Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy
<div><p>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...
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| مؤلفون آخرون: | , , , |
| منشور في: |
2021
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| _version_ | 1864513517658308608 |
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| author | Hibah Shaath (5599658) |
| author2 | Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Shahryar Khattak (291870) Nehad M. Alajez (7397276) |
| author2_role | author author author author |
| author_facet | Hibah Shaath (5599658) Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Shahryar Khattak (291870) Nehad M. Alajez (7397276) |
| author_role | author |
| dc.creator.none.fl_str_mv | Hibah Shaath (5599658) Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Shahryar Khattak (291870) Nehad M. Alajez (7397276) |
| dc.date.none.fl_str_mv | 2021-01-25T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41420-020-00383-y |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Single-cell_long_noncoding_RNA_lncRNA_transcriptome_implicates_MALAT1_in_triple-negative_breast_cancer_TNBC_resistance_to_neoadjuvant_chemotherapy/25713825 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis TNBC triple-negative breast cancer neoadjuvant chemotherapy lncRNA long noncoding RNA |
| dc.title.none.fl_str_mv | Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Cell Death Discovery<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41420-020-00383-y" target="_blank">https://dx.doi.org/10.1038/s41420-020-00383-y</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_140dabb9aba9f13e99d93d936e4ab5d8 |
| identifier_str_mv | 10.1038/s41420-020-00383-y |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25713825 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapyHibah Shaath (5599658)Radhakrishnan Vishnubalaji (3563306)Ramesh Elango (7542068)Shahryar Khattak (291870)Nehad M. Alajez (7397276)Biomedical and clinical sciencesOncology and carcinogenesisTNBCtriple-negative breast cancerneoadjuvant chemotherapylncRNAlong noncoding RNA<div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Cell Death Discovery<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41420-020-00383-y" target="_blank">https://dx.doi.org/10.1038/s41420-020-00383-y</a></p>2021-01-25T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41420-020-00383-yhttps://figshare.com/articles/journal_contribution/Single-cell_long_noncoding_RNA_lncRNA_transcriptome_implicates_MALAT1_in_triple-negative_breast_cancer_TNBC_resistance_to_neoadjuvant_chemotherapy/25713825CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/257138252021-01-25T03:00:00Z |
| spellingShingle | Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy Hibah Shaath (5599658) Biomedical and clinical sciences Oncology and carcinogenesis TNBC triple-negative breast cancer neoadjuvant chemotherapy lncRNA long noncoding RNA |
| status_str | publishedVersion |
| 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 | Biomedical and clinical sciences Oncology and carcinogenesis TNBC triple-negative breast cancer neoadjuvant chemotherapy lncRNA long noncoding RNA |