Biology subjects

Borges, V. F.

Publications and source records attributed to Borges, V. F..

5 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↗

bioRxiv2022

Replicative Instability Drives Cancer Progression

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress have been shown to exhibit genomic instability and poor survival rates across tumor types. Here we utilize-omics data from two independent consortia to identify the genetic underpinnings of replication stress, therapy resistance, and primary carcinoma to brain metastasis in BRCA wildtype tumors. In doing so, we have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by genomic evolution secondary to replicative challenge. Our data supports a model whereby defective single-strand break repair, translesion synthesis, and non-homologous end joining effectors drive RIN. Collectively, we find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Statement of SignificanceDefining the genetic basis of genomic instability with wildtype BRCA repair effectors is a significant unmet need in cancer research. Here we identify and characterize a pan-cancer cohort of tumors driven by replicative instability (RIN). We find that RIN drives therapy resistance and distant metastases across multiple tumor types.

cancer biology↗

bioRxiv2022

IL-33 regulates age-dependency of long-term immune dysfunction induced by sepsis

Sepsis survival in adults is commonly followed by immunosuppression and increased susceptibility to secondary infections. However, the long-term immune consequences of pediatric sepsis are unknown. Here, we compared the frequency of Tregs, the activation of the IL-33/ILC2s axis in M2 macrophages, and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. In contrast to adults, infant mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in post-septic adults but not infant mice. Impaired IL-33 production in post-septic infant mice was associated with increased DNA-methylation on lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in infant mice. Clinically, adults but not pediatric post-septic patients exhibited higher counts of Tregs and sera IL-33 levels. Hence, we describe a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression.

immunology↗

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↗

bioRxiv2019

Semaphorin 7a dependent programs of cell surivival, matrix remodeling, and EMT drive postpartum breast tumor progression

Young women diagnosed with breast cancer (BC) have poor prognosis due to increased rates of metastasis. Additionally, women within 10 years of most recent childbirth at diagnosis are [~]3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis, all of which are also increased in pre-clinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. Our results presented herein show that silencing of SEMA7A decreases tumor growth in a model of PPBC while overexpression is sufficient to increase growth in nulliparous hosts. Further, we show that SEMA7A promotes multiple known drivers of PPBC progression including tumor associated COX-2 expression and fibroblast-mediated collagen deposition in the tumor microenvironment. Additionally, we show for the first time that SEMA7A expressing cells deposit fibronectin to promote tumor cell survival. Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts. These studies suggest SEMA7A as a key mediator of BC progression and that targeting SEMA7A may open avenues for novel therapeutic strategies.

cancer biology↗