Cross-talk between SOX2 and TGFβ Signaling Regulates EGFR–TKI Tolerance and Lung Cancer Dissemination

Abstract

Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFb signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFb stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFb signaling affects EGFR-TKI tolerance and lung cancer dissemination.Significance: These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFb stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination.

The SOX2 Status of Disseminated Tumor Cells in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy

“…Furthermore, SOX2 expression has been linked to tamoxifen resistance in BC (44) and was shown to significantly affect adhesion properties of BC cells (45). SOX2 was also recently shown to mediate proliferation and dissemination in lung cancer cells resistant to tyrosine kinase inhibitors (46). The CSC hypothesis is supported by the phenomenon of tumor cell dormancy, clinically well-known in BC patients, who can experience a relapse after a very long period, sometimes up to 25 years, without evidence of the disease (47,48).…”

Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

“…Further convolution in EGFR TKI resistance (tolerance) is the role of SOX2 and TGFβ signalling [ 81 – 84 ]. As aforementioned, TKI therapy favoured mesenchymal traits in lung cancer cells, with deficient SOX2 expression, whereas SOX2 expression promotes TKI sensitivity and inhibited the mesenchymal phenotype [ 81 ]. SOX2 belongs to the SOX (Syr-related HMG Box) family of proteins and responds to respiratory tract injuries.…”

“…SOX2, in conjunction with OCT4, KLF4 and MYC, can reverse the mesenchymal morphology of fibroblasts and reprogramme them into pluripotent stem cells. Inhibition of TGβ signalling facilitates the SOX2-mediated reprogramming process of fibroblasts [ 81 ]. Tumours expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in EGFR-mutant patients [ 81 ].…”

“…Inhibition of TGβ signalling facilitates the SOX2-mediated reprogramming process of fibroblasts [ 81 ]. Tumours expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in EGFR-mutant patients [ 81 ]. Moreover, TGFBR1/2 receptors were up-regulated in HCC827 GR and H1975 AZDR-resistant lines.…”

“…Epigenetic modifications of H3K27ac and H3K4m3 (which marks the active enhancer and promoter, respectively) were higher in the SOX2 locus in HCC827 cells compared with its TKI-tolerant counterpart, HCC827 GR. The study clearly shows that the loss of SOX2 expression by TGFβ switches off SOX2-EGFR signalling and induces EMT with decreased BCL2L11 (Bim) pro-apoptotic signalling; henceforth, increasing EGFR TKI tolerance [ 81 ].…”