Biology subjects

Saad, E.

Publications and source records attributed to Saad, E..

9 recordsLinked to original sources

bioRxiv2026

CACNA1C as a Prognostic Biomarker and Therapeutic Target in High-Grade Serous Ovarian Cancer: Clinical Validation and Molecular Dynamics of Nifedipine Blockade

High-Grade Serous Ovarian Cancer (HGSOC) is the most lethal gynecological malignancy due to aggressive growth, widespread metastases, and high intra-tumoral heterogeneity. Poor prognosis is largely due to late diagnosis, hence there is an urgent need to identify novel biomarkers for screening, diagnosis, and monitoring. Here, we propose the voltage-dependent calcium channel hCaV1.2 encoded by CACNA1C as a potential biomarker and therapeutic target in HGSOC. Using IHC analysis for ten ovarian cancer patients, cytotoxicity assay, TCGA gene expression and survival analyses, homology modeling, molecular docking, Calcium channel membrane assembly and molecular dynamics simulations, we tested CACNA1Cs role in HGSOC progression and the effect of blocking on cancer cell survival. We show that nifedipine (NIFE), a calcium channel blocker (CCB), had a tumor suppressive effect based on binding models predicted by three-dimensional computer assisted molecular modeling and in vitro validation using human HGSOC cell line. Using The Cancer Genome Atlas ovarian public cohort, we found CACNA1C mRNA expression strongly correlated with poor patient survival for late-stage and metastasis than primary. We also show strong correlation of CACNA1C protein expression using immunohistochemistry correlating with COH ovarian carcinomas patients disease progression. This research demonstrates that targeting HGSOC via CCBs may be therapeutically beneficial. By establishing further in vitro, in vivo, and clinical trials using FDA approved NIFE may be repurposed to target CACNA1C for HGSOC. Novelty and ImpactHigh-grade serous ovarian cancer (HGSOC) remains lethal due to late diagnosis and drug resistance. This study identifies CACNA1C (Cav1.2) as a novel prognostic biomarker and therapeutic target in HGSOC, showing that elevated expression correlates with metastatic/recurrent disease and poor survival. Using molecular dynamics and in vitro models, we demonstrate that the FDA-approved calcium channel blocker nifedipine binds stably to Cav1.2 and suppresses tumor cell growth more effectively than cisplatin. These findings support repurposing nifedipine for biomarker-driven HGSOC therapy. Translational RelevanceLate diagnosis and progressive relapses significantly contribute to the poor prognosis of ovarian cancer. Identification of a tumor biomarker that can be used for screening, diagnosis, and monitoring is critical for improving clinical outcome. Our findings demonstrate that CACNA1C is a viable diagnostic marker for HGSOC and that its blockade with CCBs reduces tumor progression, highlighting their therapeutic potential.

cancer biology↗

bioRxiv2026

Tumor-Intrinsic IL-17 Signaling Correlates with Multimodal Resistance Phenotypes Following Oncolytic Adenovirus Challenge

Oncolytic adenovirus (ADV) therapy faces heterogeneous responses, implying tumor-intrinsic resistance. We identify interleukin-17 (IL-17) signaling as a novel potential barrier associated with multi-modal cellular reprogramming. Transcriptomic analysis of ADV-treated 4T1 murine mammary carcinoma cells revealed specific upregulation of Il17rb, Il17rd, and Il17f, indicating viral induction of this inflammatory axis. The IL-17 signature correlates strongly with a cancer stemness phenotype. Metabolically, it associates with increased lipid metabolism and suppressed glycolysis, suggesting a state resistant to viral replication. Furthermore, it broadly negatively correlates with programmed cell death pathways (apoptosis, necrosis) while positively associating with pro-survival autophagy. IL-17 component expression effectively stratifies samples into distinct metastatic risk categories, underscoring its prognostic potential. Our findings reveal a previously unrecognized, tumor-intrinsic role for IL-17 signaling in ADV resistance, associated with enhanced stemness, altered metabolism, and impaired cell death. This nominates the IL-17 pathway as both a predictive biomarker and a therapeutic target for combination strategies. HighlightsO_LIOncolytic adenovirus infection selectively upregulates IL-17 receptor subunits (IL17RB, IL17RD) and IL17F ligand in 4T1 tumor cells C_LIO_LIIL-17 receptor expression strongly correlates with cancer stemness gene signatures, particularly through IL17RB and IL17RD C_LIO_LIThe IL-17 axis associates with broad suppression of lytic cell death pathways (apoptosis, necrosis, necroptosis) while positively correlating with autophagy C_LIO_LIIL-17 pathway activity correlates with metabolic reprogramming favoring lipid turnover over glycolysis C_LIO_LIIL-17 expression levels stratify samples into distinct metastatic risk categories, suggesting biomarker potential C_LI

cancer biology↗

bioRxiv2025

HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma, is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in ccRCC patients, including in some patients who did not exhibit objective tumor shrinkage.

cancer biology↗

bioRxiv2025

Dual Inhibition of CDK4/6 and mTORC1 Establishes a Preclinical Strategy for Translocation Renal Cell Carcinoma

PurposeTranslocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of kidney cancer driven by an oncogenic fusion involving a transcription factor in the MiT/TFE gene family, most commonly TFE3. Treatment of tRCC currently lacks a clear standard of care, underscoring the pressing need to nominate new therapeutic targets with mechanistic rationale in this cancer. Experimental DesignIn this study, we applied integrative genomic approaches to identify activation of the cyclin-dependent kinase 4/6 (CDK4/6) and mammalian target of rapamycin complex 1 (mTORC1) pathways in tRCC. We tested the activity of CDK4/6 inhibitors (CDK4/6i), alone or in combination with mTORC1-selective inhibition, using in vitro and in vivo models of tRCC. ResultstRCC tumors displayed multiple genomic and transcriptional features associated with activation of the CDK4/6 and mTORC1 signaling pathways. Genetic or pharmacologic inhibition of CDK4/6 suppressed tRCC cell growth and induced cell cycle arrest in vitro but was not cytotoxic, with rapid cell regrowth observed after drug withdrawal. The mTORC1-selective inhibitor, RMC-5552, potently reduced translation of Cyclin D1, which complexes with CDK4/6 proteins to regulate G1-S cell cycle progression. Combined treatment with the CDK4/6 inhibitor, palbociclib, and RMC-5552 resulted in synergistic suppression of tRCC cell viability and increased markers of apoptosis in vitro. The combination of palbociclib and RMC-5552 in a tRCC xenograft model showed greater eOicacy than either single agent while also being well-tolerated. ConclusionsOur study indicates the therapeutic potential of combined CDK4/6 and mTORC1 inhibition in tRCC, providing the rationale for further clinical evaluation of this strategy. Translational RelevanceTranslocation renal cell carcinoma (tRCC) is a rare and aggressive form of kidney cancer that accounts for 2-5% of all RCCs in adults and around 50% of RCCs in children. tRCC lacks effective therapies and represents a significant unmet clinical need. Therapies approved for clear cell RCC (ccRCC), including VEGF/multikinase inhibitors and immune checkpoint blockade, typically show decreased efficacy in tRCC. Via an integrative genomic analysis, we nominate combined inhibition of the cyclin-dependent kinase 4/6 (CDK4/6) and mammalian target of rapamycin complex 1 (mTORC1) pathways in tRCC. We demonstrate that combining the CDK4/6 inhibitor palbociclib with the mTORC1-selective inhibitor RMC-5552 synergistically inhibits the growth of tRCC cells in vitro and of tRCC xenografts in vivo, where the combination is well-tolerated. This proof-of-concept study provides preclinical evidence supporting CDK4/6 inhibitor-based combination regimens tailored to tRCC biology, offering a foundation for future clinical studies in tRCC, which currently has no clear standard of care.

cancer biology↗

bioRxiv2025

Immune Spatial Organization Predicts Metastasis Risk in Aggressive Localized Prostate Cancer

Risk stratification in localized prostate cancer (PCa) remains imprecise. Computational pathology has emerged as an attractive option for improving risk stratification, but current approaches either lack interpretability or focus solely on tumor morphology. Here, we identify, validate, and provide interpretability for an immune microenvironment-derived computational pathology biomarker for high-grade PCa. Using digitized hematoxylin and eosin-stained (H&E) slides from two independent cohorts of patients treated with radical prostatectomy (n=490), we found that spatial clustering of immune clusters, but not immune cell abundance, was independently associated with reduced risk of distant metastasis for high-grade disease but not low-grade. Joint analysis of H&E images and RNA sequencing (n=326) revealed that in high-grade disease, high-cluster samples were enriched in CD8+ T cells, activated memory CD4+ T cells, and Tregs, as well as clonal T cell populations, overall suggestive of an underlying T cell-mediated antitumor response. No such enrichment was found in low-grade tumors. These findings establish immune spatial architecture as a novel, interpretable computational pathology biomarker and provide insight into the immune landscape of high-grade PCa.

bioinformatics↗

bioRxiv2024

Single-cell epigenetic profiling reveals an interferon response-high program associated with BAP1 deficiency in kidney cancer

Renal cell carcinoma (RCC) is characterized by recurrent somatic mutations in epigenetic regulators, which stratify patients into clinically significant subgroups with distinct prognoses and treatment responses. However, the cell type-specific epigenetic landscape of RCC--broadly and in the context of these mutations--is incompletely understood. To investigate these open questions, we integrated single nucleus ATAC sequencing data from RCC tumors across four independent cohorts. In clear cell RCC tumors, we identified four shared malignant epigenetic programs related to angiogenesis, proximal tubule-like features, interferon (IFN) signaling, and one that lacked distinct genomic regions with increased accessibility. Among the mutated epigenetic regulators, BAP1 mutation exhibited the most significant impact on chromatin accessibility in tumor cells, and the associated epigenetic changes were linked to IFN response. We identify multiple potential sources of elevated IFN signaling in these lesions, such as increased immune infiltration and increased accessibility and expression of an IFN-associated ERV, ERV3-16A3_LTR. We find that the expression of ERV3-16A3_LTR may itself be a negative prognostic biomarker in ccRCC. Our findings highlight the convergence of malignant epigenetic programs across ccRCC tumors and suggest that BAP1 loss, potentially through ERV3-16A3_LTR dysregulation, is associated with an IFN response-high epigenetic program.

