Biology subjects

Parrish, M.

Publications and source records attributed to Parrish, M..

6 recordsLinked to original sources

bioRxiv2026

Environmental chemical mixtures reprogram mammary epithelial development to epigenetic states associated with breast cancer

Environmental exposures occur as complex mixtures, yet the mechanisms by which they alter human tissue development and confer cancer susceptibility remain poorly defined. Here, we establish a physiological 3D human breast organoid high-content screening (3D-HCS) platform that quantitatively links exposure-induced developmental disruption to cancer-relevant cell states. Screening of structurally diverse environmental chemicals as single agents but also as mixtures reveals heterogeneous but reproducible developmental responses, indicating that distinct environmental chemicals perturb different aspects of mammary morphogenesis. Focusing on bisphenols, we show that a physiological-dose mixture (BPA, BPS, and BPF; 3BPX) disrupts organoid development and induces transcriptional programs characterized by extracellular matrix remodeling, epithelial plasticity, and partial epithelial-mesenchymal transition (EMT), accompanied by widespread DNA methylation remodeling. The 3BPX exposure signature maps to ER luminal breast cancers and is preferentially enriched in invasive lobular carcinoma (ILC), a subtype characterized by epithelial plasticity and stromal interaction. Genome-wide DNA methylation profiling revealed that the 3BPX-associated methylation signature is detectable in primary tumors and adjacent normal tissue and is enriched in Normal-like tumors and ILC. Together, these findings demonstrate that environmentally relevant chemical exposures induce heterogeneous developmental perturbations that converge on conserved transcriptional and epigenetic programs associated with epithelial plasticity, tissue remodeling, and cancer susceptibility. These exposure-induced states persist as molecular "scars" that map to defined epithelial and stromal compartments in human breast cancers, supporting a model in which developmental exposures establish a field of increased oncogenic potential. Summary StatementUsing a human breast organoid high-content screening platform, we show that real-world chemical mixtures induce heterogeneous developmental disruption that converges on conserved EMT, wound-response, and epigenetic programs. These exposure-induced states persist as molecular "scars" and map to specific epithelial and stromal compartments in human breast cancers, particularly invasive lobular carcinoma, suggesting a developmental origin of cancer susceptibility.

cancer biology↗

bioRxiv2025

PPARG directs trophoblast cell fate and establishment of the uterine-placental interface

The expansion and differentiation of trophoblast stem (TS) cells are critical for defining fundamental properties of the placenta. Specialized trophoblast cells exit the placenta and enter and transform the uterus, including restructuring uterine spiral arteries. In the human these cells are named extravillous trophoblast (EVT) cells, whereas in the rat they are termed invasive trophoblast cells. Mechanisms governing invasive trophoblast cell differentiation remain poorly understood. We investigated peroxisome proliferator-activated receptor gamma (PPARG) as a potential regulator of EVT/invasive trophoblast cell development. In first trimester human placentas, PPARG was expressed in the EVT cell column and increased in amount as human TS cells differentiated into EVT cells. PPARG disruption impaired EVT cell differentiation. Rat invasive trophoblast cells similarly expressed PPARG. Conditional inactivation of PPARG within rat invasive trophoblast cells was used to assess the in vivo role of PPARG on the uterine-placental interface. PPARG was established as an essential cell-autonomous regulator of the invasive trophoblast cells. In conclusion, PPARG is a conserved regulator of placentation and is essential for directing trophoblast cell-guided uterine transformation.

developmental biology↗

bioRxiv2025

Immune-Epithelial Interactions via TGF-β Orchestrates Stem-Cell Niche Formation and Morphogenesis

Mesenchymal-epithelial interactions are well-established for organogenesis, but the role of immune cells in these processes remains less explored. Organoids offer powerful models for studying tissue development, especially where in vivo models are limited. In this study, we established an immune-epithelial co-culture model using an advanced 3D hydrogel-based breast organoid model that enables real-time investigation of human breast organogenesis. We employed live imaging and cell tracking techniques to visualize the induction process and the formation of an immune-mediated niche. Incorporation of immune cells into the organoid structure demonstrates their dual role as inducers of epithelial proliferation and as a persistent component of the stem cell niche. In addition, co-culturing epithelial cells with tissue-resident immune cells from healthy donors, particularly those enriched in double negative T cells, significantly accelerates organoid development and increases organoid formation through TGF-{beta} signaling. These findings highlight a previously unappreciated role for immune-epithelial crosstalk in early tissue development and provide insights into the dynamic nature of stem cell niches.

developmental biology↗

bioRxiv2024

DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

The human breast is complex and comprised of multi-lineage and multi-structural elements. Recent work has shown that epithelial stem and progenitor cells use the collagen receptor Discoidin Domain Receptor 1 (DDR1) for differentiation into both basal and luminal cell lineages, which together are necessary for both ductal and alveolar morphogenesis. We developed a next-generation single cell derived organoid model that generates miniaturized breast tissue, to study how single stem cells can give rise to multiple cell types and compound tissue structures. We show that DDR1 activation triggers stem cell differentiation via RUNX1 in turn driving multilineage differentiation as well as complex ductal-lobular development. Mechanistically, DDR1 affects the interaction and expression of RUNX1 and its cofactor CBF{beta} thereby regulating its activity. Together, these findings contribute to the current understanding of how the extracellular matrix component within the stem cell niche drives organogenesis and tissue regeneration.

developmental biology↗

bioRxiv2020

Genome-wide binding analyses of HOXB1 revealed a novel DNA binding motif associated with gene repression

Knowledge of the diverse DNA binding specificities of transcription factors is important for understanding their specific regulatory functions in animal development and evolution. We have examined the genome-wide binding properties of the mouse HOXB1 protein in ES cells differentiated into neural fates. Unexpectedly, only a small number of HOXB1 bound regions (7%) correlate with binding of the known HOX cofactors PBX and MEIS. In contrast, 22% of the HOXB1 binding peaks display co-occupancy with the transcriptional repressor REST. Analyses revealed that co-binding of HOXB1 with PBX correlates with active histone marks and high levels of expression, while co-occupancy with REST correlates with repressive histone marks and repression of the target genes. Analysis of HOXB1 bound regions uncovered enrichment of a novel 15 base pair HOXB1 binding motif HB1RE (HOXB1 response element). In vitro template binding assays showed that HOXB1, PBX1 and MEIS can bind to this motif. In vivo, this motif is sufficient to direct expression of a reporter gene and over-expression of HOXB1 selectively represses this activity. Our analyses suggest that HOXB1 has evolved an association with REST in gene regulation and the novel HB1RE motif contributes to HOXB1 function in part through a repressive role in gene expression.

developmental biology↗

bioRxiv2019

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.

cancer biology↗