Biology subjects

Haro, M.

Publications and source records attributed to Haro, M..

5 recordsLinked to original sources

bioRxiv2024

M2 Macrophages are Major Mediators of Germline Risk of Endometriosis and Explain Pleiotropy with Comorbid Traits

Endometriosis is a common gynecologic condition that causes chronic life-altering symptoms including pain, infertility, and elevated cancer risk. There is an urgent need for new non-hormonal targeted therapeutics to treat endometriosis, but until very recently, the cellular and molecular signatures of endometriotic lesions were undefined, severely hindering the development of clinical advances. Integrating inherited risk data from analyses of >450,000 individuals with [~]350,000 single cell transcriptomes from 21 patients, we uncover M2-macrophages as candidate drivers of disease susceptibility, and nominate IL1 signaling as a central hub impacted by germline genetic variation associated with endometriosis. Extensive functional follow-up confirmed these associations and revealed a pleiotropic role for this pathway in endometriosis. Population-scale expression quantitative trail locus analysis demonstrated that genetic variation controlling IL1A expression is also associated with endometriosis risk variants. Manipulation of IL1 signaling in state-of-the-art in vitro decidualized assembloids impacted epithelial differentiation, and in an in vivo endometriosis model, treatment with anakinra (an interleukin-1 receptor antagonist) resulted in a significant, dose-dependent reduction in both spontaneous pain and evoked pain. Together these studies highlight non-diagnostic cell types as central to endometriosis susceptibility and support IL1 signaling as an important actionable pathway for this disease.

immunology↗

bioRxiv2023

Human fallopian tube single-cell analysis reveals monocytic transcriptional and interaction changes in high-grade serous ovarian cancers

Tumorigenesis for most high-grade serous ovarian cancers (HGSCs) likely initiates from fallopian tube (FT) epithelia. While epithelial subtypes have been characterized using single-cell RNA- sequencing (scRNA-Seq), heterogeneity of other cellular compartments and their involvement in tumor progression are poorly defined. Integrated analysis of human FT scRNA-Seq data and other relevant tissues, including HGSC tumors, revealed greater transcriptional diversity of immune and stromal cells. We identify an unprecedented abundance of monocytes in human FT myeloid cells across two independent donor cohorts. The ratio of macrophages to monocytes are relatively similar between benign FTs, ovaries, and adjacent normal tissues, but is significantly greater in tumor. FT-defined monocyte and macrophage signatures, cell-cell communication, and gene set enrichment analysis identified monocyte- and macrophage-specific ligand-receptor interactions and functional pathways in tumors and adjacent normal tissue. Further reanalysis of tumor scRNA-Seq from HGSC patients suggested different monocyte and macrophage subsets associated with neoadjuvant chemotherapy treatment. Taken together, our work provides evidence that an altered FT immune composition could inform early detection markers in HGSCs.

cancer biology↗

bioRxiv2023

Rewiring of master transcription factor cistromes during high-grade serous ovarian cancer development

The transcription factors MECOM, PAX8, SOX17 and WT1 are candidate master regulators of high-grade serous ovarian cancer (HGSC), yet their cooperative role in the hypothesized tissue of origin, the fallopian tube secretory epithelium (FTSEC) is unknown. We generated 26 epigenome (CUT&TAG, CUT&RUN, ATAC-seq and HiC) data sets and 24 profiles of RNA-seq transcription factor knock-down followed by RNA sequencing in FTSEC and HGSC models to define binding sites and gene sets regulated by these factors in cis and trans. This revealed that MECOM, PAX8, SOX17 and WT1 are lineage-enriched, super-enhancer associated master regulators whose cooperative DNA-binding patterns and target genes are re-wired during tumor development. All four TFs were indispensable for HGSC clonogenicity and survival but only depletion of PAX8 and WT1 impaired FTSEC cell survival. These four TFs were pharmacologically inhibited by transcriptional inhibitors only in HGSCs but not in FTSECs. Collectively, our data highlights that tumor-specific epigenetic remodeling is tightly related to MECOM, PAX8, SOX17 and WT1 activity and these transcription factors are targetable in a tumor-specific manner through transcriptional inhibitors.

cancer biology↗

bioRxiv2021

A cellular and molecular portrait of endometriosis subtypes

Endometriosis is a common, benign condition characterized by extensive heterogeneity in lesion appearance and patient symptoms. We profiled transcriptomes of 207,949 individual cells from endometriomata (n=7), extra-ovarian endometriosis (n=19), eutopic endometrium (n=4), unaffected ovary (n=1) and endometriosis-free peritoneum (n=4) to create a cellular atlas of endometrial-type epithelial cells, endometrial-type stromal cells and microenvironmental cell populations across tissue sites. Signatures of endometrial-type epithelium and stroma differed markedly across eutopic endometrium, endometrioma, superficial extra-ovarian disease and deep infiltrating endometriosis, suggesting that extensive transcriptional reprogramming is a core component of the disease process. Endometriomas were notable for the dysregulation of pro-inflammatory pathways and upregulation of complement proteins C3 and C7. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic factor SOX17 and remodeling of the endothelial cell compartment. Finally, signatures of endometriosis-associated endometrial-type epithelial clusters were enriched in ovarian cancers, reinforcing the epidemiologic associations between these two diseases.

genomics↗

bioRxiv2020

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous ovarian cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the early secretory population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 x 10-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

genomics↗