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Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation
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Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation
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Journal Article
Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation
2023
Overview
Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients’ lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.
Stromal cells in the tumour microenvironment are reported to regulate cancer stemness via biomechanical signals. Here the authors show that TAZ activated by biomechanical cues enhanced cancer stem cell properties via phase separation with Nanog.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 64/60
/ Breast Neoplasms - pathology
/ Cancer
/ Female
/ Humanities and Social Sciences
/ Humans
/ Mechanotransduction, Cellular
/ Nanog Homeobox Protein - genetics
/ Neoplastic Stem Cells - pathology
/ Science
/ Transcription Factors - genetics
/ Transcriptional Coactivator with PDZ-Binding Motif Proteins - genetics
/ Tumors
