P13 - Dissecting mechanisms of lung cancer transformation

The complex architecture of the respiratory system composed of different cell types that take over unique functions within the human body contributes to the complexity of different cancer types that arise within the lung. For example, the most common lung cancer, namely lung adenocarcinoma, is thought to arise from alveolar type 2 (AT2) cells, while rare pulmonary neuroendocrine cells (PNECs) are thought to be small cell lung cancer (SCLC) “precursor” cells1. Interestingly, these cells seem to be selectively sensitive to toxins and injuries: while lung adenocarcinoma are enriched in females and never-smokers, SCLC is primarily associated with smoking exposure1,2. Not surprisingly, these cancer types are unique in their genetic profiles and undergo individual selection processes that contribute to the specific morphology3. Personalized therapies that target molecular dependencies in these lung tumors need to account for these differences in order to increase the likelihood of therapeutic efficacy4. In addition, cancer cells undergo drug-induced transformation processes that are associated with loss of activity of targeted drugs. Therefore, a mechanistic understanding of the differentiation processes of lung cancer cells and the contribution of the tumor microenvironment is key to optimize future therapies.

We will apply innovative, state-of-the art technology to dissect the molecular principles of cellular transformation and will be able to test individual hypotheses using functional lung cancer models including organoids. The project is specifically tailored to address three major points:

1. Establishment of a clinically annotated library of lung cancer specimen and organoids.
2. Characterization of the transcriptomic transformation patterns in lung cancer samples and organoid models.
3. Implementation of cellular models of transformation using CRISPR-based genome editing.

These analyses will help us to identify key mechanisms that contribute to cellular transformation and may potentially open routes for the identification of novel drug regimens.

Literature:
1. Xu, J., Yu, H. & Sun, X. Less Is More: Rare Pulmonary Neuroendocrine Cells Function as Critical Sensors in Lung. Dev Cell 55, 123–132 (2020).
2. Poirier, J. T. et al. New Approaches to SCLC Therapy: From the Laboratory to the Clinic. Journal of Thoracic Oncology 15, 520–540 (2020).
3. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: The next generation. Cell vol. 144 646–674 Preprint at https://doi.org/10.1016/j.cell.2011.02.013 (2011).
4. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction. Cell vol. 136 823–837 Preprint at https://doi.org/10.1016/j.cell.2009.02.024 (2009).