
  • Latteyer, S., Tiedje, V., Konig, K., Ting, S., Heukamp, L.C., Meder, L., Schmid, K.W., Fuhrer, D., Moeller, L.C. Targeted next-generation sequencing for TP53, RAS, BRAF, ALK and NF1 mutations in anaplastic thyroid cancer. Endocrine. 2016 Dec;54(3):733-741.
  • Ortiz-Cuaran, S., Scheffler, M., Plenker, D., Dahmen, L., Scheel, A.H., Fernandez-Cuesta, L., Meder, L., Lovly, C.M., Persigehl, T., Merkelbach-Bruse, S., Bos, M., Michels, S., Fischer, R., Albus, K., Konig, K., Schildhaus, H.U., Fassunke, J., Ihle, M.A., Pasternack, H., Heydt, C., Becker, C., Altmuller, J., Ji, H., Muller, C., Florin, A., Heuckmann, J.M., Nuernberg, P., Ansen, S., Heukamp, L.C., Berg, J., Pao, W., Peifer, M., Buettner, R., Wolf, J., Thomas, R.K., Sos, M.L. Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors. Clin Cancer Res. 2016 Oct 1;22(19):4837-4847.
  • Meder, L., Buettner, R. Elucidating alternative pathways triggering small cell lung carcinoma tumor biology. Transl Cancer Res. 2016 Aug 5,S363-S365.
  • Meder, L., Konig, K., Ozretic, L., Schultheis, A.M., Ueckeroth, F., Ade, C.P., Albus, K., Boehm, D., Rommerscheidt-Fuss, U., Florin, A., Buhl, T., Hartmann, W., Wolf, J., Merkelbach-Bruse, S., Eilers, M., Perner, S., Heukamp, L.C., Buettner, R. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer. 2016 Feb 15;138(4):927-38.
  • Meder, L., König, K., Fassunke, J., Ozretić, L., Wolf, J., Merkelbach-Bruse, S., Heukamp, L.C., Buettner R. Implementing amplicon-based next generation sequencing in the diagnosis of small cell lung carcinoma metastases. Exp Mol Pathol. 2015 Dec;99(3):682-6.
  • König, K., Peifer M., Fassunke, J., Ihle, M.A., Künstlinger, H., Heydt, C., Stamm, K., Ueckeroth ,F., Vollbrecht, C., Bos, M., Gardizi, M., Scheffler, M., Nogova, L., Leenders, F., Albus, K., Meder, L., Becker, K., Florin ,A., Rommerscheidt-Fuss, U., Altmüller, J., Kloth, M., Nürnberg, P., Henkel, T., Bikár, S.E., Sos, M.L., Geese, W.J., Strauss, L., Ko Y.D., Gerigk, U., Odenthal, M., Zander, T., Wolf, J., Merkelbach-Bruse, S., Buettner, R., Heukamp, L.C. Implementation of Amplicon Parallel Sequencing Leads to Improvement of Diagnosis and Therapy of Lung Cancer Patients. J Thorac Oncol. 2015 Jul;10(7):1049-57.
  • Chatterjee, S., Heukamp, L.C., Siobal, M., Schöttle, J., Wieczorek, C., Peifer, M., Frasca, D., oker, M., König, K., Meder, L., Rauh, D., Buettner, R., Wolf, J., Brekken, R.A., Neumaier, B., Christofori, G., Thomas, R.K., Ullrich, R.T. Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest. 2013 Apr;123(4):1732-40
  • König, K., Meder, L., Kröger, C., Diehl, L., Florin, A., Rommerscheidt-Fuss, U., Kahl, P., Wardelmann, E., Magin, T.M., Buettner, R., Heukamp, L.C. Loss of the keratin cytoskeleton is not sufficient to induce epithelial mesenchymal transition in a novel KRAS driven sporadic lung cancer mouse model. PLoS One. 2013;8(3):e57996.
  • Heuckmann, J.M., Balke-Want, H., Malchers, F., Peifer, M., Sos, M.L., Koker, M., Meder, L., Lovly, C.M., Heukamp, L.C., Pao, W., Küppers, R., Thomas R.K. Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res. 2012 Sep 1;18(17):4682-90.
  • Heukamp, L.C., Thor, T., Schramm, A., De Preter, K., Kumps, C., De Wilde, B., Odersky, A., Peifer, M., Lindner, S., Spruessel, A., Pattyn, F., Mestdagh, P., Menten, B., Kuhfittig-Kulle, S., Künkele, A., König, K., Meder, L., Chatterjee, S., Ullrich, R.T., Schulte, S., Vandesompele, J., Speleman, F., Büttner, R., Eggert, A., Schulte, J.H. Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci Transl Med. 2012 Jul 4;4(141):141ra91.
PD Dr. Lydia Meder CMMC Cologne
PD Dr. Lydia Meder

MSSO & Clinic I of Internal Medicine

CMMC - PI - CAP 23

+49 221 478 96815

MSSO & Clinic I of Internal Medicine

Kerpener Str. 62

50937 Cologne

Publications - Lydia Meder

Link to PubMed

Group members

Tabea Gewalt, PhD student
Charlotte Orschel, MD student