Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation

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Abstract

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.

Abstract

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.

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Most cited references 53

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New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

E A Eisenhauer, P Therasse, J. Bogaerts … (2009)

Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

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Cancer stem cells revisited.

Eduard Batlle, Hans Clevers (2017)

The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It has gradually become clear that many tumors harbor CSCs in dedicated niches, and yet their identification and eradication has not been as obvious as was initially hoped. Recently developed lineage-tracing and cell-ablation strategies have provided insights into CSC plasticity, quiescence, renewal, and therapeutic response. Here we discuss new developments in the CSC field in relationship to changing insights into how normal stem cells maintain healthy tissues. Expectations in the field have become more realistic, and now, the first successes of therapies based on the CSC concept are emerging.

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Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Ann Boija, Isaac A. Klein, Benjamin Sabari … (2018)

Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well-characterized, but little is known about the mechanisms by which ADs effect gene activation. Here we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation. Activation domains from a diverse array of mammalian and yeast transcription factors form phase-separated condensates with mediator to activate gene expression

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Author and article information

Contributors

Shicheng Su:

ORCID: http://orcid.org/0000-0003-2280-3587

sushch@mail.sysu.edu.cn

Jian-You Liao:

ORCID: http://orcid.org/0000-0002-5586-3458

liaojy3@mail.sysu.edu.cn

Qiyi Zhao:

ORCID: http://orcid.org/0000-0003-0649-0437

zhaoqyi@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 16 January 2023

Publication date PMC-release: 16 January 2023

Publication date Collection: 2023

Volume: 14

Electronic Location Identifier: 238

Affiliations

[1 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Infectious Diseases, Third Affiliated Hospital, , Sun Yat-Sen University, ; Guangzhou, 510630 China

[2 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, Department of Breast Surgery, the First Affiliated Hospital, , Zhengzhou University, ; Zhengzhou, 450000 China

[3 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, , Sun Yat-sen University, ; Guangzhou, 510630 China

[4 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; Guangzhou, 510120 China

[5 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; Guangzhou, 510120 China

[6 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Ultrasound, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; Guangzhou, 510120 China

[7 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Immunology, Zhongshan School of Medicine, , Sun Yat-Sen University, ; Guangzhou, 510080 China

Author information

Xinwei Liu http://orcid.org/0000-0002-2860-9542

Xiaoyun Xiao http://orcid.org/0000-0001-5990-271X

Shicheng Su http://orcid.org/0000-0003-2280-3587

Jian-You Liao http://orcid.org/0000-0002-5586-3458

Qiyi Zhao http://orcid.org/0000-0003-0649-0437

Article

Publisher ID: 35856

DOI: 10.1038/s41467-023-35856-y

PMC ID: 9842735

PubMed ID: 36646707

SO-VID: e36b9c29-d962-4c81-b9fc-e0c95e20888d

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 8 March 2021

Date accepted : 4 January 2023

Funding

Funded by: Key Scientific and Technological Project of Henan Province (LHGJ20210295)

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82125017

Award ID: 92057210

Award ID: 91942309

Award ID: 81672614

Award ID: 81872155

Award ID: 82072924

Award ID: 82173064

Award ID: 81971481

Award Recipient : Shicheng Su Jian-You Liao Qiyi Zhao

Funded by: National Key Research and Development Program of China(2017YFA0106300);Guangdong Basic and Applied Basic Research Foundation(2016A030306023,2017A030313878);Science and Technology Program of Guangzhou(202103000070);Tip-top Scientific and Technical Innovative Youth Talents of Guangdong special support program (2016TQ03R553).

Funded by: Guangdong Basic and Applied Basic Research Foundation(2022B1515020100);

Funded by: ational Key Research and Development Program of China(2021YFA1302000,2021YFA1103000);Guangdong Basic and Applied Basic Research Foundation (2022B1515020023 and 2019A1515011632) ; Science and Technology Program of Guangzhou (202201020467); Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation (2020B1212060018); Fundamental Research Funds for the Central Universities (22ykqb01)

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ScienceOpen disciplines: Uncategorized

Keywords: breast cancer,cancer microenvironment,cancer stem cells

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ScienceOpen disciplines: Uncategorized

Keywords: breast cancer, cancer microenvironment, cancer stem cells

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Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation

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Most cited references 53

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

Cancer stem cells revisited.

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

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