Cancer-associated fibroblasts suppress SOX2-induced dysplasia in a lung squamous cancer coculture

Abstract

SignificanceTumor−stroma interactions play a critical role in regulating tumorigenesis. However, how these interactions contribute to changes in tissue architecture and cell polarity observed during tumor development is unclear. Here we report a 3D coculture system that recapitulates key phenotypic changes during the progression of lung squamous carcinoma (LUSC) as well as the dynamic interactions between LUSC cells and components of the tumor microenvironment (TME). Our data suggest that two major components of TME, including the extracellular matrix and cancer-associated fibroblasts, could override cell intrinsic oncogenic changes in determining the disease phenotype in the context of LUSC. These findings may have broad implications for LUSC biology as well as the design of future therapies.

Applications of patient-derived tumor xenograft models and tumor organoids

“…Chen et al recently demonstrated an unexpected plasticity and interaction of lung squamous cancer cells (LSCCs) with the tumor microenvironment [62]. Overexpression of SOX2 in the TUM622 cell line, which was established from a PDX model, enhances spheroidforming potential and drives a hyperplastic to dysplastic alteration in acinar phenotype, in which apical-basal cell polarity is disrupted, and solid non-invasive spheroids are formed.…”

“…Overexpression of SOX2 in the TUM622 cell line, which was established from a PDX model, enhances spheroidforming potential and drives a hyperplastic to dysplastic alteration in acinar phenotype, in which apical-basal cell polarity is disrupted, and solid non-invasive spheroids are formed. Remarkably, the presence of CAFs inhibits SOX2-induced dysplasia and restores an acinar-like phenotype, but TUM622 cells appear to exhibit epithelial-mesenchymal transition (EMT) at the invasive front towards CAFs, thereby forming "teardrop"-shaped structures [62,63]. Indeed, CAF-secreted stromal cellderived factor-1 (SDF-1) promoted EMT and the acquisition of stemness in LSCCs [64].…”

“…Indeed, CAF-secreted stromal cellderived factor-1 (SDF-1) promoted EMT and the acquisition of stemness in LSCCs [64]. Although the majority of LSCCs were positive for E-cadherin and only a small population were positive for Vimentin and SOX2, these factors showed considerable heterogeneity in TUM622derived spheroids [62]. Because there were cells positive for both E-cadherin and Vimentin, it is likely that partial EMT occurs in spheroids, the PDX model and the original tumor [62,65].…”

“…Leader cells expressing mesenchymal-like or basal epithelial traits are located at the front of the follower epithelial cancer clusters, and drive their collective migration in response to microenvironmental cues. SOX2 appears to induce the commitment and differentiation of TUM622 cells to the squamous lineage instead of regulating epithelial/mesenchymal plasticity [62,67]. SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4 in LSCCs, which is the preferred SOX2-binding partner in embryonic stem cells [68].…”

“…Furthermore, CAF-derived CD81-positive exosomes mobilize Wnt11 produced by breast carcinoma cells, thereby activating β-catenin-independent Wnt planar cell polarity (PCP) signaling, which promotes lung metastasis [70]. Chen et al suggested that the β-catenindependent canonical Wnt signaling pathway and cancer stem cell marker SOX2 synergistically induce acinar morphogenesis of TUM622 cells in three-dimensional culture [62]. Further investigations are warranted to determine how SOX2 overexpression and co-culture with CAFs affects the β-catenin-independent PCP pathway when spheroid cells derived from this PDX model of lung cancer acquire an invasive phenotype via partial EMT.…”