Biology subjects

Boerner, J.

Publications and source records attributed to Boerner, J..

5 recordsLinked to original sources

bioRxiv2026

S100A9-Dependent CXCR2hi Neutrophils Mediate Systemic Immune Suppression and Checkpoint Resistance in Metastatic TNBC

Most high-dimensional studies of tumor-immune interactions focus on metastatic models, limiting insight into how immune remodeling in primary tumors shapes metastatic competence. Here, integrating single-cell RNA sequencing, CyTOF, and functional studies across metastatic (4T1) and non-invasive (EMT6) triple-negative breast cancer (TNBC) murine models, we define tumor state-specific immune programs that distinguish metastatic competence. Tumors with metastatic capacity uniquely drive early bone marrow expansion of CXCR2 neutrophils, which infiltrate primary tumors acquiring a CXCL2-producing phenotype that promotes EMT-associated cancer stem cell (CSC) plasticity. This program depends on TGF-{beta}/CEBPD-mediated induction of S100A9. Elevated CXCL2, together with G-CSF, establishes a feed-forward circuit that drives systemic neutrophil mobilization and recruitment to distant organs, where neutrophil-derived S100A8/A9 (calprotectin) promotes MET-driven CSC outgrowth and metastatic colonization. Clinically, gene signatures associated with CXCR2 neutrophils predict poor survival in TNBC patients, whereas monocyte/macrophage (CX3CR1) and T cell activation signatures correlate with improved outcomes. S100A9 ablation disrupts this cascade and enhances immunotherapy responsiveness, defining a TGF-{beta}/S100A9/CXCR2 axis linking immune remodeling, CSC plasticity and metastasis. HighlightsO_LIMetastatic TNBC engages a TGF-{beta}/C/EBP{delta}/S100A9 axis that expands CXCR2 neutrophils C_LIO_LINon-invasive EMT6 tumors retain a CX3CR1 monocyte/macrophage and T-cell landscape C_LIO_LICXCR2+ neutrophils in pre-metastatic niches suppress T cell response while promoting tumor cell proliferation C_LIO_LIS100A9 loss redirects myelopoiesis and potentiates anti-PD-L1 in TNBC models C_LI In BriefAlkan et al. dissect how tumor state programs the myeloid compartment in TNBC. Metastatic 4T1 tumors uniquely engage a TGF-{beta}/C/EBP{delta}/S100A9 axis driving CXCR2 neutrophil expansion and CXCL2/G-CSF-dependent systemic mobilization, coupling immune remodeling to EMT/MET cancer-stem-cell plasticity, while S100A9 loss restores CX3CR1 myeloid identity and unlocks checkpoint-inhibitor responsiveness.

cancer biology↗

bioRxiv2025

FRAZZLED/DCC REGULATES GAP JUNCTION FORMATION AT A DROSOPHILA GIANT SYNAPSE THROUGH TRANSCRIPTION

Loss of function Frazzled/DCC mutants demonstrate that the gene regulates synaptogenesis in the Giant Fiber System of Drosophila. In frazzled loss of function (LOF) mutants, we observe weaker physiology, characterized by longer latencies and reduced response frequencies between the GFs and the motor neurons. These physiological phenotypes are linked to a loss of gap junctions in the GFs, specifically the loss of the shaking-B(neural+16) isoform of innexin in the presynaptic terminal. A GF biophysical computational model is provided to test the role of gap junctions and the function of the Giant Fiber System. We present evidence of Frazzleds role in gap junction regulation by utilizing the UAS-GAL4 system in Drosophila to rescue mutant phenotypes. Expression of various UAS-Frazzled constructs in a Frazzled LOF background was used to dissect the role of different parts of the Frazzled receptor in the assembly of electrical synapses. Driving Frazzleds intracellular domain in Frazzled LOF mutants rescued axon pathfinding and synaptogenesis. This is supported by the fact that Frazzled fails to rescue the synaptic function when its transcriptional activation domain is disrupted, as shown by the deletion of the highly conserved intracellular P3 domain or by a construct with a point-mutation in the highly conserved P3 domain known to be required for transcriptional activation. The present work is the first to show how a guidance molecule regulates synaptogenesis through transcriptional regulation of synaptic components.