cancer biology↗

bioRxiv2024

Concurrent maintenance of visual imagery and short-term memory provides evidence for their distinct representations

Recent research indicates there is overlap in the neural resources used during imagery and visual short-term memory. But do visual short-term memory and visual imagery operate on similar representations during recall? Here we investigated this question by asking participants to perform a delayed match to sample task for the contrast of visual gratings as cues. In the "Imagery" condition, participants were asked to form an accurate mental image of the visual cue, and at the end of the trial, perform a matching task on the mental image contrast. In the "Memory" condition, participants were not required to perform visual imagery but merely instructed to perform the delayed contrast-matching task. In Experiment 1, participants were told at the beginning of each block whether to engage in memory or imagery. The results showed that for the relevant contrast feature, matching judgments were more accurately in the "Memory" than in the "Imagery" condition. Thus imagery did not maintain an accurate representation of the encoded image, even when the visual features could still be maintained in visual short-term memory. In Experiment 2, participants were required to engage in memory and imagery simultaneously, and were told which to base their judgment on after each trial. The key finding was that the superior accuracy for memory over imagery remained, indicating that the contents of VSTM and imagery are based on distinct representations.

neuroscience↗

bioRxiv2023

Epigenomic signatures as circulating and predictive biomarkers in sarcomatoid renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are (1) a limited understanding of its gene regulatory programs and (2) difficulty identifying sarcomatoid differentiation on tumor biopsies due to spatial heterogeneity. To address these challenges, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries in tissue and plasma samples from 50 patients with RCC and healthy volunteers. We identified highly recurrent epigenomic reprogramming, as assessed by histone modifications and DNA methylation, that distinguishes sRCC from non-sarcomatoid RCC. Computational analysis of RCC epigenomic profiles and CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs. Analysis of two randomized clinical trials identified FOSL1 expression as a predictive biomarker of response to ICIs in RCC. Finally, we demonstrate that epigenomic signatures of sRCC are detectable in patient plasma, establishing an approach for blood-based diagnosis of this clinically important phenotype. These findings provide a framework for the discovery and non-invasive detection of epigenomic correlates of tumor histology via liquid biopsy.

genomics↗

bioRxiv2021

Reemergence of yellow fever virus in southeastern Brazil, 2017-2018: what sparked the spread?

BackgroundThe 2017-2018 yellow fever virus (YFV) outbreak in southeastern Brazil marked a reemergence of YFV in urban states that had been YFV free for nearly a century. Unlike earlier urban YFV transmission, this epidemic was also driven by forest mosquitos. The objective of this study was to evaluate environmental drivers of this outbreak. Methodology/Principal FindingsUsing surveillance data from the Brazilian Ministry of Health of human and non-human primate (NHP) cases of yellow fever, we traced the spatiotemporal progression of the outbreak. We then assessed the epidemic timing in relation to drought using a monthly Standardized Precipitation Evapotranspiration Index (SPEI). Lastly, we evaluated demographic risk factors for rural or outdoor exposure amongst YFV cases. Both human and NHP cases were first identified in a hot, dry, rural area in northern Minas Gerais before spreading southeast into the more cool, wet urban states of Espirito Santo, Sao Paulo, and Rio de Janeiro. Outbreaks also coincided with drought in all four southeastern states of Brazil. Confirmed YFV cases had an increased odds of being male (OR 2.58; 95% CI 2.28-2.92), working age (OR: 2.03; 95% CI: 1.76-2.35), and reporting recent travel from an urban to a rural area (OR: 5.02; 95% CI: 3.76-6.69). Conclusions/SignificanceThe 2017-2018 YFV epidemic in Brazil originated in hot, dry rural areas of Minas Gerais before expanding south into urban centers. An unusually severe drought in this region may have created environmental pressures that sparked the reemergence of YFV in Brazils southeastern cities. Author SummaryIn 2017-2018, cities in southeastern Brazil experienced an unusual outbreak of yellow fever virus. In the early 20th century, these cities had large outbreaks of yellow fever, spread by Aedes mosquitos. But until this recent outbreak, they had been free of yellow fever for nearly a century. While this outbreak was spread by Haemagogous forest mosquitos, the reemergence of yellow fever in densely populated urban areas raises serious concerns about it reestablishing ongoing transmission in cities, spread by urban Aedes mosquitos. Our study sought to understand how and why yellow fever virus remerged in this area. We traced the outbreak, finding that it started in hot, dry, rural areas and spread south into cool, wet urban areas. Additionally, the outbreak coincided with a severe drought; this extreme weather may have promoted the spread of yellow fever. Infection was also associated with rural and outdoor exposure, further suggesting this epidemic originated in rural areas.

ecology↗