Biology subjects

Boyer, A.

Publications and source records attributed to Boyer, A..

6 recordsLinked to original sources

bioRxiv2026

Cell-type-specific decoding of Hippo pathway inactivation drives seminiferous epithelial collapse and rete testis hyperplasia in the adult mouse testis

The Hippo pathway is a major regulator of epithelial homeostasis, but its role in the adult testis remains poorly defined. Here, we conditionally deleted Lats1 and Lats2 in WT1-expressing cells of the adult mouse testis, targeting both Sertoli cells and rete testis epithelial cells. Deletion of Lats1/2 caused rapid degeneration of the seminiferous epithelium, leading to near-complete germ cell loss, while simultaneously inducing marked hyperplasia of the rete testis. These tissue alterations were accompanied by vascular remodeling, macrophage accumulation, and extracellular matrix deposition. Cell-type-resolved transcriptomic analyses showed that Sertoli cells and rete testis epithelial cells have distinct baseline identities that shape their response to Hippo pathway inactivation. While both lineages activated shared YAP/TAZ-responsive genes, their broader outputs diverged sharply, with Sertoli cells preferentially activated structural remodeling programs, whereas rete testis epithelial cells robustly activated cell-cycle pathways and lost ciliogenesis-associated features. Regulatory network analysis further identified a conserved Hippo-responsive transcriptional backbone that was redeployed through lineage-specific regulons in each cell type. Together, these findings identify LATS1/2-mediated Hippo signaling as an essential regulator of adult testicular epithelial homeostasis and show that neighboring epithelial lineages decode Hippo pathway disruption through distinct transcriptional programs, resulting in divergent pathological outcomes.

cell biology↗

bioRxiv2025

Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the USA due to chemo- and immuno-therapy resistance. We show that focal adhesion kinase (FAK) inhibition with ifebemtinib or tumor genetic FAK knockout (KO) in syngeneic ovarian tumor models stimulated resident large peritoneal macrophages to express CXCL13 chemokine and promoted B cell infiltration. Macrophage GATA6 inactivation prevented CXCL13 expression and enhanced FAK-KO tumor growth. Combining ifebemtinib with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody extended survival with tumor-associated tertiary lymphoid structure formation. Mechanistically, FAK-KO heat-treated conditioned media contained exosomes enriched with omega-3 fatty acids which stimulated macrophage CXCL13 production. Ifebemtinib-treated tumors, FAK-KO exosomes, and purified eicosapentaenoic acid enhanced murine and human HGSOC-associated tumor macrophage reprogramming and CXCL13 expression. Overall, our studies define a tumor to macrophage signaling linkage via omega-3 exosome lipids supporting B cell recruitment, survival, immunotherapy enhancement, and actionable via small molecule FAK inhibition. eTOC BlurbHigh-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation. Bullet pointsO_LIGenetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltration C_LIO_LITumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13 C_LIO_LIFAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structures C_LIO_LIOmega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13 C_LI

cancer biology↗

bioRxiv2025

Strain Matters: The 129S1/SvlmJ Mouse Model Reveals the Genetic and Inflammatory Susceptibility to Hypertensive Complications

BackgroundHypertension is a leading cause of microvascular injury, yet the genetic determinants of organ-specific vulnerability remain poorly understood. Yest, we need good mouse models to investigate the complication of hypertension. This study investigates the role of genetic background in shaping hypertensive complications by comparing two mouse strains with divergent inflammatory responses. MethodsThree-month-old 129S1/SvlmJ and C57BL/6J mice received 600 ng/kg/min of angiotensin II (AngII) or saline. We compared the consequences of ANG2-induced blood pressure elevation on kidney function, BBB intergrity and cardiac hypertropy. Blood pressure (BP) was assessed by telemetry. Vascular injury markers in the brain, heart, kidneys, and retinas were systematically evaluated. ResultsBoth strains developed similar moderate hypertension with AngII. Only 129S1/SvlmJ mice exhibited spatial learning and memory deficits, blood-brain barrier hyperpermeability, astrocyte activation, retinal artery damage, hypertrophic cardiomyopathy, and renal podocyte lesions with urinary albumin/creatinine ratio (UACR) after AngII treatment. Transcriptomic analysis of brain microvessels highlighted strain-specific differences in gene regulation, particularly in inflammatory pathways, which may explain the higher vulnerability of 129S1/SvlmJ mice to hypertensive organ damage. These findings were supported in vivo by increased resident and perivascular macrophage recruitment in the brain of C57BL6/J mice under AngII compared to the 129S1/SvlmJ strain. ConclusionOur findings highlight the critical role of genetic background in shaping hypertensive complications. The 129S1/SvlmJ strain serves as a valuable model for dissecting the molecular mechanisms of hypertensive organ damage, emphasizing neurovascular inflammation as a potential therapeutic target. Translational PerspectiveThis study highlights the 129/Sv mouse strain as a superior translational model compared to the widely used C57BL/6J strain, which, despite being a standard in cardiovascular research, fails to reliably reproduce severe hypertensive organ complications. The 129/Sv strain closely mimics human hypertensive damage, including cerebral small vessel disease, nephropathy, cardiomyopathy, and retinopathy. Transcriptomic analysis of cerebral microvessels identifies maladaptive inflammation as a critical mechanistic driver of susceptibility. These findings underline the clinical relevance of genetic predisposition, improving risk stratification and providing a robust preclinical platform to develop targeted anti-inflammatory therapies aimed at preventing hypertension-induced end-organ damage in patients.

