Biology subjects

Melocchi, V.

Publications and source records attributed to Melocchi, V..

4 recordsLinked to original sources

bioRxiv2023

Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness

In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we exploit a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. The pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/stem cells crosstalk, contributing to the identification of tumor vulnerabilities.

cancer biology↗

bioRxiv2022

Matrix Gla Protein acts as a driver of stemness and tumor initiation in ovarian cancer

Ovarian cancer (OC) displays the highest mortality among gynecological tumors, mainly due to early peritoneal dissemination, the high frequency of tumor relapse following primary debulking and the development of chemoresistance. All these events are thought to be initiated and sustained by a subpopulation of neoplastic cells, termed ovarian cancer stem cells (OCSC), that are endowed with self-renewing and tumor-initiating properties. This implies that interfering with OCSC function should offer novel therapeutic perspectives to defeat OC progression. To this aim, a better understanding of the molecular and functional makeup of OCSC in clinically relevant model systems is essential. We have profiled the transcriptome of OCSC vs. their bulk cell counterpart from a panel of patient-derived OC cell cultures. This revealed that Matrix Gla Protein (MGP), classically known as a calcification-preventing factor in cartilage and blood vessels, is markedly enriched in OCSC. Functional assays showed that MGP confers several stemness-associated traits to OC cells, including a transcriptional reprogramming. Patient-derived organotypic cultures pointed to the peritoneal microenvironment as a major inducer of MGP expression in OC cells. Furthermore, MGP was found to be necessary and sufficient for tumor initiation in OC mouse models, by shortening tumor latency and increasing dramatically the frequency of tumor-initiating cells. Mechanistically, MGP-driven OC stemness was mediated by the stimulation of Hedgehog signaling, in particular through the induction of the Hedgehog effector GLI1, thus highlighting a novel MGP/Hedgehog pathway axis in OCSC. Finally, MGP expression was found to correlate with poor prognosis in OC patients, and was increased in tumor tissue after chemotherapy, supporting the clinical relevance of our findings. Thus, MGP is a novel driver in OCSC pathophysiology, with a major role in stemness and in tumor initiation.

cancer biology↗

bioRxiv2022

miRNome profiling of lung cancer metastases revealed a key role for miRNA-PD-L1 axis in the modulation of chemotherapy response

Locally-advanced non-small-cell lung cancer (NSCLC) is frequent at diagnosis and requires multimodal treatment approaches. Neoadjuvant chemotherapy (NACT) followed by surgery is the treatment of choice for operable locally-advanced NSCLC (Stage IIIA). However, the majority of patients are NACT-resistant and shows persistent lymph nodal metastases (LNmets) and an adverse outcome. Therefore, the identification of mechanisms and biomarkers of NACT resistance is paramount for ameliorating prognosis of patients with Stage IIIA NSCLC. Here, we investigated the miRNome and transcriptome of chemo naive LNmets collected from patients with Stage IIIA NSCLC (N=64). We found that a microRNA signature accurately predicts NACT response. Mechanistically, we discovered a miR-455-5p/PD-L1 regulatory axis which drives chemotherapy resistance, hallmarks metastases with active IFN-{gamma} response pathway (an inducer of PD-L1 expression), and impacts T cells viability and relative abundances in tumor-microenviroment (TME). Our data provides new biomarkers to predict NACT response and adds molecular insights relevant for improving the management of patients with locally-advanced NSCLC.

cancer biology↗

bioRxiv2022

Extracellular vesicle microRNAs contribute to Notch signaling pathway in T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive T-cell malignancy characterized by genotypically-defined and phenotypically divergent cell populations, governed by adaptive landscapes. Clonal expansions are associated to genetic and epigenetic events, and modulation of external stimuli that affect the hierarchical structure of subclones and support the dynamics of leukemic subsets. Recently, small extracellular vesicles (sEV) such exosomes were also shown to play a role in leukemia. Here, by coupling miRNome, bulk and single cell transcriptome profiling, we found that T-ALL-secreted sEV contain NOTCH1-dependent microRNAs (EV-miRs), which control oncogenic pathways acting as autocrine stimuli and ultimately promoting the expansion/survival of highly proliferative cell subsets of human T-cell leukemias. Of interest, we found that NOTCH1-dependent EV-miRs mostly comprised members of miR-17-92a cluster and paralogues, which rescued in vitro the proliferation of T-ALL cells blocked by {gamma}-secretase inhibitors (GSI) and regulate network of genes characterizing patients with relapsed/refractory early T-cell progenitor (ETP) ALLs. All these findings suggest that NOTCH1 dependent EV-miRs may sustain the growth/survival of immunophenotypically defined cell populations, altering the cell heterogeneity and the dynamics of T-cell leukemias in response to conventional therapies.

cancer biology↗