For many years, a prevailing paradigm in cancer biology was that mutational aberrations in neoplastic cells are both necessary and sufficient for tumorigenesis, and thus cancer was believed to be a cell-autonomous process. However, it is now recognized that tumors are heterogeneous “organs”, composed of diverse stromal components, which are important players and not just innocent bystanders in the tumorigenic process. The tissue-derived and tissue-specific tumor microenvironment or niche contains a plethora of cell types that act in concert to support the tumor structure. This mutual cooperation between tumor cells and their hosting niche eventually leads to cancer progression and is also involved in metastasis development and even determines anti neoplastic drug sensitivity. The idea that cancer cells evolve with their niche fundamentally changes how we view cancer.
Cancer development thus essentially requires a successful niche construction and this framework is critically involved in the selection of cancer driver mutations. Consequently, the understanding of tumor cell evolution in the context of its niche requires a deeper knowledge of the non-neoplastic cellular components and a comprehensive analysis of cell–cell interactions within the heterogeneous tumor tissue. Expanding our knowledge of that aspect of tumor complexity is fundamental for the development of novel therapeutic strategies. Notably, targeting niche components may allow shaping approaches for treatment that are less sensitive to tumor cell plasticity. Therefore, efforts are required to expand the to-date limited knowledge of the crucial tumor niche components and the mechanisms of their co-evolution with tumor cells.
Importantly, compared with other organs, the normal lung architecture represents a special microenvironment because of its high degree of vascularization (it is the only organ passed by the entire blood flow), double vascular bed supply, hyper-oxygenation, specialized macrophage pool and distinct bone marrow interplay to mount a potent immune defense in case of acute microbial challenge. Its rich vascularization makes the lung a very suitable environment for metastatic outgrowth. However, our understanding of the niche components of the lung parenchyma being centrally involved in lung cancer mutational drive, growth, metastasis and resistance to currently available therapies is still rudimentary. Among the lung niche components, inflammation has emerged as an important player and it has become evident that an inflammatory microenvironment is an essential component of all lung cancer types. Many environmental causes of lung cancer and risk factors are associated with some form of chronic inflammation, such as chronic infections, tobacco smoking and inhaled pollutants. Most importantly, solid malignancies can also trigger an intrinsic inflammatory response (tumor-associated inflammation) that induces a pro-tumorigenic microenvironment and favors malignant cell growth.
Correspondingly, the lung cancer microenvironment typically contains a drastically increased number of innate (monocyte-derived cells such as macrophages and circulating fibrocytes) and adaptive immune cells (CD4+ and CD8+ T-cells). Notably, tumor-associated macrophages (TAMs) may represent up to 50% of the total tumor mass. How these immune cells interact with lung cancer cells - by means of direct contact or paracrine mechanisms – is still largely unresolved. However, there is now clear evidence that interference with such interaction offers as novel potent strategy to treat lung cancer. Thus, a deeper understanding of the immune cell subpopulations and functional phenotypes (plasticity) that – upon interaction with lung parenchymal cells - characterize the lung cancer microenvironmental niche is essential for harnessing such knowledge for future tailored therapies targeting the cancer microenvironment. Employing both innate and adaptive lung immunity for interference with lung cancer growth and metastasis and even for regressing lung cancer, offers a most appealing novel approach in the therapy of this world-leading cancer threat.
These topics will be addressed in three work packages. The studies will based on a large number of mouse lung cancer models (including human xenografts), cell culture and human organoid models of lung cancer and its niche, extensive biobank material of human lung tumors in all cancer stages and a broad array of analytical techniques, most of them already available in the consortium.
The long-term goal of this research area is the identification of novel therapeutic strategies to target lung cancer. Cancer cells require an enormous variety of genetic changes to elicit tumorigenesis. The clinical therapies for many types of human cancers have mainly focused on the malignant cancer cell itself and have made great achievements, yet therapy of many cancers still remains an unresolved challenge. This is particularly true for lung cancer and may partly be caused by the important role and the specific features of the cancer cell-harboring lung microenvironment. This niche substantially participates in the initiation, progression and metastatic spreading of lung cancer, providing hope that therapeutic “niche targeting” represents a novel efficient avenue for lung cancer treatment. To achieve this goal, transgenic mouse technology, humanized mouse models, human lung organoid models and human biobank materials will be employed. Imaging and “omics” technologies will be scaled-down to the single cell level, but also applied to resolve intact organismal questions in animal models and lung cancer patients. Novel targets identified for selectively manipulating the lung cancer niche will be addressed by employing screening platforms, small molecule libraries and innovative molecular tools. Moreover, cell-based therapies will further broaden the therapeutic armamentarium employed to target tumor and metastatic niches. Such approaches will be forwarded to the clinical arena by capitalizing on the board expertise in investigator-initiated early trials and industry-sponsored clinical studies available in the scientific environment of the Institute for Lung Health.