pathology↗

bioRxiv2024

Inducible FAK Deletion but not FAK Inhibition in Endothelial Cells Activates p53 to Suppress Tumor Growth in PYK2-null Mice

Focal adhesion kinase (FAK) functions as a signaling and scaffolding protein within endothelial cells (ECs) impacting blood vessel function and tumor growth. Interpretations of EC FAK-null phenotypes are complicated by related PYK2 (protein tyrosine kinase 2) expression, and to test this, we created PYK2-/- FAKfl/fl mice with tamoxifen-inducible EC-specific Cre recombinase expression. At 11 weeks of age, EC FAK inactivation resulted in increased heart and lung mass and vascular leakage only on a PYK2-/- background. Surprisingly, [~]90% of PYK2-/- EC FAK-/- mice survived to 75 weeks of age. Syngeneic melanoma, breast, or lung carcinoma tumors did not grow in PYK2-/- EC FAK-/- mice, but tumors grew normally in PYK2-/- EC FAKfl/fl mice lacking Cre. This tumor inhibitory phenotype was associated with abortive EC vessel sprouting, enhanced EC p53 tumor suppressor and p21CIP1 (cyclin-dependent inhibitor 1) expression, and alterations in serum cytokine levels. To discern the role of FAK kinase versus scaffolding activity in ECs, we generated kinase defective (FAK K454R, KD) PYK2-/- EC FAKfl/KD and PYK2-/- EC FAKfl/WT (WT, wildtype) mice. Hemizygous EC FAK-/KD expression supported primary tumor growth but not metastasis, implicating EC FAK activity in tumor dissemination. In vitro, hemizygous expression of either WT or KD FAK suppressed EC p21CIP1 levels and cell death observed in primary PYK2-/- EC FAK-/- ECs. Combined FAK and PYK2 knockdown in tumor cells also increased p21CIP1 and PARP1 (poly ADP-ribose polymerase 1) levels in a p53-associated manner impacting anchorage-independent growth. Together, these results underscore the linkage between PYK2 and FAK loss with p53 activation impacting tumor growth. Impact StatementPYK2-null combined with endothelial cell-specific FAK transgenic mouse models show that loss of FAK activity limits tumor spread and that genetic or chemical degradation preventing combined FAK-PYK2 expression may be an approach to induce a p53-associated anti-tumor response.

cell biology↗

bioRxiv2019

Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non-Small Cell Lung Cancer

Bevacizumab-pemetrexed/cisplatin (BEV-PEM/CIS) is a first line therapeutic for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab potentiates PEM/CIS cytotoxicity by inducing transient tumor vasculature normalization. BEV-PEM/CIS has a narrow therapeutic window. Therefore, it is an attractive target for administration schedule optimization. The present study leverages our previous work on BEV-PEM/CIS pharmacodynamic modeling in NSCLC-bearing mice to estimate the optimal gap in the scheduling of sequential BEV-PEM/CIS. We predicted the optimal gap in BEV-PEM/CIS dosing to be 2.0 days in mice and 1.2 days in humans. Our simulations suggest that the efficacy loss in scheduling BEV-PEM/CIS at too great of a gap is much less than the efficacy loss in scheduling BEV-PEM/CIS at too short of a gap.

pharmacology and toxicology↗

bioRxiv2018

Computational modeling reveals dynamics of brain metastasis in non-small cell lung cancer and provides a tool for personalized therapy

Brain metastases (BMs) are associated with poor prognosis in non-small cell lung cancer (NSCLC), but are only visible when large enough. Therapeutic decisions such as whole brain radiation therapy would benefit from patient-specific predictions of radiologically undetectable BMs. Here, we propose a mathematical modeling approach and use it to analyze clinical data of BM from NSCLC.\n\nPrimary tumor growth was best described by a gompertzian model for the pre-diagnosis history, followed by a tumor growth inhibition model during treatment. Growth parameters were estimated only from the size at diagnosis and histology, but predicted plausible individual estimates of the tumor age (2.1-5.3 years). Multiple metastatic models were assessed from fitting either literature data of BM probability (n = 183 patients) or longitudinal measurements of visible BMs in two patients. Among the tested models, the one featuring dormancy was best able to describe the data. It predicted latency phases of 4.4 - 5.7 months and onset of BMs 14 - 19 months before diagnosis. This quantitative model paves the way for a computational tool of potential help during therapeutic management.

cancer biology↗