Biology subjects

Madak-Erdogan, Z.

Publications and source records attributed to Madak-Erdogan, Z..

8 recordsLinked to original sources

bioRxiv2026

Loss of Mast cells and histaminergic signaling link diet to platelet-mediated NETosis and mammary cancer recurrence

Breast cancer recurrence remains a clinical challenge. The period after the treatment of the primary tumor while cancer cells that evaded initial treatment lay dormant, provides a unique window of opportunity for interventions to prevent recurrence. Specific modifiable factors such as consumption of high fat diets or elevated circulating cholesterol are associated with decreased time to recurrence. Mechanistically, oxidized cholesterol and lipid species have been implicated in the regulation of the tumor microenvironment. This suggests that consumption of food prepared under oxidizing conditions such as pan-frying, may be an underappreciated risk. Using murine models of mammary cancer dormancy, we found that a diet enriched with fat from fried, cured bacon (cfBF) decreased dormancy latency times. Resulting lesions had fewer mast cells (MCs). Loss of MCs alone resulted in reemergence from dormancy. Elevated expression of a MC gene signature in breast tumors was associated with improved progression free and overall survival, highlighting the human relevance of these findings. MCs are a major source of tissue histamine, and lesions from mice fed cfBF had decreased concentrations. Importantly, antagonists of the histamine receptor 2 (H2R) sparked reemergence from dormancy. H2R antagonists are over-the-counter drugs are taken to alleviate gastroesophageal reflux disease. Chronic treatment of mice with H2R-antagonists sensitized platelets towards activation and crosstalk with neutrophils, and subsequent formation of neutrophil extracellular traps (NETs). The loss of platelet or NETosis activity mitigated the H2R-antagonist stimulated reemergence from dormancy. Therefore, we establish a novel metastatic axis which links diet to recurrence via MCs, histaminergic signaling and NETosis: Diet -- MC -- H2R -- (decreased) Platelet Activity -- (decreased) Neutrophil-NETosis -- (decreased) Reemergence from Dormancy. Our data reveal several potential intervention strategies: lifestyle, MC stabilization, histaminergic signaling, and neutrophil and platelet activity.

cancer biology↗

bioRxiv2025

In silico reconstruction of primary and metastatic tumor architecture using GIS-augmented spatial transcriptomics

The tumor microenvironment (TME) comprises different cell populations that interact, contributing to tumor heterogeneity and therapy response. Spatial transcriptomics offers valuable insights into transcriptional complexity and heterogeneity of the TME. We established Geographic Information System (GIS)-augmented In-Silico Reconstruction of Tumor Architecture (GIS-ROTA), a biologically informed analytic framework that integrates pathway or cell type-based enrichment analysis with local Morans I to uncover functional spatial domains. In our Visium dataset of primary and metastatic estrogen receptor-positive breast tumor samples, GIS-ROTA revealed extensive co-localization of estrogen response with metabolic pathway gene sets and mutual exclusivity with metastasis-related and specific immune-related pathway gene sets. The novelty of our approach lies in considering biological functions prior to identifying any spatial domains, providing direct interpretability and minimizing the subjectivity of interpreting clusters observed from conventional analytic methods. Overall, our GIS-ROTA framework integrates biological knowledge first, yielding spatial patterns with functional relevance and enabling identification of novel targets for development of therapeutic strategies.

cancer biology↗

bioRxiv2025

ACSS2-Mediated Metabolic-Epigenetic Crosstalk Drives Fulvestrant Resistance and Represents a Novel Therapeutic Target

1.Endocrine therapies target hormone-dependent cancer cells, primarily through estrogen receptor alpha (ER), expressed in [~]70% of breast cancers (ER+). Despite treatment advances, 30-40% of ER+ breast cancer patients experience recurrence and metastasis, with 5-year survival rates of only 31.9%. We validated poor outcomes for liver metastasis patients treated with Fulvestrant (Fulv) using the local Carle Foundation Hospital cohort and examined metabolic pathways in liver metastatic patient-derived xenograft (PDX) models, revealing upregulated lipid and acetyl-CoA production. Our previous work demonstrated that combining Fulv with acetyl-CoA synthase inhibitor (ACSI) targeting Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2), synergistically reduced ER+ metastatic breast cancer (MBC) cell viability in vitro. Using multiple analytical approaches-isotope tracing, CUT&RUN sequencing, immunofluorescence, western blot, and RNA sequencing-we characterized the effects of acetyl-CoA synthesis inhibition on Fulv-induced alterations. Fulv treatment of MBC cells increased ACSS2 expression and acetate utilization. Isotope tracing revealed that Fulv decreased acetate flux to the TCA cycle while promoting fatty acid synthesis. Importantly, ACSS2 was predominantly nuclear and CUT&RUN sequencing showed that Fulv treatment increased ACSS2 chromatin occupancy and ER/ACSS2/H3K27ac overlapping sites near genes associated with tumor progression, which was eliminated by combination of ACSI and Fulv. RNA sequencing revealed reduction of Fulv-induced expression of genes involved in cancer cell metabolism and key signaling pathways in cancer with the Fulv+ACSI combination. In a therapy-resistant xenograft model, combining Fulv and ACSI reduced Fulv-dependent increase in metastatic burden. Our findings indicate ACSS2 contributes to endocrine therapy resistance through nuclear acetyl-CoA provision for epigenetic alterations. Targeting these cancer cell adaptations represents a novel therapeutic approach potentially reducing metastasis-related mortality and improving breast cancer treatment outcomes.

