Biology subjects

Lyons, T. R.

Publications and source records attributed to Lyons, T. R..

7 recordsLinked to original sources

bioRxiv2025

Targeting Semaphorin 7a signaling in preclinical models of estrogen receptor-positive breast cancer

Estrogen receptor-positive (ER+) breast cancer (BC) comprises over 70% of breast cancers and is the leading cause of BC-related deaths in women worldwide. Despite available therapies targeting ER in BC, recurrence occurs in many patients due to therapeutic resistance. Semaphorin 7a (SEMA7A) is a biomarker associated with poor prognosis and endocrine therapy resistance for BC patients. Survival analyses of ER+ BC patients on endocrine therapy confirm early recurrence in patients with SEMA7A+ tumors. Thus, we aim to establish novel treatment strategies to improve outcomes for patients with ER+ SEMA7A+ BC. In this paper we investigate the mechanisms by which SEMA7A promotes resistance to endocrine therapy and its potential as a therapeutic target for ER+ BC. Our studies suggest that SEMA7A binds to integrins {beta}1 and {beta}4 and activates AKT mediated pro-survival signaling via its RGD domain. Using syngeneic ER+ models, tumors in were treated with PI3K inhibitors (20mg/kg alpelisib; 10mg/kg GCT-007), alone or in combination with tamoxifen (0.5 mg/100uL peanut oil), which resulted in decreased tumor growth. Tumors were also treated with a combination of an anti-SEMA7A antibody (SmAbH1) (100-250mg/kg) and fulvestrant (83mg/kg), compared to single agents. Our results demonstrate that direct inhibition of SEMA7A via SmAbH1 significantly reduces tumor growth of SEMA7A+ tumors, and the combination with fulvestrant may be even more effective. Our studies suggest that patients with ER+SEMA7A+ tumors should be candidates for PI3K-targeted therapies or anti-SEMA7A-based therapy. TRANSLATIONAL RELEVANCEOur studies propose inhibition of a novel target in estrogen receptor-positive (ER+) breast cancer (BC) with an anti-Semaphorin 7a (SEMA7A) monoclonal antibody (SmAbH1). We show efficacy of SmAbH1 as a single agent and in combination with endocrine therapy in preclinical models. We also show that targeting of SEMA7A signaling, including the use of well-known and novel PI3K inhibitors, could be an effective treatment strategy for patients with SEMA7A+ BC, particularly in combination with standard of care. Our mechanistic studies detail the cellular signaling pathway activated by SEMA7A and support the further investigation of these novel drug combinations for clinical use. Further, SEMA7A is a biomarker for poor prognosis and decreased patient survival, posing the need for a clinical diagnostic test for SEMA7A levels in BC patients, which we are currently developing. O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/655360v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@18f3790org.highwire.dtl.DTLVardef@188cfbcorg.highwire.dtl.DTLVardef@fe71aaorg.highwire.dtl.DTLVardef@d87f98_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer

Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of immunosuppression. Here we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to PD-1/PD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a novel monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody also reduces tumor growth or promotes complete regression of mouse mammary tumors, reduces the immunosuppressive phenotypes in the tumor microenvironment and restores cytotoxic T cells suggesting that SEMA7A may be a candidate for a novel immune-based therapy for breast cancer patients.

cancer biology↗

bioRxiv2021

Anoikis resistance in mammary epithelial cells is mediated by semaphorin-7a.

Semaphorin-7a (SEMA7A), best known as a neuroimmune molecule, plays a diverse role in many cellular processes and pathologies. Here, we show that SEMA7A promotes anoikis resistance in cultured mammary epithelial cells through integrins and activation of pro-survival kinase AKT, which led us to investigate a role for SEMA7A during postpartum mammary gland involution--a normal developmental process where cells die by anoikis. Our results reveal that SEMA7A is expressed on live mammary epithelial cells during involution, that SEMA7A expression is primarily observed in 6-integrin expressing cells, and that luminal progenitor cells, specifically, are decreased in mammary glands of SEMA7A-/- mice during involution. We further identify a SEMA7A-6/{beta}1-integrin dependent mechanism of mammosphere formation and chemoresistance in mammary epithelial cells and suggest that this mechanism is relevant for recurrence in breast cancer patients.

cell biology↗

bioRxiv2021

Rab40/Cullin5 complex regulates EPLIN and actin cytoskeleton dynamics during cell migration and invasion

