Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

Abstract

Identification of target cells in lung tumorigenesis and characterization of the signals that control their behavior is an important step toward improving early cancer diagnosis and predicting tumor behavior. We identified a population of cells in the adult lung that bear the EpCAM þ CD104 þ CD49f þ CD44 þ CD24loSCA1 þ phenotype and can be clonally expanded in culture, consistent with the properties of early progenitor cells. We show that these cells, rather than being restricted to one tumor type, can give rise to several different types of cancer, including adenocarcinoma and squamous cell carcinoma. We further demonstrate that these cells can be converted from one cancer type to the other, and this plasticity is determined by their responsiveness to transforming growth factor (TGF)-beta signaling. Our data establish a mechanistic link between TGF-beta signaling and SOX2 expression, and identify the TGF-beta/SMAD/SOX2 signaling network as a key regulator of lineage commitment and differentiation of lung cancer cells. Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. Lung cancers are divided into two major categories: non-small-cell lung cancer (NSCLC) and small-cell lung cancer. NSCLC accounts for B80% of all lung cancers and is divided further into adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large-cell lung carcinoma. Of the four major types of lung cancer, Kras mutations are present in about 30-50% of ADC, a smaller percentage of SCC (5-7%) and o1% of SCLC.

Dysregulated Tgfbr2/ERK-Smad4/SOX2 Signaling Promotes Lung Squamous Cell Carcinoma Formation

“…We further revealed a positive correlation between TGFBR2 expression and prognosis of patients with human lung SCC. Although Tgfbr2 depletion could promote squamous lineage commitment in isolated lung epithelial precursor cells that harbor Kras G12D and p53 double mutants, genetic deletion of Tgfbr2 combined with other mutants in several mouse models significantly promotes lung ADC development, with absent or scarce SCC, challenging its in vivo role in determining squamous cell fate (18)(19)(20)(21). In this study, SCCs driven by Tgfbr2 loss exhibited the characteristic histopathology and biomarker expression of human SCC, manifesting the in vivo function of Tgfbr2 on suppressing SCC formation.…”

“…Sox2 is a well-established crucial transcription factor for squamous lineage commitment (8,11,19,(22)(23)(24). We next investigated the effects of canonical TGFb signaling pathway as well as ERK1/2 on SOX2 expression in two human lung ADC cell lines H441 and H358 and two human lung SCC cell lines SK-MES-1 and H520.…”

“…In previous clinical researches, reduced TGFBR2 expression is observed in 77% of non-small cell lung cancer samples by Western blot analysis (17), and reduced TGFBR2 expression is more common in human lung SCC samples than in ADC samples (18). Moreover, an ex vitro study using isolated murine lung cancer progenitor cells with mutations of Kras and p53 has demonstrated that repression of Tgfbr2 contributes to squamous differentiation (19). However, the in vivo effect of Tgfbr2 loss on squamous lineage differentiation has not been fully verified in several genetically engineered mouse models (18,20,21).…”

A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC

“…This analysis revealed that SMAD2 binding sequences were enriched at differentially methylated regions ( Figure 5D), potentially implicating the TGF beta pathway in sensitivity to GSK2879552. TGFbeta signaling is important throughout development and has been implicated in regulation of lung cancer cell plasticity, linking this pathway to cellular differentiation (Ischenko et al, 2014). Specific modulation of TGF-beta signaling in SCLC cells can inhibit their growth (Nørgaard et al, 1994;Sumitomo et al, 2000).…”

Targeting cancer stem cells by using the nanoparticles

“…Transforming growth factor-β (TGF-β) signaling provides important regulatory signals during the initial phase of normal development and regeneration 113,114 and exerts promoting effects in the initiation and progression of multiple cancer types including breast, 115 colon, 116 liver, 117 lung, 118 and ovary. 119 TGF-β ligands bind to a type II receptor, which constitutively recruits and phosphorylates a type I receptor.…”