Dataset Information

Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

ABSTRACT: The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology.

SUBMITTER: Casey AE

PROVIDER: S-EPMC6080920 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

Casey Alison E AE Sinha Ankit A Singhania Rajat R Livingstone Julie J Waterhouse Paul P Tharmapalan Pirashaanthy P Cruickshank Jennifer J Shehata Mona M Drysdale Erik E Fang Hui H Kim Hyeyeon H Isserlin Ruth R Bailey Swneke S Medina Tiago T Deblois Genevieve G Shiah Yu-Jia YJ Barsyte-Lovejoy Dalia D Hofer Stefan S Bader Gary G Lupien Mathieu M Arrowsmith Cheryl C Knapp Stefan S De Carvalho Daniel D Berman Hal H Boutros Paul C PC Kislinger Thomas T Khokha Rama R

The Journal of cell biology 20180619 8

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chroma ...[more]

PMID: 29921600

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Project description:BackgroundTumor recurrence is one of the major challenges in clinical management of chordoma. Despite R0-resection, approximately 50% of chordomas recur within ten years after initial surgery. The underlying molecular processes are poorly understood resulting in the lack of associated therapeutic options. This is not least due to the absence of appropriate cell culture models of this orphan disease.MethodsThe intra-personal progression model cell lines U-CH11 and U-CH11R were compared using array comparative genomic hybridization, expression arrays, RNA-seq, and immunocytochemistry. Cell line origin was confirmed by short tandem repeat analysis. Inter-personal cell culture models (n = 6) were examined to validate whether the new model is representative. Cell viability after HOX/PBX complex inhibition with small peptides was determined by MTS assays.ResultsUsing whole genome microarray analyses, striking differences in gene expression between primary and recurrent chordomas were identified. These expression differences were confirmed in the world's first intra-personal model of chordoma relapse consisting of cell lines established from a primary (U-CH11) and the corresponding recurrent tumor (U-CH11R). Array comparative genomic hybridization and RNA-sequencing analyses revealed profound genetic similarities between both cell lines pointing to transcriptomic reprogramming as a key mechanism of chordoma progression. Network analysis of the recurrence specific genes highlighted HOX/PBX signaling as a common dysregulated event. Hence, HOX/PBX complexes were used as so far unknown therapeutic targets in recurrent chordomas. Treating chordoma cell lines with the complex formation inhibiting peptide HXR9 induced cFOS mediated apoptosis in all chordoma cell lines tested. This effect was significantly stronger in cell lines established from chordoma relapses.ConclusionClearly differing gene expression patterns and vulnerabilities to HOX/PBX complex inhibition in highly therapy resistant chordoma relapses were identified using the first intra-personal loco-regional and further inter-personal chordoma progression models. For the first time, HOX/PBX interference was used to induce cell death in chordoma and might serve as the basic concept of an upcoming targeted therapy for chordomas of all progression stages.

Dataset Information

Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

Publications

Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

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