SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis

Abstract

Although cancers are considered stem cell diseases, mechanisms involving stem cell alterations are poorly understood. Squamous cell carcinoma (SQCC) is the second most common lung cancer, and its pathogenesis appears to hinge on changes in the stem cell behavior of basal cells in the bronchial airways. Basal cells are normally quiescent and differentiate into mucociliary epithelia. Smoking triggers a hyperproliferative response resulting in progressive premalignant epithelial changes ranging from squamous metaplasia to dysplasia. These changes can regress naturally, even with chronic smoking. However, for unknown reasons, dysplasias have higher progression rates than earlier stages. We used primary human tracheobronchial basal cells to investigate how copy number gains in SOX2 and PIK3CA at 3q26-28, which co-occur in dysplasia and are observed in 94% of SQCCs, may promote progression. We find that SOX2 cooperates with PI3K signaling, which is activated by smoking, to initiate the squamous injury response in basal cells. This response involves SOX9 repression, and, accordingly, SOX2 and PI3K signaling levels are high during dysplasia, while SOX9 is not expressed. By contrast, during regeneration of mucociliary epithelia, PI3K signaling is low and basal cells transiently enter a SOX2LoSOX9Hi state, with SOX9 promoting proliferation and preventing squamous differentiation. Transient reduction in SOX2 is necessary for ciliogenesis, although SOX2 expression later rises and drives mucinous differentiation, as SOX9 levels decline. Frequent coamplification of SOX2 and PIK3CA in dysplasia may, thus, promote progression by locking basal cells in a SOX2HiSOX9Lo state with active PI3K signaling, which sustains the squamous injury response while precluding normal mucociliary differentiation. Surprisingly, we find that, although later in invasive carcinoma SOX9 is generally expressed at low levels, its expression is higher in a subset of SQCCs with less squamous identity and worse clinical outcome. We propose that early pathogenesis of most SQCCs involves stabilization of the squamous injury state in stem cells through copy number gains at 3q, with the pro-proliferative activity of SOX9 possibly being exploited in a subset of SQCCs in later stages.

SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond

“…As such, Helicobacter pylori infections was shown to influence SOX2 expression in gastric cancer [60,61], where SOX2 has been described as a transactivator of PTEN, thus inhibiting PI3K/AKT-driven cell cycle progression and anti-apoptosis effects [55,62,63]. External influences also concern non-small cell lung cancer, where a smoking-induced injury response [64] was shown to trigger a premalignant state characterized by PI3K induction and molecularly uncoupled SOX2 expression in basal epithelial cells [64], while in dysplasia expression of SOX2 may depend on FGF triggered MAPK/ERK signaling [65].…”

“…Interestingly, cancers of immanent high SOX2 expression often show intrinsically high mutations rates in PI3KCA or PTEN genes as well [50,64], thus suggesting functional connectivity between PI3K/AKT signaling and stemness-inductory roles of SOX2.…”

Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling

“…Because this precise spatiotemporal segregation of Sox2 and Sox9 as canonical proximal and distal lung markers, respectively, has been described in developing mouse lungs it remains somewhat unclear whether these markers may be similarly used as equally faithful proximal-distal epithelial patterning markers in early human lung development. However, recent studies have demonstrated low levels of SOX2 in the human distal lung and high levels in the proximal airways (Kim et al, 2016; Xu et al, 2016), and a variety of additional markers of proximal and distal epithelial differentiation in humans is emerging in single-cell RNA sequencing studies (Xu et al, 2016) to facilitate the study of airway patterning in early human development.…”

Expression and correlation of MALAT1 and SOX9 in non‐small cell lung cancer

“…In addition, it was found that the abnormal expression was related to many human disease and especially in tumours formation and development . SOX9 is over‐expressed in various cancers, such as colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, brain cancer, and melanoma …”