Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression

Abstract

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. We investigated the therapeutic potential of MALAT1-targeting antisense oligonucleotides (ASOs) 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. Across three independent PDO-X models of triple negative breast cancer (TNBC), MALAT1 depletion reproducibly drove widespread alternative splicing changes across all event types, with an enrichment of intron retention. Differentially spliced transcripts were enriched for targets of shared cancer-associated transcription factors, and MALAT1 knockdown specifically 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. Our data defines MALAT1s multifaceted role in TNBC, coordinating alternative splicing, 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. SignificanceUsing clinically relevant human PDO-X models, we show that MALAT1 influences alternative splicing, metastatic potential and the tumor microenvironment. These data support the potential of oncogenic lncRNA MALAT1 as a therapeutic target.