Molecular Mechanisms in Lung Cancer
Our aim is to understand the molecular mechanisms mediated by tumor cell stromal cell crosstalk by analyzing secretome, miRome, epigenome and transcriptome profile to develop new therapeutic targets to cancer.
The Savai laboratory is mainly interested in several aspects of lung cancer namely cancer progression, cancer treatment, and cancer imaging.
Dr. Rajkumar Savai is appointed as a principle investigator in the Department of Lung Development and Remodelling at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, where he serves as a Principal Investigator, leading the research group “Molecular Mechanisms of Lung Cancer”. Dr. Savai is jointly appointed at the Department of Internal Medicine (Pulmonology/Oncology), at the University Hospital Giessen and Marburg. He is also project leader and member of the German Lung Center (DZL), Collaborative Research Center on Cardiopulmonary Systems (ECCPS) and Collaborative Research Centre on Lung Diseases (UGMLC). He has received national and international awards for his scientific accomplishments and has been invited to present his work at several national and international conferences. He published 45 research articles in well-renowned scientific journals such as Nature Medicine, Nature Chemical Biology, Science translational medicine, Circulation and Journal of Clinical Investigation, Cancer Research, Oncogene, American Journal of Respiratory and Critical Care Medicine etc.
Statistically, lung cancer is the leading cause of death from cancer worldwide, regardless of gender - it is responsible for approximately 170.000 deaths per year, corresponding to one-sixth of all cancer deaths. Lung cancer affects a greater number of people worldwide (approximately 1.2 million new cases per year) than does any other cancer. Because lung cancer patients are typically diagnosed at a late/severe stage of the disease, the five-year survival rate is less than 15 %.
Savai lab aimed to analyze basic cellular and molecular mechanisms of lung cancer growth and metastasis. Specifically, focused on the relationship between tumor cells and stromal cells in the lung microenvironment. They follow the view/concept that increasing our knowledge in this area is critical for further advances in the early diagnosis, prevention, and treatment of lung cancer, and thus Savai lab placed major emphasis on addressing the following topics.
Savai lab established several xenograft/orthrotropic models in which mouse and human tumor xenografts are implanted in immune-deficient mice (athymic nude mice and SCID mice) or wild type mouse. Orthotropic/xenograft models are established using several human and mouse lung cell lines. For the development of primary tumors, tumor cells are instilled intratracheally into mice. For the development of lung tumor metastasis, i) tumor cells are injected via tail vein (i.v.), and ii) primary tumors are surgically removed and mice are left to develop lung metastasis. In addition, we are using transgenic lung tumor models employing oncogenes such as KRas LA2 and KRas GD12 (collaboration with Prof. Tyler Jacks), cRaf and bRaf (collaboration with Prof. Ulf Rapp). To gain new insight into lung tumor evolution and progression and to monitor therapeutic effects, we introduced or optimized several recently developed high-resolution small-animal in vivo imaging techniques such as µCT, multi-slice CT (MSCT), and fpvCT (collaboration with Giessen Radiology Department).
Savai lab is interested to study the tumor microenvironment role in cancer. The host microenvironment is increasingly recognized as an essential component of the tumorigenesis. The interaction between the different cancer cells and stromal cells results in tumor progression. The tumor stroma, a “compartment providing the connective-tissue framework of the tumor”, includes cellular components as inflammatory and immune cells, cells of the vasculature, fibroblasts, endothelial cells and smooth muscle cells, along with blood vessels and the extracellular matrix. Deciphering the molecular cross talk/ interaction between tumor cells and lung stromal cells represents the major research focus of this group, striving to harness the results for developing novel cancer therapy modalities that focus on tumor microenvironment. Savai lab is mainly interested to understand the below major cell types in stroma.
1. Tumor-Associated Macrophages (TAMs): Their Role in Cancer Invasion and Metastasis
Macrophages represent a key component of the innate immune system, with effector functions that are far beyond their classical functions as phagocytic, antigen-presenting immune cells. With their plasticity and ability to secrete a wide variety of cytokines, chemokines and growth factors they direct countless regulatory mechanisms and exert a huge influence on variety of cellular processes.
As macrophage therapeutic strategies we will (i) blocking monocyte recruitment, (ii) macrophage activation (iii) depleting or decreasing macrophage survival and (iv) re-educating TAMs toward anti-tumor immune responses.
2. Circulating Fibrocytes (CFs): Their Role in Cancer Invasion and Metastasis
Circulating Fibrocytes (CFs) are a mesenchymal progenitor cell population, which derives from the bone marrow and possess features of both hematopoietic and mesenchymal cells. The role of circulating fibrocytes has been defined in many diseases particularly in the pulmonary field. However, no research focus has been placed so far on the influence of CFs in the tumor microenvironment. The hypothesis of this study is that bone marrow derived circulating fibrocytes are involved in the progression of adenocarcinomas and lead to increased tumor proliferation, migration and augmented tumor vascularization, and may be used as a target cell type for therapy.
Aim 3: Targeting of tumor and its vasculature with small molecule inhibitors of tyrosine kinase, phosphodiesterase (PDEs) and DNA methylation inhibitors.
Our aim is to understand the molecular mechanisms mediated by tumor cell stromal cell crosstalk by analyzing secretome, miRome, epigenome and transcriptome profile to develop new therapeutic targets against cancer.
Dr. med. Philipp Arndt
Dr. med. Michael Cekay