Figure 7: Lkb1 deletion drives squamous transition of club cell- and BASC-derived KRAS+ populations.
From: Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2
(a) Schematic of Lkb1 deletion in three-dimensional KRAS+ cultures derived from non-basal tracheal cells, bronchioalveolar stem cells (BASCs) or alveolar type II (AT2) cells. (b) Representative brightfield images of KRAS+ colonies from alveolar type II cells treated with placebo or 4-hydroxy tamoxifen for 7 days, scale bar, 200 μm. (c) RT-qPCR for Lkb1and Sox2 in tumour organoid 3D cultures treated with 100 nM tamoxifen for 9–12 days, mean±s.e.m. on log2 scale is graphed, n varies by sample. (d) Representative haematoxylin and eosin staining from non-basal cell derived subcutaneous tumour (left) and BASC-derived orthotopic tumours (right), tumour histologies are indicated, scale bar, 100 μm. (e) Model: Here we combined Cre and FlpO recombinase technologies to temporally delete Lkb1 in established KRAS-driven lung adenocarcinomas. Serially transplanted KRAS+ adenocarcinoma could transdifferentiate into squamous disease when Lkb1 was deleted in the transplanted tumours. The Polycomb Repressive Complex 2 (PRC2), which represses genes through the histone H3K27me3 mark, was abrogated in the KRAS/Lkb1 squamous tumours through loss of expression of the EED subunit. This led to derepression of key squamous genes including Sox2, ΔNp63 and Ngfr. See also Supplementary Fig. 7a–c.
