Biology subjects

Schedin, P. J.

Publications and source records attributed to Schedin, P. J..

9 recordsLinked to original sources

bioRxiv2026

SOX9 and SEMA7A regulate cell plasticity in the postpartum mammary gland with implications for breast cancer

Postpartum mammary gland involution is a coordinated process of cell death and remodeling that returns the tissue to a near pre-pregnant state following lactation and weaning. In models of postpartum breast cancer, defined as breast cancer diagnosed in women under age 45 and within 10 years of recent childbirth, involution induces durable phenotypes in breast tumor cells that promote progression and are associated with increased risk for therapeutic resistance, metastasis, and death in patients. SRY-Box Transcription Factor 9 (SOX9), a known regulator of mammary stem and progenitor cells, also promotes resistance to therapy and metastasis in breast cancers. Yet the contribution of SOX9 to the involution process is not well understood. We utilized single-cell RNA sequencing of mouse mammary glands during involution to delineate Sox9-expressing cell populations during lactation and involution. We found that Sox9 mRNA is primarily expressed in luminal progenitor cells that are largely absent during lactation and present during early involution. We also reveal that Sox9 is involved in a shift in cell state from lactational to non-lactational and is expressed in the surviving cells during involution. Prior work revealed that Semaphorin-7a (SEMA7A) also promotes cancer stem cell and pro-survival phenotypes in luminal progenitor cells during involution, and we observe a population of luminal progenitor cells that co-expresses Sox9 and Sema7a during involution. Mechanistically, we demonstrate that knockdown of Sox9 in cultured mammary epithelial cells results in increased SEMA7A expression, mesenchymal phenotypes, and loss of lactogenic differentiation capacity, identifying a potential regulatory axis where SOX9 balances SEMA7A expression in normal mammary epithelium and that disruption of this balance results in a dedifferentiated state that resembles mesenchymal cells. We validated a spatial relationship between SOX9 and SEMA7A proteins in a unique set of breast tissue samples from healthy human donors to show co-expression during early involution. In breast cancer datasets, we observe elevated expression of SOX9 and SEMA7A in triple-negative breast cancers, as well as in the mesenchymal subtype of triple-negative breast cancers, suggesting disruption of this regulatory axis in breast cancer. Finally, we observe that co-expression increases metastatic risk in both estrogen receptor-negative and -positive breast cancers. Collectively, these findings define a novel SOX9-SEMA7A relationship in healthy mammary tissues and illustrate how studies of normal progenitor cell phenotypes can delineate cellular mechanisms that contribute to breast tumor progression.

developmental biology↗

bioRxiv2025

S-Nitrosylated COX-2 is a TME-regulated breast cancer biomarker of mesenchymal phenotypes

COX-2 is an inducible enzyme key to the production of inflammatory prostaglandins. COX-2 also has tumor intrinsic oncogenic activity in mouse models of breast cancer. Previously, we reported increased expression of Cys-526-nitrosylated COX-2 (SNO-COX-2), but not non-nitrosylated COX-2, with progression of early-stage human breast cancer to invasive ductal carcinoma. Here, we used a 3D culture model of early-stage human breast cancer (MCF10DCIS cells) to investigate the relationship between SNO-COX-2 expression and mesenchymal/invasive tumor cell morphology. We find that SNO-COX-2, but not non-nitrosylated COX-2, closely associated with mesenchymal phenotypes induced by fibrillar type I collagen. Interestingly, invasive phenotypes did not associate with induction of the classic epithelial-to-mesenchymal transition (EMT) markers SNAIL, CDH2 (N-cadherin), and VIM (vimentin). By contrast TGF{beta}-1 strongly induced EMT-related transcripts, but not SNO-COX-2 protein expression or mesenchymal phenotypes. These observations suggest that in MCF10DCIS cells, SNO-COX-2 associates with mesenchymal phenotypes more strongly than non-nitrosylated COX-2 protein, or expression of classic EMT transcripts. In a mouse model with breast tumor heterogeneity, mesenchymal tumor regions also have increased SNO-COX-2 expression. Testing 300 distinct tumor microenvironment conditions, we find SNO-COX-2 protein expression is driven by inflammation, wound resolution, and cancer-associated factors, especially TNC, SPP1, decorin, fibrillar type I and III collagens, INF-{gamma}, and IL-4/13, with evidence for specific extracellular matrix-ligand interactions driving both high and low SNO-COX-2 expression. In sum, in MCF10DCIS cells, expression of SNO-COX-2 is highly microenvironment-dependent and strongly associated with invasive/mesenchymal growth, indicating potential for SNO-COX-2 as a biomarker to assess risk of early-stage breast cancer progression.

cancer biology↗

bioRxiv2025

Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. Here we report that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." We document neoplastic cells engaging in immune mimicry within public human breast tumor single-cell RNA-seq datasets, histopathological breast tumor specimens, breast cancer cell lines, as well as in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and are enriched in treatment-resistant and high-grade breast tumors. We corroborated these observations in aggressive breast cancer cell lines where anti-proliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Moreover, in subsequent proof-of-concept studies, we demonstrate that expression of the CD69 leukocyte activation protein by neoplastic cells confers a proliferative advantage that facilitates early tumor growth and therefore conclude that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy. Moving forward, neoplastic immune mimicry should be evaluated for prognostic utility in additional breast cancer cohorts to determine its potential for patient stratification. Future research should evaluate correlates with distal metastases, progression-free survival, overall survival, and therapeutic response/resistance. Statement of SignificanceNeoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

cancer biology↗

bioRxiv2024

Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis

Liver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an influx of immune suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver pre-metastatic niches. This work identifies features of reproductive control of liver biology that sets a foundation for better understanding the potential role of the liver in maternal health.

cancer biology↗

bioRxiv2021

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer.

Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. Here, we tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (ie, BNDF, TNF, FGF2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1, and reduced phosphorylated FGFR in tumors. Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multifactorial, and that weight maintenance during the peri-/post-menopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

cancer biology↗

bioRxiv2021

Multiplex spatial systems analysis of local nanodose drug responses predicts effective treatment combinations of immunotherapies and targeted agents in mammary carcinoma

Better methods are needed to identify effective combinations of immunotherapies with chemotherapies and targeted anti-cancer agents. Here we present a Multiplex Implantable Microdevice Assay (MIMA) system for rapid in vivo assessment of the effects of multiple, spatially separate anticancer drugs directly in the complex tumor microenvironment. In prototypic experiments, olaparib, lenvatinib, palbociclib, venetoclax, panobinostat, doxorubicin, and paclitaxel and combinations thereof were administered simultaneously to murine mammary tumor models. Quantitative multiplex immunohistochemistry and spatial systems analyses of each local drug response defined cellular relations of fibroblasts, endothelial cells, immune lineages, immunogenic cell death, tumor proliferation and/or cancer stem cells that were used to predict effective drug combinations. A predicted combination of panobinostat, venetoclax and anti-CD40 showed long-term anti-tumor efficacy in multiple mouse models with no observable toxicity when administered systemically. Future MIMA use promises to design effective drug combinations for tumor cell control and immune activation on a personalized basis.

cancer biology↗

bioRxiv2021

Pregnancy and weaning regulate human maternal liver size and function

BACKGROUNDDuring pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a pro-metastatic niche. These data suggest a mechanism for increased liver metastasis in postpartum breast cancer patients. OBJECTIVESInvestigate if the human liver changes in size and function during pregnancy and weaning. METHODSAbdominal imaging was obtained in healthy women at early and late pregnancy, and post-wean. During pregnancy time points, endogenous glucose production was measured and fasting blood taken to measure bile acids. RESULTSIndependent of weight gain, most womens livers increased in size with pregnancy, returning to baseline post-wean. Putative roles for bile acids in liver growth were observed in pregnant women and rodents. CONCLUSIONSThe human liver is regulated by reproductive state with growth during pregnancy and volume loss post-wean. These findings may have broad implications for sex-specific liver diseases and cancer.

physiology↗

bioRxiv2020

Phenotype-guided subpopulation identification from single-cell sequencing data

Single-cell sequencing yields novel discoveries by distinguishing cell types, states and lineages within the context of heterogeneous tissues. However, interpreting complex single-cell data from highly heterogeneous cell populations remains challenging. Currently, most existing single-cell data analyses focus on cell type clusters defined by unsupervised clustering methods, which cannot directly link cell clusters with specific biological and clinical phenotypes. Here we present Scissor, a novel approach that utilizes disease phenotypes to identify cell subpopulations from single-cell data that most highly correlate with a given phenotype. This "phenotype-to-cell within a single step" strategy enables the utilization of a large amount of clinical information that has been collected for bulk assays to identify the most highly phenotype-associated cell subpopulations. When applied to a lung cancer single-cell RNA-seq (scRNA-seq) dataset, Scissor identified a subset of cells exhibiting high hypoxia activities, which predicted worse survival outcomes in lung cancer patients. Furthermore, in a melanoma scRNA-seq dataset, Scissor discerned a T cell subpopulation with low PDCD1/CTLA4 and high TCF7 expressions, which is associated with a favorable immunotherapy response. Thus, Scissor provides a novel framework to identify the biologically and clinically relevant cell subpopulations from single-cell assays by leveraging the wealth of phenotypes and bulk-omics datasets.

bioinformatics↗

bioRxiv2020

S-nitrosylated and non-nitrosylated COX2 has differential expression and distinct subcellular localization in normal and breast cancer tissue

Immunohistochemical staining in breast cancer shows both gain and loss of COX2 expression with disease risk and progression. We investigated four common COX2 antibody clones and found high specificity for purified human COX2 for three clones; however, recognition of COX2 in cell lysates was clone dependent. Biochemical characterization revealed two distinct forms of COX2, with SP21 recognizing an S-nitrosylated form and CX229 and CX294 appearing to recognize the same non-nitrosylated COX2 antigen. We found S-nitrosylated and non-nitrosylated COX2 occupy different subcellular locations in normal and breast cancer tissue, implicating distinct synthetic/trafficking pathways and function. Dual stains of ~2000 breast cancer cases show early onset breast cancer has increased expression of both forms of COX2 compared to postmenopausal cases. Our results highlight the strengths of using multiple, highly characterized antibody clones for COX2 immunohistochemical studies and raise the prospect that S-nitrosylation of COX2 may play a role in breast cancer biology.

cancer biology↗