Cell of origin and molecular drivers of non-small cell lung cancer

Cell of origin and molecular drivers of non-small cell lung cancer

Rocío Sotillo

German Cancer Research Center (DKFZ), Heidelberg (Germany)

Date: 18/04/2024
Time: 12:30
CIC Lecture Hall
Host: Matthias Drosten
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The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD). Alveolar type 2 (AT2) cells have been readily recognized by the community to be the cells responsible to initiate LUAD. We employed lineage-tracing mouse models to investigate the cell-of-origin of Eml4-Alk LUAD, and show that Club and AT2 cells give rise to tumors. We demonstrate an epigenetic switch by which Club cells lose their lineage fidelity and acquire an AT2 phenotype after oncogenic transformation. Using single-cell RNA-sequencing we prove that Club cells transition to cellular states that until now had only been described during lung regeneration, providing an important link between lung cancer and regeneration (Chen et al. Nat Commun 2022).

Additionally, we are also interested in dissecting the impact of coincident alterations on the growth and progression of EML4-ALK lung cancers. We have inactivated a panel of putative tumor suppressor genes to study the synergistic and antagonistic effects of genomic alterations on Eml4-Alk tumors.

We combine CRISPR-Cas9-based induction of specific Eml4-Alk variants and tumor suppressor gene inactivation with tumor barcoding and high-throughput barcode sequencing to quantify tumor growth and metastatic ability.