Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma

Abstract

Lineage transition in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of non-small cell lung cancer, as implicated by clinical observation of mixed ADC and SCC pathologies in adenosquamous cell carcinoma, remains a fundamental yet unsolved question. Here we provide in vivo evidence showing the transdifferentiation of lung cancer from ADC to SCC in mice: Lkb1-deficient lung ADC progressively transdifferentiates into SCC, via a pathologically mixed mAd-SCC intermediate. We find that reduction of lysyl oxidase (Lox) in Lkb1-deficient lung ADC decreases collagen disposition and triggers extracellular matrix remodelling and upregulates p63 expression, a SCC lineage survival oncogene. Pharmacological Lox inhibition promotes the transdifferentiation, whereas ectopic Lox expression significantly inhibits this process. Notably, ADC and SCC show differential responses to Lox inhibition. Collectively, our findings demonstrate the de novo transdifferentiation of lung ADC to SCC in mice and provide mechanistic insight that may have important implications for lung cancer treatment.

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

“…Our data showed that most of these genes were robustly decreased in SCC relative to ADC ( Supplementary Fig. 7a), consistent with our previous report 17 . We also found that ECM depletion by b-aminoproprionitrile (BAPN) treatment in KL mice significantly decreased the level of nuclear YAP in lung ADC ( Supplementary Fig.…”

“…Our previous study identified a very distinct expression pattern of ECM components between ADC and SCC 17 . In an effort to investigate the potential involvement of ECM remodelling in modulating YAP activity and lung cancer transdifferentiation, we checked an expanded the list of genes involved in ECM remodelling (for example, collagen family and the collagen crosslinking key enzyme Lox family).…”

“…It is worth noting that the ADC to SCC transdifferentiation is unlikely related to the classical cancer stem cell theory, in which only a small population of cancer cells were endowed with strong plasticity 32,33 . Indeed, multiple lines of evidences from previous study have supported that the majority, if not all, of lung ADC cells with Lkb1 deficiency are capable to transit to SCC 17 . As the Hippo signalling is actively involved in cell-fate determination from early embryonic development to adult tissue homeostasis, we speculate that YAP might potentially contribute to cell lineage transition and regulate cancer phenotypic plasticity.…”

“…Moreover, YAP inactivation promotes cell-fate conversion and tumour subtype transition. Our previous report shows that ADC and SCC might display different response towards certain therapies 17 . Thus, the cell-fate transition might represent a mechanism for lung ADC developing resistance towards YAP-targeted therapy.…”

“…Our recent work has shown that Lkb1 inactivation confers lung adenocarcinoma (ADC) with strong plasticity and makes them progressively transit to squamous cell carcinoma (SCC) in mice 17 . This provides the first evidence to support the potential cell fate conversion implicated by the clinical observation of lung adenosquamous carcinoma (Ad-SCC), which contains mixed adenomatous and squamous pathologies with identical genetic alterations 18 .…”