Rab40b is a SOCS box containing protein that regulates the secretion of MMPs to facilitate extracellular matrix remodeling during cell migration. Here we show that Rab40b interacts with Cullin5 via the Rab40b SOCS domain. We demonstrate that loss of Rab40b/Cullin5 binding decreases cell motility and invasive potential, and show that defective cell migration and invasion stem from alteration to the actin cytoskeleton, leading to decreased invadopodia formation, decreased actin dynamics at the leading edge, and an increase in stress fibers. We also show that these stress fibers anchor at less dynamic, more stable focal adhesions. Mechanistically, changes in the cytoskeleton and focal adhesion dynamics are mediated in part by EPLIN, which we demonstrate to be a binding partner of Rab40b and a target for Rab40b/Cullin5 dependent localized ubiquitylation and degradation. Thus, we propose a model where the Rab40b/Cullin5 dependent ubiquitylation regulates EPLIN localization to promote cell migration and invasion by altering focal adhesion and cytoskeletal dynamics.

cell biology↗

bioRxiv2019

Hormonal regulation of Semaphorin 7a in ER+ breast cancer drives therapeutic resistance

Approximately 70% of all breast cancers are estrogen receptor positive (ER+BC) and endocrine therapy has improved survival for patients with ER+BC. Yet, up to half of these tumors recur within 20 years. Recurrent ER+BCs develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER+BC. We found that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER+BC. We show that SEMA7A is hormonally regulated in ER+BC, but its expression does not uniformly decrease with anti-estrogen treatments. Additionally, overexpression of SEMA7A in ER+ cell lines drives increased in vitro growth in the presence of estrogen-deprivation, tamoxifen, and fulvestrant. In in vivo studies, we found that SEMA7A confers primary tumor resistance to fulvestrant and, importantly, induced lung metastases. Finally, we identify pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors and propose that targeting with inhibitors of survival signaling such as venetoclax may have efficacy for treating SEMA7A+ tumors. SIGNIFICANCEWe report that SEMA7A predicts for, and likely contributes to, poor response to standard-of-care therapies and suggest that patients with SEMA7A+ER+ tumors may benefit from alternative therapeutic strategies.

cancer biology↗

bioRxiv2019

Cross-talk between SIM2s and NFkB regulates cyclooxygenase 2 expression in breast cancer

BackgroundBreast cancer is a leading cause of cancer-related death for women in the United States. Thus, there a need to investigate novel prognostic markers and therapeutic strategies. Inflammation raises challenges to both treating and preventing the spread of breast cancer. Specifically, the nuclear factor kappa b (NFkB) pathway contributes to cancer progression by stimulating proliferation and preventing apoptosis. One target gene of this pathway is PTGS2, the gene that encodes for cyclooxygenase 2 (COX-2), which is upregulated in 40% of human breast carcinomas. COX-2 is an enzyme involved in inflammation. Here we investigate the effect of Singleminded 2s, a transcriptional tumor suppressor that is implicated in inhibition of tumor growth and metastasis, in regulating NFkB and COX-2.\n\nMethodsWe utilized in vitro reporter assays, immunoblot analyses, qPCR and immunohistochemical analysis to dissect the relationship between NF{kappa}B, SIM2s, and COX-2. Furthermore, we utilized COX-2 targeting strategies to determine tumor suppressive activities.\n\nResultsOur results reveal that SIM2s attenuates the activation of a NF{kappa}B via luciferase reporter assays. Furthermore, immunostaining of lysates from breast cancer cells over expressing SIM2s showed reduction in various NF{kappa}B signaling proteins, whereas knockdown of SIM2 revealed increases in the same NF{kappa}B signaling proteins. Additionally, by increasing NF{kappa}B translocation to the nucleus in DCIS.COM cells, we show that NF{kappa}B signaling can act in a reciprocal manner to decrease expression of SIM2s. Likewise, suppressing NF{kappa}B translocation in DCIS.COM cells increases SIM2s expression. We also found that NF{kappa}B/p65 represses SIM2 in via dose-dependent manner and when NF{kappa}B is suppressed the effect on the SIM2 is negated. Additionally, our CHIP analysis confirms that NF{kappa}B/p65 binds directly to SIM2 promoter site and that the NF{kappa}B sites in the SIM2 promoter are required for NFkB-mediated suppression of SIM2s. Finally, over expression of SIM2s decreases PTGS2 in vitro and COX-2 staining in vivo while decreasing PTGS2 and/or Cox-2 activity results in re-expression of SIM2. Our findings identify a novel role for SIM2s in NF{kappa}B signaling and COX-2 expression.\n\nConclusionsThese findings provide evidence for a mechanism where SIM2s may represses COX-2 expression to provide an overall better prognosis for breast cancer patients.

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↗