Biology subjects

Leary, A.

Publications and source records attributed to Leary, A..

3 recordsLinked to original sources

bioRxiv2025

The extracellular matrix dictates ovarian cancer cell migration in an in vivo-derived circulating environment

Ovarian cancer (OC) disseminates via ascites and interaction with peritoneal extracellular matrix (ECM). To dissect the crosstalk between ECM and ascites in OC cell migration, we developed an ovarian tumor-on-chip integrating OC tumor spheroids, perfusion-induced shear stress of fluid supplemented with key components of ascites or patient-derived ascites, and biomimetic ECMs mimicking either early-stage basement membrane or late-stage connective tissues. We evaluated the individual and combined effects of two key ascitic components, fibronectin and TGF-{beta}, and compared these results with the perfusion of patient ascites. Results showed that cell migration, morphology, and epithelial-to-mesenchymal transition (EMT) markers such as the reorganization of vimentin cytoskeleton depend strongly on ECM composition, regardless of biochemical cues. Fibronectin and TGF-{beta} synergistically enhanced migration and EMT signatures, especially on basement membrane-rich ECM. Patient ascites further promoted migration but did not override ECM-driven migration patterns. Our findings show that clinical ascites perfusion exemplifies the ECM-dependence of cancer cell migration. This highlights that ECM protein composition is a dominant regulator of OC cell migration, providing key insights for in vitro tumor modeling and therapeutic strategies targeting the metastatic microenvironment.

cancer biology↗

bioRxiv2024

Preclinical evaluation of pharmacological inhibition of SIRT1 on the growth of tumoral and metastatic granulosa cells

BackgroundClinical management of patients with recurrent ovarian granulosa cell tumor (GCT) remains poor. Sirtuin-1 (SIRT1), a deacetylase enzyme involved in the regulation of tumor growth and metastasis, may represent a therapeutic target due to the availability of selective pharmacological inhibitors with minimal toxicity. MethodsWe assessed the possible overexpression of SIRT1 during tumorigenesis by Western blot and immunohistochemistry. We tested the effects of SIRT1 inhibition by EX-527 on growth, proliferation, death, migration and gene expression by RNA sequencing and RT-qPCR in vitro on three GCT cell lines (AT29, KGN, COV434). Tumor growth in response to EX-527 treatment was examined in nude mice carrying subcutaneous GCT cell grafts using an electronic caliper and in GCT of AT83 mice by 3D ultrasound imaging system. ResultsSIRT1 abundance increased during tumorigenesis. In vitro treatment with EX-527 efficiently reduced cell growth, either by inducing apoptosis or by inhibiting proliferation. EX-527 induced alterations in pathways driven by mTOR, Myc and E2F, and in pathways controlling cell metabolism and oxidative stress. The administration of this treatment for 4 weeks efficiently reduced tumor progression in vivo. ConclusionsOur study reveals a new therapeutic potential of SIRT1 targeting as a treatment option for patients with recurrent GCT.

cancer biology↗

bioRxiv2018

Bipolar spindle formation is a fast, irreversible process requiring Kinesin-5 crosslinking and sliding modalities

GRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC=\"FIGDIR/small/452821_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (30K):\norg.highwire.dtl.DTLVardef@ad6c3corg.highwire.dtl.DTLVardef@19cf957org.highwire.dtl.DTLVardef@b5c2a8org.highwire.dtl.DTLVardef@fece04_HPS_FORMAT_FIGEXP M_FIG C_FIG Separation of duplicated spindle poles is the first step in forming the mitotic spindle. Kinesin-5 crosslinks and slides anti-parallel microtubules, but it is unclear how these two activities contribute to the first steps in spindle formation. In this study we report that in monopolar spindles, the duplicated spindle poles snap apart in a fast and irreversible step that produces a nascent bipolar spindle. Using mutations in Kinesin-5 that inhibit microtubule sliding, we show crosslinking alone drives the fast, irreversible pole separation. Electron tomography revealed microtubule pairs in monopolar spindles have short overlaps that intersect at high angles and are unsuited for ensemble Kinesin-5 sliding. However, maximal extension of a subset of microtubule pairs approaches the length of nascent bipolar spindles and is consistent with a Kinesin-5 crosslinking driven transition. Finally, stochastic microtubule sliding by Kinesin-5 stabilizes the nascent spindle and sets a stereotyped equilibrium length.

biophysics↗