Human Lung Cell Methylation Atlas

Neoplastic growth of non-small cell lung cancer (NSCLC) is initiated by genetic and epigenetic alterations, occurring in the cell-of-origin. During evolution of the cancer genome, additional alterations are acquired, which accelerate tumorigenesis. These modifications are translated into unique gene expression profiles that determine the malignant phenotype, including aggressiveness and response to therapy. The altered epigenetic landscapes seen in cancer provide a mixture of both tumor- and cell-of-origin-specific signatures providing clues for thorough molecular characterization of tumors and biomarker development.

We have initiated the Human Lung Cell Methylome and Transcriptome Atlas project in close collaboration with our DZL partners in the Thorax Clinic in Heidelberg and the DKFZ teams of Prof. Rocio Sotillo and Prof. Ursula Klingmüller. To build a Human Lung Cell Methylome and Transcriptome Atlas, we will:

  1. define DNA methylomes and transcriptomes of normal lung, NSCLC and tumor-adjacent normal (TAN) cell populations. A novel cryopreservation protocol for lung samples will be used, followed by cell isolation from well-characterized specimens prior to whole genome bisulfite sequencing (WGBS), RNA-seq and scRNA-seq profiling.
  2. perform integrative bioinformatical analysis of DNA methylomes, transcriptomes and scRNA-seq data. Resulting data will be used to identify the NSCLC cell-of-origin and retrieve tumor-specific signatures. The Human Lung Cell Methylome Atlas will be complemented by 400 DNA methylomes from NSCLC using Illumina EPIC arrays as well as 100 WGBS data sets to initiate the molecular classification of NSCLC.
  3. utilize the data set for developing highly effective biomarkers for disease prediction, early detection and treatment response monitoring. A special feature of this compendium will be the development of epigenomic and transcriptomic profiles from TAN derived lung cells. TAN-specific signatures will be developed into and tested as novel biomarkers for early detection of NSCLC.

Together, this work will establish the Human Lung Cell Methylome and Transcriptome Atlas, a resource that will support international activities in translational lung cancer research.

Figure 1: Schematic representation of the Human Lung Cell Methylome and Transcriptome Atlas Project and its use for tumor classification and biomarker development. Images created with BioRender.

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