Aggarwal, Disha, Russo, Suzanne, Anderson, Kendall, Floyd, Taylor, Utama, Raditya, Rouse, James A, Naik, Payal, Pawlak, Sara, Iyer, Shruti V, Kramer, Melissa, Satpathy, Shuchismita, Wilkinson, John E, Gao, Qing, Bhatia, Sonam, Arun, Gayatri, Akerman, Martin, McCombie, W Richard, Revenko, Alexey, Kostroff, Karen, Spector, David L (April 2026) Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression. bioRxiv. ISSN 2692-8205 (Submitted)
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Abstract
Background: Long non-coding RNAs (lncRNAs) have emerged as key regulators of tumor biology, however, thus far none have translated to cancer therapies. The lncRNA MALAT1 is overexpressed in more than 20 cancers, including breast cancer and has been shown to function via various mechanisms in a context-dependent manner, in 2D cell lines and mouse models. However, its functional role and therapeutic potential have not been evaluated in clinically relevant patient-derived models. Methods: We investigated the therapeutic potential of a MALAT1- targeting antisense oligonucleotide (ASO) for breast cancer, using clinically relevant 3D human patient-derived organoids (PDOs) and PDO-xenograft (PDO-X) models. We systematically evaluated the efficiency of MALAT1 -targeting ASOs using a biobank of 28 PDO models. Using three independent PDO-X models of triple negative breast cancer (TNBC), we targeted MALAT1 in vivo to study its impact on transcription, alternative splicing, stromal remodeling and metastasis. Results: Across PDO-X models, MALAT1 depletion reproducibly drove widespread alternative splicing changes across all event types, particularly intron retention events, accompanied by modest gene expression alterations. Differentially spliced transcripts were enriched for targets of shared cancer-associated transcription factors, and MALAT1 knockdown altered the relative abundance of previously unannotated splicing isoforms. Beyond tumor-intrinsic effects, tumor-specific MALAT1 depletion induced a consistent reduction in macrophage-associated gene signatures and reduced lung metastatic burden. Conclusions: Our data define MALAT1 's multifaceted role in TNBC, coordinating alternative splicing, transcriptional fine-tuning, tumor-stroma crosstalk, and metastatic progression. Our study provides strong preclinical evidence supporting MALAT1 -targeted ASO therapy and establishes PDO-X models as a clinically relevant platform for functional interrogation of TNBC therapies.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders Investigative techniques and equipment diseases & disorders > cancer > cancer types > breast cancer Investigative techniques and equipment > cell culture > cancer organoids Investigative techniques and equipment > cell culture diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Koo Lab CSHL labs > McCombie lab CSHL labs > Spector lab CSHL Post Doctoral Fellows |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 3 April 2026 |
| Date Deposited: | 13 Apr 2026 12:37 |
| Last Modified: | 13 Apr 2026 12:37 |
| PMCID: | PMC13060066 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42152 |
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