Biology subjects

Pooladanda, V.

Publications and source records attributed to Pooladanda, V..

3 recordsLinked to original sources

bioRxiv2026

Extracellular vesicles facilitate the horizontal transfer of drug resistance and stem-like properties between ovarian tumor cells

Ovarian cancer stem cells (CSCs) can seed recurrent drug-resistant disease. Likewise, non-CSCs can acquire CSC phenotypic properties. How this process is orchestrated is of interest to inform how it might be prevented. We tested the hypothesis that ovarian CSC and/or drug-resistant tumor cells confer stem-like properties via extracellular vesicles (EVs). We focused our investigation on how EVs might mediate EZH2 signaling to promote a phenotypic change in drug-sensitive, non-CSCs. To accomplish this, we utilized paired PARP inhibitor-sensitive and - resistant ovarian cancer (OvCa) cell lines, EZH2 knockdown lines, and patient-derived organoids (PDOs) originating from recurrent high-grade serous OvCa. Small EVs isolated from drug-sensitive, CSC and/or drug-resistant enriched cultures, PARP inhibitor (olaparib) resistant lines, or drug-treated (olaparib or carboplatin) lines were cultured with treatment naive or sensitive lines for defined time points. The impact of small EV exposure was determined by assessing cell number, metabolic activity, viability, sphere and colony-forming capacity, ALDH activity, DNA damage, and changes in associated signaling pathways. We found that EVs from CSC or drug-resistant enriched cell fractions communicate CSC-like phenotypes to the more sensitive tumor cells via EZH2 canonical and non-canonical signaling pathways, promoting stemness. We conclude that EV-mediated activation of EZH2 signaling represents a targetable mechanism contributing to stemness-associated drug resistance in OvCa. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/699925v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@6b4ffborg.highwire.dtl.DTLVardef@1501931org.highwire.dtl.DTLVardef@1a5f31aorg.highwire.dtl.DTLVardef@1fb475f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Extracellular vesicles regulate metastable phenotypes of lymphangioleiomyomatosis cells via shuttling ATP synthesis to pseudopodia and activation of integrin adhesion complexes.

Pulmonary lymphangioleiomyomatosis (LAM) is metastatic sarcoma but mechanisms regulating LAM metastasis are unknown. Extracellular vesicle (EV) regulate cancer metastasis but their roles in LAM have not yet been investigated. Here, we report that EV biogenesis is increased in LAM and LAM EV cargo is enriched with lung tropic integrins, metalloproteinases, and cancer stem cell markers. LAM-EV increase LAM cell migration and invasion via the ITG6/{beta}1-c-Src-FAK-AKT axis. Metastable (hybrid) phenotypes of LAM metastasizing cells, pivotal for metastasis, are regulated by EV from primary tumor or metastasizing LAM cells via shuttling ATP synthesis to cell pseudopodia or activation of integrin adhesion complex, respectively. In mouse models of LAM, LAM-EV increase lung metastatic burden through mechanisms involving lung extracellular matrix remodeling. Collectively, these data provide evidence for the role of EV in promoting LAM lung metastasis and identify novel EV-dependent mechanisms regulating metastable phenotypes of tumor cells. Clinical impact of research is that it establishes LAM pathway as novel target for LAM therapy.

cancer biology↗

bioRxiv2023

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, its unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H2O2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H2O2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

molecular biology↗