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NEDD9 links anaplastic thyroid cancer stemness to chromosomal instability through integrated centrosome asymmetry and DNA sensing regulation

Oncogene volume 41, pages 2984–2999 (2022)Cite this article

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Abstract

Stemness and chromosomal instability (CIN) are two common contributors to intratumor heterogeneity and therapy relapse in advanced cancer, but their interplays are poorly defined. Here, in anaplastic thyroid cancer (ATC), we show that ALDH+ stem-like cancer cells possess increased CIN-tolerance owing to transcriptional upregulation of the scaffolding protein NEDD9. Thyroid patient tissues and transcriptomic data reveals NEDD9/ALDH1A3 to be co-expressed and co-upregulated in ATC. Compared to bulk ALDH− cells, ALDH+ cells were highly efficient at propagating CIN due to their intrinsic tolerance of both centrosome amplification and micronuclei. ALDH+ cells mitigated the fitness-impairing effects of centrosome amplification by partially inactivating supernumerary centrosomes. Meanwhile, ALDH+ cells also mitigated cell death caused by micronuclei-mediated type 1 interferon secretion by suppressing the expression of the DNA-sensor protein STING. Both mechanisms of CIN-tolerance were lost upon RNAi-mediated NEDD9 silencing. Both in vitro and in vivo, NEDD9-depletion attenuated stemness, CIN, cell/tumor growth, while enhancing paclitaxel effectiveness. Collectively, these findings reveal that ATC progression can involve an ALDH1A3/NEDD9-regulated program linking their stemness to CIN-tolerance that could be leveraged for ATC treatment.

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Fig. 1: ALDH+ ATC cells exhibit stem-like features, asymmetrical division, and harbours higher rate of chromosomal instability.
Fig. 2: NEDD9 is upregulated in ALDH + ATC cells and NEDD9/ALDH1A3 are co-overexpressed in ATC patients.
Fig. 3: ALDH+ATC cells display centrosome asymmetry, which is disrupted by NEDD9-depletion.
Fig. 4: ALDH+ATC cells with centrosome amplification experience milder spindle multipolarity due to NEDD9-mediated centrosome inactivation.
Fig. 5: NEDD9 help supernumerary-centrosome-harbouring ALDH+ cells complete mitosis and increase the rate of CIN.
Fig. 6: NEDD9 upregulation in ALDH+ cells shut down micronuclei-rupture stimulated DNA sensing pathway by limiting STING protein expression.
Fig. 7: shNEDD9-induced STING activation suppresses ALDH+ cell growth independently from shNEDD9-induced spindle multipolarity.
Fig. 8: NEDD9-depletion in ATC xenografts inhibits tumor growth, reduces chromosome missegregation, and enhances the efficacy of paclitaxel.

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Acknowledgements

We thank Dr. John Copland for providing the cell lines THJ-11T and THJ-16T, and Dr. Mark Trifiro for providing the cell lines 8505c, TPC, and BCPAP. We thank Dr. Long Yang for the NEDD9-KO construct. Representative schematics in Fig. 5a and Fig. 6k weres created using Biorender.com.

Funding

This study was supported by the Canadian Institutes of Health Research (Grant# 178116) and in part by McGill Interdisciplinary Initiative in Infection and Immunity (MI4); GB Morand was supported by the Swiss Cancer League (BIL KFS-3002-08-2012).

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  1. Departments of Medicine, Oncology, Lady Davis Institute for Medical Research and Segal Cancer Centre, the Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada

    Henry G. Yu, Krikor Bijian, Jie Su & Moulay A. Alaoui-Jamali

  2. Departments of Medicine, Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, the Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada

    Sabrina D. da Silva & Gregoire Morand

  3. Departments of Medicine, Pathology, Lady Davis Institute for Medical Research and Segal Cancer Centre, the Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada

    Alan Spatz

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HY, KB and MA conceived and designed the experiments and wrote the manuscript. HY performed all the ATC cell-based experiments and generated the stable inducible knockdown cell lines for in vivo studies. GM and JS performed in vivo experiments. SDS and AS supervised the immunohistochemistry studies.

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Correspondence to Moulay A. Alaoui-Jamali.

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Yu, H.G., Bijian, K., da Silva, S.D. et al. NEDD9 links anaplastic thyroid cancer stemness to chromosomal instability through integrated centrosome asymmetry and DNA sensing regulation. Oncogene 41, 2984–2999 (2022). https://doi.org/10.1038/s41388-022-02317-7

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