FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer

Abstract

Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FoxA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner.

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

“…7B). Similar GI transformation is also reported for Nkx2-1 mutant AT2 cells and lung tumor cells, possibly as the result of ectopic transcriptional activation by FOXA1/2 that are freed from their normal partner NKX2-1 (35,37). However, Nkx2-1 mutant AT1 cells are notably different from mutant AT2 cells in that the former do not express Pdx1 nor do they have uniform Hnf4a expression, suggesting that cell of origin influences the repertoire of activatable GI genes.…”

“…6E and SI Appendix, Fig. S5D) (34)(35)(36)(37)(38)(39)(40). However, other key transcriptional regulators including Pdx1 and Cdx2 that were activated upon Nkx2-1 deletion or Sox2 whose ectopic expression drove esophageal differentiation in AT2 and lung tumor cells (34,37,38) were absent in both up-regulated groups (SI Appendix, Fig.…”

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

“…Analyses of the histologic spectrum of LUAD in patients and mouse models have identified two cellular differentiation programs that impose barriers to lung tumor progression (Winslow et al 2011;Snyder et al 2013;Li et al 2015;Camolotto et al 2018). Initially, NKX2-1/FOXA1/2 transcriptional networks maintain a well-differentiated pulmonary identity.…”

“…1a and Supplementary Figure 1a). In lung tumors, NKX2-1 is required for sustained expression of surfactant protein genes including Sftpb and Sftpc (Snyder et al 2013) as well as the cell surface protein CD36 (Camolotto et al 2018). Accordingly, immunohistochemical analysis showed that mucinous NKX2-1-negative tumors in BPN mice did not express pro-surfactant proteins B and C as well as CD36 ( Supplementary Figure 1b).…”

“…In contrast to EGFR mutant LUAD, NKX2-1 expression is lost in a subset of KRAS and BRAF mutant tumors (Skoulidis et al 2015;Zhang et al 2015). In a Kras G12D -mutant LUAD GEMM, Nkx2-1 deletion enhances tumor growth and causes pulmonary to gastric transdifferentiation (Snyder et al 2013), which is driven by the transcription factors FoxA1 and FoxA2 (Camolotto et al 2018). Stochastic NKX2-1 loss has a similar effect on a distinct KRas-mutant LUAD GEMM (Maeda et al 2012) and can promote metastasis when tumors progress in the absence of p53 function (Winslow et al 2011).…”