Biology subjects

Iwanicki, M.

Publications and source records attributed to Iwanicki, M..

5 recordsLinked to original sources

bioRxiv2026

PFOS Disrupts Membrane Signaling and Epithelial Integrityin Fallopian Tube Cells

Perfluorooctane sulfonic acid (PFOS), a per- and polyfluoroalkyl substance (PFAS), is a widespread persistent environmental pollutant that has been implicated in various human health conditions, including infertility and cancer. Here, we investigate the effects of acute exposure to PFOS on human fallopian tube epithelial (FNE) cells that are essential for fertility and increasingly recognized as the origin site for high-grade serous ovarian cancer. We show that acute PFOS exposure changes morphology, arrests proliferation, impairs adhesion, and compromises epithelial integrity of FNE cells. Using transcriptomic profiling of FNE cells exposed to PFOS, we found increased expression of genes associated with stress-response signal transduction, including KRAS, and decreased expression of genes related to cholesterol transport and lipid homeostasis. We show that inhibition of MEK/ERK or cholesterol supplementation rescued changes in cell morphology. Further, we performed membrane fluidity measurements of cells exposed to PFOS and found elevated membrane disorder and fluidity. Our results are consistent with a model in which PFOS perturbs plasma membrane, activates stress-response signaling pathways, and impairs epithelial cell function. These studies establish a framework for understanding the effects of PFAS on cell physiology.

cell biology↗

bioRxiv2025

Mutant p53R175H-Associated Protection of Ovarian Cancer Precursor Cells from Cisplatin Requires Expression of SLC6A6 Taurine Transporter

Tumor suppressor gene TP53 is ubiquitously mutated in ovarian cancer precursor lesions that undergo pervasive accumulation of DNA damage. Prior literature provides evidence that the expression of mutant p53 protein in epithelial cells is associated with increased survival in response to DNA-damaging treatments. Hence, identification and understanding of the mechanisms that, in response to DNA damage accumulation, support survival of ovarian cancer precursor cells carrying p53 mutations might provide important information about the evolution of the disease. Here we used a combination of OC precursor cell models, biochemistry, microscopy, and flow cytometry to provide evidence that the taurine transporter, the SLC6A6 molecule, contributes to cell protection from DNA-damaging (cisplatin) treatment. We found that expression of mutant p53R175H in OC precursor cells, the fallopian tube non-ciliated epithelial (FNE) cells, induced resistance to the DNA-damaging agent cisplatin. Most importantly, shRNA-mediated targeting of SLC6A6 transcript re-sensitized FNE cells expressing mutant p53R175H to cisplatin treatment. Our studies are consistent with the model that the loss of SLC6A6 alters mechanisms involved in the regulation of cell survival in response to DNA damage.

cancer biology↗

bioRxiv2023

The Dietary Supplement Taurine Suppresses Ovarian Cancer Growth

Taurine, a non-proteogenic amino acid, and commonly used nutritional supplement can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We have found that OC ascites-derived cells contained significantly more intracellular taurine than cell cultures modeling OC. In culture, elevation of intracellular taurine concentration to OC ascites-cells-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant- or wild-type p53 binding to DNA, and activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurines suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurines ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurines cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth, metabolism, and activate cell protective mechanisms involving mTOR and DNA damage sensing signal transduction.

cancer biology↗

bioRxiv2022

Extracellular Matrix Levels Modulate Outgrowths Dynamics in Ovarian Cancer.

Ovarian carcinoma (OC) forms outgrowths that extend from the outer surface of an afflicted organ into the peritoneum. OC outgrowth formation is poorly understood because there is limited availability of OC cell culture models to examine the behavior of cell assemblies that form outgrowths. Prompted by immunochemical evaluation of extracellular matrix (ECM) components, laminin {gamma}1 and collagens, in human tissues representing untreated and chemotherapy-recovered OC, we developed laminin- and collagen-rich ECM-reconstituted cell culture models amenable to studies of cell clusters that can form outgrowths. We demonstrate that ECM promotes outgrowth formation in fallopian tube non-ciliated epithelial cells (FNE) expressing mutant p53-R175H and various OC cell lines. Outgrowths were initiated by cells that had undergone outward translocation and, upon mechanical detachment, could intercalate into mesothelial cell monolayers. Electron microscopy, optical coherence tomography (OCT), and small amplitude oscillatory shear experiments revealed that high ECM concentration increased ECM fibrous network thickness and led to high shear elasticity in the ECM environment. These physical characteristics were associated with the suppression of outgrowths. A culture environment with low ECM concentration mimicked viscoelasticity of malignant peritoneal fluids (ascites) and supported cell proliferation, cell translocation, and outgrowth formation. These results highlight the importance of ECM microenvironments in modulating OC growth and could provide an additional explanation of why primary and recurrent ovarian tumors form outgrowths that protrude into the peritoneal cavity.

cancer biology↗

bioRxiv2020

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand, which exacerbate misfolded, unfolded and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. In this study, we report that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion through the outer layers of omentum as well as significantly decreased the in vivo metastatic tumor growth in ovarian cancer xenografts. Transcriptional profiling of UCHL1 silenced HGSOC cells revealed the down-regulation of genes implicated with proteasome activity along with the upregulation of endoplasmic reticulum (ER) stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH) resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1 silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7-APEH-proteasome axis. O_FIG O_LINKSMALLFIG WIDTH=183 HEIGHT=200 SRC="FIGDIR/small/316810v2_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@d38d5borg.highwire.dtl.DTLVardef@e58513org.highwire.dtl.DTLVardef@83e274org.highwire.dtl.DTLVardef@884ec3_HPS_FORMAT_FIGEXP M_FIG C_FIG ImplicationsThis study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC. It recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress and as novel alternative therapeutic approaches.

cancer biology↗