cancer biology↗

bioRxiv2024

Glutamate Transport Proteins and Metabolic Enzymes are Poor Prognostic Factors in Invasive Lobular Carcinoma

Invasive Lobular Carcinoma (ILC) is a subtype of breast cancer characterized by distinct biological features, and limited glucose uptake coupled with increased reliance on amino acid and lipid metabolism. Our prior studies highlight the importance of glutamate as a key regulator of ILC tumor growth and therapeutic response. Here we examine the expression of four key proteins involved in glutamate transport and metabolism - SLC3A2, SLC7A11, GPX4, and GLUD1/2 - in a racially diverse cohort of 72 estrogen receptor-positive (ER+) ILC and 50 ER+ invasive ductal carcinoma, no special type (IDC/NST) patients with primary disease. All four proteins associate with increased tumor size in ILC, with three showing stronger associations in Black women, but not in IDC/NST. Among these three proteins in ILC, GLUD1/2 uniquely associates with ER expression in all women, while GLUD1/2 and SLC3A2 are enriched in hypertensive women. GLUD1/2 and GPX4 are upregulated in endocrine therapy-resistant ILC cell lines, and pharmacological inhibition of GLUD1 reduces ER protein levels and cell viability. Together, these findings support a potentially important role for glutamate metabolism in ILC and suggest GLUD1 and other glutamate-handling proteins as candidate targets for therapeutic intervention in ILC.

cancer biology↗

bioRxiv2024

MicroRNAs and PFAS: A Pilot Study in Blood Collected from Firefighters

Per- and polyfluoroalkyl substances (PFAS) are chemicals with widespread industrial and consumer applications, and firefighters are known to be at risk of elevated PFAS exposure due to their occupational activities. This study aims to assess PFAS exposure and explore potential mechanistic insights through miRNA sequencing of plasma exosomes, in relation to PFAS levels in the general population. The study included 34 firefighter participants. PFAS levels in plasma were analyzed, and miRNA sequencing of plasma exosomes was conducted. The findings were compared with the general population data from the National Health and Nutrition Examination Survey (NHANES). While total PFAS levels did not significantly differ between firefighters and the general population in the cohort considered, variations in individual PFAS compounds were observed. MiRNA sequencing revealed substantial heterogeneity in miRNA expression patterns. Associations between serum PFAS levels and biochemical indicators suggested potential health implications, although further mechanistic insights need to be explored.

pharmacology and toxicology↗

bioRxiv2022

WNT4 executes estrogen regulation of cellular metabolism via intracellular activity at the mitochondria

Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Further, ovarian cancer cell lines with rs3820282 variant genotype are WNT4-dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulate the distinct metabolic phenotypes of ILC and gynecologic cancers. SignificanceWNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT4 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment.

cancer biology↗

bioRxiv2021

Targeting metabolic adaptations in the breast cancer liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant (Fulv) as standard-of-care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ER activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. ImplicationsOur findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.

cancer biology↗

bioRxiv2020

Circulating bile acid levels direct sex-differences in liver cancer development

Hepatocellular carcinoma (HCC), the most common liver cancer, exhibits a higher incidence in males. Here, we report that mice lacking the bile acid regulators, Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and FXR and SHP double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. We examined if the obtained transcriptomic signatures correlate with the survival outcomes for HCC patients to assess the translational potential of this murine HCC model. Gene signatures that are unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes in female livers and promotes tumorigenesis that, intriguingly, coincides with increases in serum bile acid (BA) levels. Despite similar genetics, we found higher serum BA concentrations in males, whereas female knockout mice excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC. SignificanceWe show that female-specific gene profiles identified in Fxr-/-, Shp-/- double knockout (DKO) mice correlate with better outcomes for HCC patients and uncover sex differences in circulation and excretion of bile acid. Overall, we demonstrate that increasing (ovariectomy or chemical injury) or decreasing (pharmacologically with FDA-approved resin) serum bile acids, not hepatic bile acids, promoted or alleviated liver cancer burden.

cancer biology↗