neuroscience↗

bioRxiv2023

Glial swip-10 expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Cuprous copper (Cu(I)) is an essential cofactor for enzymes supporting many cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly dependent on these pathways, with multiple neurodegenerative diseases, including Alzheimers disease (AD), Parkinsons disease, associated with their dysfunction. Key features of Cu(I) contributions to neuronal health in vivo remain to be defined, owing largely to the complex processes involved in Cu(I) production, intracellular transport, and systemic redistribution. Here, we provide genetic and pharmacological evidence that swip-10 is a critical determinant of systemic Cu(I) levels in C. elegans, with deletion leading to systemic deficits in mitochondrial respiration, production of oxidative stress, and neurodegeneration. These phenotypes can be reproduced in wild-type worms by Cu(I)-specific chelation and offset in swip-10 mutants by growth on the Cu(I) enhancing molecule elesclomol, as well as by glial expression of wildtype swip-10. MBLAC1, the most closely related mammalian ortholog to swip-10, encodes for a pre-mRNA processing enzyme for H3 histone, a protein whose actions surprisingly include an enzymatic capacity to produce Cu(I) via the reduction of Cu(II). Moreover, genome-wide association studies and post-mortem molecular studies implicate reductions of MBLAC1 expression in risk for AD with cardiovascular disease comorbidity. Consistent with these studies, we demonstrate that the deposition of {beta}-amyloid plaques, an AD pathological hallmark, in worms engineered to express human A{beta}1-42, is greatly exaggerated by mutation of swip-10. Together, these studies identify a novel glial-expressed, and pathway for Cu(I) production that may be targeted for the treatment of AD and other neurodegenerative diseases. Significance StatementDevastating neurodegenerative diseases such as Alzheimers disease, and Parkinsons disease are associated with disruptions in copper (Cu) homeostasis. Alterations in Cu(I) give rise to increased oxidative stress burden, mitochondrial and metabolic dysfunction, and can accelerate production and/or potentiate toxicity of disease-associated protein aggregates. Here, using the model system Caenorhabditis elegans, we establish a role for the gene swip-10 in systemic Cu(I) homeostasis. Perturbation of this pathway in worms recapitulates biochemical, histological, and pathological features seen in human neurodegenerative disease. We reveal that these changes can be suppressed pharmacologically and arise when swip-10 expression is eliminated from glial cells. Our work implicates swip-10 and orthologs as key players in Cu(I) homeostasis that may be exploitable to treat multiple neurodegenerative diseases.

neuroscience↗

bioRxiv2023

The relationships between genetic ancestry, somatic mutation frequency, and histologic subtypes in high-grade endometrial cancer

High-grade endometrial cancer, like numerous other cancer types, exhibits clear racial disparities in the United States for both the incidence and outcomes of the disease. While institutional factors are likely the primary contributor to these disparities, other underlying causes cannot be ignored (i.e., molecular, genetic, and histopathologic factors). This study seeks to interrogate the role that germline genetic influences, specifically genetic ancestry, may play in contributing to characteristics of high-grade endometrial cancer. This is mainly accomplished by examining the relationship between local ancestry inferences and somatic mutation frequency as well as histologic subtypes. An association between clinical characteristics and patient survival was also interrogated, and while global ancestry was seen to have no significant effect, tumor mutation burden (TMB) did impact patient survival. Here, we identify associations between local ancestry segments on chromosomes 1 and 14 and an increased TMB in self-described (SD) Black patients. We also highlight a complex relationship between heterozygous ancestry combinations within genomic regions (i.e., [European/African] vs. [African/African]) and an increase in local somatic mutation frequency. Furthermore, we explore the relationship between local ancestry and histologic subtype. We identify one region (chr9q32) wherein the African/European local ancestry diplotype was associated with a higher incidence of serous carcinoma. We also underline a difference in somatic mutation frequency between endometrioid and serous carcinoma. While highly exploratory, these findings begin to characterize the complex relationship between genetic ancestry and characteristics of high-grade endometrial cancer, which may impact patient survival.

genomics↗

bioRxiv2018

Novel immune cell subtypes linked to survival among African American women with triple-negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive disease that is twice as likely to be diagnosed in African American (AA) women compared to white women, with poor clinical outcomes. Tumor infiltrating lymphocytes (TILs) are associated with improved survival for TNBC, but the relevance of TILs and immune cell subtypes to survival in AA women with TNBC is unknown. We evaluated histopathologic TIL counts and molecular characteristics among 60 AA women diagnosed with TNBC with linkage to clinical outcomes using data from the Metropolitan Detroit Cancer Surveillance System. We utilized whole genome expression profiling of TN tumors and cell type deconvolution analysis to evaluate the underlying mechanisms and immune cell subtypes associated with survival patterns in the context of TILs. TILs were significantly associated with improved survival [1-10% Hazard Ratio (HR)=0.32, 95% Confidence Interval (CI) 0.12-0.90, p=0.031; >10% HR=0.18, 95% CI 0.05-0.67, 9.9x10-3]. 524 transcripts (326 coding, 198 non-coding) were associated with TIL levels, 34 of which were associated with both TILs and survival (p<0.05). While only naive B cells were associated with survival when considering individual cell types [Median HR=2.43, 95% CI 1.07-5.55, p=0.035], increased naive B cells, plasma cells, and activated NK cells, and decreased resting mast cells, M1 macrophages, and monocytes were associated with transcripts that predicted worse survival. These data provide evidence for novel roles for these immune cells types in TNBC, and further studies are needed to validate these findings and identify determinants of patterns of immune response in TNBC relevant to the AA population.\n\nSummaryWe found that increased naive B cells, plasma cells, and activated natural killer cells, and decreased resting mast cells, M1 macrophages, and monocytes were associated with expression biomarkers of worse survival among African American women with triple negative breast cancer.

epidemiology↗