Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
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This work was supported in part by PF-12-151-01-DMC from the American Cancer Society, the Uniting Against Lung Cancer Young Investigator Award and NCI K22 CA201036 (to C.F.B.), R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402 RFA-HL-09-004, American Cancer Society Research Scholar Grant RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O’Conner March of Dimes Starter Award and the Harvard Stem Cell Institute (to C.F.K.), the NIH/NCI P01 CA120964, 5R01CA163896-04, 1R01CA195740-01, 5R01CA140594-07, 5R01CA122794-10 and 5R01CA166480-04 grants and Support from Gross-Loh Family Fund for Lung Cancer Research and Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute (to K.K.W.).
Zhang, Haikuo; Fillmore Brainson, Christine; Koyama, Shohei; Redig, Amanda J.; Chen, Ting; Li, Shuai; Gupta, Manav; Garcia-de-Alba, Carolina; Paschini, Margherita; Herter-Sprie, Grit S.; Lu, Gang; Zhang, Xin; Marsh, Bryan P.; Tuminello, Stephanie J.; Xu, Chunxiao; Chen, Zhao; Wang, Xiaoen; Akbay, Esra A.; Zheng, Mei; Palakurthi, Sangeetha; Sholl, Lynette M.; Rustgi, Anil K.; Kwiatkowski, David J.; Diehl, J. Alan; Bass, Adam J.; Sharpless, Norman E.; Dranoff, Glenn; Hammerman, Peter S.; Ji, Hongbin; Bardeesy, Nabeel; Saur, Dieter; Watanabe, Hideo; Kim, Carla F.; and Wong, Kwok-Kin, "Lkb1 Inactivation Drives Lung Cancer Lineage Switching Governed by Polycomb Repressive Complex 2" (2017). Toxicology and Cancer Biology Faculty Publications. 55.