Biology subjects

Bartoletti, M.

Publications and source records attributed to Bartoletti, M..

3 recordsLinked to original sources

bioRxiv2024

Longitudinal Prediction of Drug Response in High-Grade Serous Ovarian Cancer Organoid Cultures Aligning with Clinical Responses

High-grade serous ovarian cancer (HGSOC) ranks among the most aggressive gynecological malignancies. Its high mortality stems from frequent recurrence post-primary treatments and development of platinum resistance. Since, traditional drug development via animal models is time-consuming and lacks reproducibility, in precision cancer medicine, primary patient-derived organoids (PDOs) offer a solution by replicating disease pathophysiology and expediting drug screening. We developed an expandable HGSOC organoid platform for rapid drug screening and resistance testing. Our study aimed to validate the stability of seven PDO pairs in predicting drug responses over time. Organoids underwent low- and high-passage drug screenings over nine months, involving 21 conventional and FDA-approved drugs and proteomic analyses. Comparison of in vitro outcomes with clinical data confirmed the platforms predictive capacity. Notably, a PDO with BRCA1 mutation exhibited resistance to Carboplatin and PARP inhibitors, highlighting organoid models clinical relevance for novel targeted therapies such as the Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1), a valuable target for HGSOC patients.

cancer biology↗

bioRxiv2021

Glia-neuron signaling mediated by two different BMP ligands impacts synaptic growth

The nervous system is a complex network of cells whose interactions provide circuitry necessary for an organism to perceive and move through its environment. Revealing the molecular basis of how neurons and non-neuronal glia communicate is essential for understanding neural development, behavior, and abnormalities of the nervous system. BMP signaling in motor neurons, activated in part by retrograde signals from muscle expressed Gbb (BMP5/6/7) has been implicated in synaptic growth, function and plasticity in Drosophila melanogaster. Through loss-of-function studies, we establish Gbb as a critical mediator of glia to neuron signaling important for proper synaptic growth. Furthermore, the BMP2/4 ortholog, Dpp, expressed in a subset of motor neurons, acts by autocrine signaling to also facilitate neuromuscular junction (NMJ) growth at specific muscle innervation sites. In addition to signaling from glia to motor neurons, autocrine Gbb induces signaling in larval VNC glia which strongly express the BMP type II receptor, Wit. In addition to Dpps autocrine motor neuron signaling, Dpp also engages in paracrine signaling to adjacent glia but not to neighboring motor neurons. In one type of dorsal midline motor neuron, RP2, dpp transcription is under tight regulation, as its expression is under autoregulatory control in RP2 but not aCC neurons. Taken together our findings indicate that bi-directional BMP signaling, mediated by two different ligands, facilitates communication between glia and neurons. Gbb, prominently expressed in glia, and Dpp acting from a discrete set of neurons induce active Smad-dependent BMP signaling to influence bouton number during neuromuscular junction growth.

neuroscience↗

bioRxiv2019

The Bric-a-Brac transcription factors are necessary for formation of functional germline stem cell niches through control of dpp expression in the Drosophila melanogaster ovary

Many studies have focused on the mechanisms of stem cell maintenance via their interaction with a particular niche or microenvironment in adult tissues, but how formation of a functional niche is initiated, including how stem cells within a niche are established, is less well understood. Adult Drosophila melanogaster ovary Germline Stem Cell (GSC) niches are comprised of somatic cells forming a stack called a Terminal Filament (TF) and underlying Cap Cells (CCs) and Escort Cells (ECs), which are in direct contact with GSCs. In the adult, the Engrailed (En) transcription factor is specifically expressed in niche cells where it directly controls expression of the decapentaplegic gene (dpp) encoding a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules, which are key factors for GSC maintenance. In late third instar larval ovaries, in response to BMP signaling from newly-formed niches, adjacent primordial germ cells become GSCs. The bric-a-brac paralogs (bab1 and bab2) encode BTB/POZ-domain containing transcription factors, that are also expressed in developing GSCs niches where they are required for TF formation. Here, we demonstrate that Bab1 and Bab2 display redundant cell autonomous function for TF morphogenesis and we identify a new function for these genes in GSC establishment. Moreover, we show that Bab proteins control dpp expression in otherwise correctly specified CCs, independently of En and its paralog Invected (Inv). In fact, our results also indicate that en/inv function in larval stages are neither essential for TF formation, nor GSC establishment. Finally, when bab2 was overexpressed in ovarian somatic cells outside of the niche, where en/inv were not expressed, ectopic BMP signaling activation was induced in adjacent germ cells of adult ovaries, which formed GSC-like tumors. Together, these results indicate that Bab transcription factors are positive regulators of BMP signaling for acquisition of GSC status.

developmental biology↗