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.
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.
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.
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:
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.
Tabea Gewalt, PhD student
Charlotte Orschel, MD student