Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA in breast cancer progression.
[BACKGROUND] Long non-coding RNAs (lncRNAs) have emerged as key regulators of tumor biology, however, thus far none have translated to cancer therapies.
APA
Aggarwal D, Russo S, et al. (2026). Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA in breast cancer progression.. bioRxiv : the preprint server for biology. https://doi.org/10.64898/2026.04.02.716096
MLA
Aggarwal D, et al.. "Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA in breast cancer progression.." bioRxiv : the preprint server for biology, 2026.
PMID
41959295
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 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 -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 -targeting ASOs using a biobank of 28 PDO models. Using three independent PDO-X models of triple negative breast cancer (TNBC), we targeted to study its impact on transcription, alternative splicing, stromal remodeling and metastasis.
[RESULTS] Across PDO-X models, 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 knockdown altered the relative abundance of previously unannotated splicing isoforms. Beyond tumor-intrinsic effects, tumor-specific depletion induced a consistent reduction in macrophage-associated gene signatures and reduced lung metastatic burden.
[CONCLUSIONS] Our data define 's multifaceted role in TNBC, coordinating alternative splicing, transcriptional fine-tuning, tumor-stroma crosstalk, and metastatic progression. Our study provides strong preclinical evidence supporting -targeted ASO therapy and establishes PDO-X models as a clinically relevant platform for functional interrogation of TNBC therapies.
[METHODS] We investigated the therapeutic potential of a -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 -targeting ASOs using a biobank of 28 PDO models. Using three independent PDO-X models of triple negative breast cancer (TNBC), we targeted to study its impact on transcription, alternative splicing, stromal remodeling and metastasis.
[RESULTS] Across PDO-X models, 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 knockdown altered the relative abundance of previously unannotated splicing isoforms. Beyond tumor-intrinsic effects, tumor-specific depletion induced a consistent reduction in macrophage-associated gene signatures and reduced lung metastatic burden.
[CONCLUSIONS] Our data define 's multifaceted role in TNBC, coordinating alternative splicing, transcriptional fine-tuning, tumor-stroma crosstalk, and metastatic progression. Our study provides strong preclinical evidence supporting -targeted ASO therapy and establishes PDO-X models as a clinically relevant platform for functional interrogation of TNBC therapies.