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.
Highlights
Cancer progression is often accompanied by profound changes in cellular identity
Additional markers of gastrointestinal differentiation, including Gastrokine 1, Cathepsin E and Galectin 4, were not expressed in these lesions (Figure 1—figure supplement 1C). All these markers were retained in lesions lacking either FoxA1 or FoxA2 alone (Figure 1C and Figure 1—figure supplement 1C). These data show that FoxA1 and FoxA2 are required for mucin production and key elements of the gastrointestinal differentiation program in NKX2-1-negative lung tumors in a functionally redundant manner
Lung adenocarcinomas can adopt a variety of differentiation states, and changes in cellular identity can have both prognostic and therapeutic implications for patients with this disease
Summary
Cancer progression is often accompanied by profound changes in cellular identity. Cellular identity, or differentiation state, influences intrinsic malignant potential, and response to therapy, even in tumors harboring the same targetable mutations (Cohen and Settleman, 2014). These tumors morphologically resemble a subtype of human lung cancer called invasive mucinous adenocarcinoma (IMA), which expresses gastrointestinal markers and is predominantly driven by KRAS mutations (Guo et al, 2017). We previously found that Nkx deletion in autochthonous lung tumors caused FoxA1/2 to re-localize from the regulatory elements of pulmonary-specific genes (such as Sftpa1) to those of genes (such as Hnf4a) that are expressed in both the GI tract and IMA (Snyder et al, 2013). We found that the cellular identity adopted by tumors was highly dependent on the context in which FoxA1/2 activity is lost, suggesting that a cell’s baseline epigenetic state can influence the identity it adopts in response to changes in lineage specifier expression
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