Role of PTEN in basal cell derived lung carcinogenesis

Abstract

Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting KrasG12D activation and transforming growth factor β receptor type II (TGFβRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than KrasG12D with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than KrasG12D initiated tumors. That PTEN deletion did not increase lung SCC formation compared to KrasG12D activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types.

Non-small-cell lung cancers: a heterogeneous set of diseases

“…Loss of the tumour suppressor liver kinase B1 ( Lkb1 ; also known as Stk11 ) in the oncogenic Kras G12D model produces a mixture of tumours, including ADC, SCC and large cell carcinoma 65 . Similarly, a mixture of ADC and SCC is found in mice after targeted deletion of Pten or transforming growth factor-β receptor 2 ( Tgfbr2 ) in proximal cells with keratin-driven Cre alleles in the Kras G12D background 66 . Expression of the transcription factor Sox2 (overexpressed in 20–60% of human SCCs) in club cells and BASCs produces lung tumours that express the marker p63 but histologically resemble ADCs 7 .…”

Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance

“…Additionally, some data suggest that Krt5 expressing cells may be able to give rise to LUADs. Specifically, Krt5 CrePR -mediated Kras activation or Pten deletion resulted in mixed LSCC and LUAD tumors, although as the authors point out, this may have been due to leakiness of the promoter that was used (51). Thus, it appears that the cell of origin may dictate the lung cancer subtype that forms for certain mutations such as Trp53 but not for others such as Kras and Sox2 .…”

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression

“…The Ad-Cre inhalation method may specifically target more distal lung progenitors, thus selecting for tumor cells of origin that predispose toward an ADC phenotype. Several studies have targeted deletion of squamous tumor suppressors, such as Pten , or activation of squamous oncogenes, such as Sox2 , but despite these efforts, only partial SCC differentiation was observed in either model (Lu et al, 2010; Malkoski et al, 2013). Here, we demonstrate that deletion of both Pten and Lkb1 , via the traditional Ad-Cre inhalation system, is able to produce lung tumors of purely squamous phenotype.…”

“…PTEN negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, and PI3K pathway gene alterations are found in more than half of human lung SCCs (Cancer Genome Atlas Research Network, 2012). In the mouse model, Pten deletion alone in airway basal cells can initiate lung tumor formation, but with low tumor incidence, long latency, and mixed ADC and SCC phenotype (Malkoski et al, 2013). …”