2. Academic Validation
  3. Cross-talk between SOX2 and TGFβ Signaling Regulates EGFR-TKI Tolerance and Lung Cancer Dissemination

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

  • Cancer Res. 2020 Oct 15;80(20):4426-4438. doi: 10.1158/0008-5472.CAN-19-3228.
Ming-Han Kuo  # 1,  An-Chun Lee  # 1,  Shih-Hsin Hsiao  # 2 3,  Sey-En Lin 4,  Yu-Fan Chiu 1,  Li-Hao Yang 1,  Chia-Cherng Yu 5,  Shih-Hwa Chiou 6 7,  Hsien-Neng Huang 8,  Jen-Chung Ko 9,  Yu-Ting Chou 10
Affiliations

Affiliations

  • 1 Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
  • 2 Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Xinyi, Taipei, Taiwan.
  • 3 Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Xinyi, Taipei, Taiwan.
  • 4 Department of Pathology, New Taipei City Municipal Tucheng Hospital (Chang Gung Memorial Hospital, Tucheng Branch, Taiwan), New Taipei City, Taiwan.
  • 5 Department of Medical Research, National Taiwan University Hospital, Zhongzheng, Taipei, Taiwan.
  • 6 Institute of Pharmacology, National Yang-Ming University, Beitou, Taipei, Taiwan.
  • 7 Department of Medical Research, Taipei Veterans General Hospital, Beitou, Taipei, Taiwan.
  • 8 Department of Pathology, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan.
  • 9 Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan. ytchou@life.nthu.edu.tw e1205470@ms22.hinet.net.
  • 10 Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan. ytchou@life.nthu.edu.tw e1205470@ms22.hinet.net.
  • # Contributed equally.
PMID: 32816907 DOI: 10.1158/0008-5472.CAN-19-3228
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 TGFβ 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. TGFβ 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 TGFβ 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 TGFβ stimulation and epigenetic control affects EGFR-TKI tolerance and Cancer dissemination.

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