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David L. Spector鈥檚 laboratory is focused on characterizing long non-coding RNAs (lncRNAs) that exhibit altered levels of expression in breast cancer progression and during embryonic stem cell differentiation. A major focus of their efforts has been on Malat1 lncRNA, which is one of the most abundant lncRNAs. The Spector lab previously identified a novel mechanism of 3鈥�-end processing of this RNA. More recent studies have revealed that increased levels of Malat1 lncRNA impacts breast cancer progression and metastasis. Knockout or antisense oligonucleotide knockdown of Malat1 results in the differentiation of mammary tumors and a significant reduction in metastasis. Studies are currently under way to elucidate the mechanism of action of this abundant nuclear retained lncRNA and to implement innovative therapeutic approaches that can impact its function in vivo. In addition, they have developed and genomically and transcriptomically characterized patient-derived breast tumor organoid models from patients with triple negative breast cancer or invasive lobular carcinoma of the breast. These models are being used to identify and characterize additional lncRNAs that are over-expressed in breast cancer. Several candidates will be pursued at the functional level and as new therapeutic targets, as well as for drug development and screening in a patient-specific manner.

A second area of study in the Spector lab is focused on identifying and characterizing lncRNAs that play critical roles in pluripotency and/or lineage commitment, and to identify the specific pathways that they regulate. To do so they have reanalyzed the raw data from their previously published differential RNA-seq screen comparing lncRNA expression in na茂ve mouse embryonic stem cells (mESCs) vs neural progenitor cells (NPCs). They prioritized transcripts that were more than 2-fold upregulated in mESCs compared to NPCs. This resulted in the identification of 147 mESC specific transcripts of which 105 have potential human orthologs. From this analysis several exciting candidates have been prioritized and are being pursued at the functional level. These studies will provide new insights as to how regulatory signals instructed by lncRNAs can impact pluripotency and/or lineage commitment which will influence basic biology and/or disease states.