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Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy

Cumulative evidence suggests added benefit for neoadjuvant chemotherapy (NAC) in a subset of triple-negative breast cancer (TNBC) patients. Herein we identified the long noncoding RNA (lncRNA) transcriptional landscape associated with TNBC resistance to NAC, employing 1758 single cells from three ex...

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Autores principales: Shaath, Hibah, Vishnubalaji, Radhakrishnan, Elango, Ramesh, Khattak, Shahryar, Alajez, Nehad M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835365/
https://www.ncbi.nlm.nih.gov/pubmed/33495450
http://dx.doi.org/10.1038/s41420-020-00383-y
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author Shaath, Hibah
Vishnubalaji, Radhakrishnan
Elango, Ramesh
Khattak, Shahryar
Alajez, Nehad M.
author_facet Shaath, Hibah
Vishnubalaji, Radhakrishnan
Elango, Ramesh
Khattak, Shahryar
Alajez, Nehad M.
author_sort Shaath, Hibah
collection PubMed
description Cumulative evidence suggests added benefit for neoadjuvant chemotherapy (NAC) in a subset of triple-negative breast cancer (TNBC) patients. Herein we identified the long noncoding RNA (lncRNA) transcriptional landscape associated with TNBC resistance to NAC, employing 1758 single cells from three extinction and three persistence TNBC patients. Using Iterative Clustering and Guide-gene Selection (ICGS) and uniform manifold approximation and projection (UMAP) dimensionality reduction analysis, we observed single cells derived from each patient to largely cluster together. Comparing the lncRNA transcriptome from single cells through the course of NAC treatment revealed minimal overlap based on lncRNA transcriptome, suggesting substantial effects of NAC on lncRNA transcription. The differential analysis revealed upregulation of 202 and downregulation of 19 lncRNAs in the persistence group, including upregulation of five different transcripts encoding for the MALAT1 lncRNA. CRISPR/Cas9-mediated MALAT1 promoter deletion in BT-549 TNBC model enhanced sensitivity to paclitaxel and doxorubicin, suggesting a role for MALAT1 in conferring resistance. Mechanistically, whole transcriptome analysis of MALAT1-KO cells revealed multiple affected mechanistic networks as well as oxidative phosphorylation canonical and angiogenesis functional category. Interestingly, lncRNA profiling of MALAT1-depleted TNBC also revealed a number of altered lncRNAs in response to MALAT1 deletion, suggesting a reciprocal relationship between MALAT1 and a number of lncRNAs, including NEAT1, USP3-AS1, and LINC-PINT, in TNBC. Elevated expression of MALAT1, USP3-AS1, and LINC-PINT correlated with worse clinical outcomes in BC patients. Our data revealed the lncRNA transactional portrait and highlighted a complex regulatory network orchestrated by MALAT1 in the context of TNBC resistance to NAC therapy.
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spelling pubmed-78353652021-01-29 Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy Shaath, Hibah Vishnubalaji, Radhakrishnan Elango, Ramesh Khattak, Shahryar Alajez, Nehad M. Cell Death Discov Article Cumulative evidence suggests added benefit for neoadjuvant chemotherapy (NAC) in a subset of triple-negative breast cancer (TNBC) patients. Herein we identified the long noncoding RNA (lncRNA) transcriptional landscape associated with TNBC resistance to NAC, employing 1758 single cells from three extinction and three persistence TNBC patients. Using Iterative Clustering and Guide-gene Selection (ICGS) and uniform manifold approximation and projection (UMAP) dimensionality reduction analysis, we observed single cells derived from each patient to largely cluster together. Comparing the lncRNA transcriptome from single cells through the course of NAC treatment revealed minimal overlap based on lncRNA transcriptome, suggesting substantial effects of NAC on lncRNA transcription. The differential analysis revealed upregulation of 202 and downregulation of 19 lncRNAs in the persistence group, including upregulation of five different transcripts encoding for the MALAT1 lncRNA. CRISPR/Cas9-mediated MALAT1 promoter deletion in BT-549 TNBC model enhanced sensitivity to paclitaxel and doxorubicin, suggesting a role for MALAT1 in conferring resistance. Mechanistically, whole transcriptome analysis of MALAT1-KO cells revealed multiple affected mechanistic networks as well as oxidative phosphorylation canonical and angiogenesis functional category. Interestingly, lncRNA profiling of MALAT1-depleted TNBC also revealed a number of altered lncRNAs in response to MALAT1 deletion, suggesting a reciprocal relationship between MALAT1 and a number of lncRNAs, including NEAT1, USP3-AS1, and LINC-PINT, in TNBC. Elevated expression of MALAT1, USP3-AS1, and LINC-PINT correlated with worse clinical outcomes in BC patients. Our data revealed the lncRNA transactional portrait and highlighted a complex regulatory network orchestrated by MALAT1 in the context of TNBC resistance to NAC therapy. Nature Publishing Group UK 2021-01-25 /pmc/articles/PMC7835365/ /pubmed/33495450 http://dx.doi.org/10.1038/s41420-020-00383-y Text en © The Author(s) 2021 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/.
spellingShingle Article
Shaath, Hibah
Vishnubalaji, Radhakrishnan
Elango, Ramesh
Khattak, Shahryar
Alajez, Nehad M.
Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy
title Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy
title_full Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy
title_fullStr Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy
title_full_unstemmed Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy
title_short Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy
title_sort single-cell long noncoding rna (lncrna) transcriptome implicates malat1 in triple-negative breast cancer (tnbc) resistance to neoadjuvant chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835365/
https://www.ncbi.nlm.nih.gov/pubmed/33495450
http://dx.doi.org/10.1038/s41420-020-00383-y
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