👤 Paolo Verderio

Ovarian carcinoma has still a poor prognosis. CRISPR/Cas9 loss-of-function screen revealed a relationship between the PSMC6 proteasome subunit expression and survival of cisplatin-sensitive and -resistant ovarian carcinoma cells. Increased levels of PSMC6 were evidenced in multiple ovarian carcinoma cell lines versus normal cells. An association between PSMC6 levels and tumour stages as well as with a reduced progression-free survival was found. Since a PSMC6 interactome analysis evidenced limited knowledge on PSMC6 biology, mechanistic studies were carried out. PSMC6 knockdown indicated reduced cell growth and clonogenicity in cisplatin-sensitive IGROV-1 and -resistant IGROV-1/Pt1 cells, with a higher impact in resistant cells. This behaviour was accompanied by the accumulation of ubiquitinated proteins and down-regulation of ERK1/2 phosphorylation mediated by increased DUSP6. PSMC6 silencing increased sensitivity to cisplatin in IGROV-1/Pt1 cells as shown by clonogenic assay and 3D spheroids. Since PSMC6 knockdown did not change sensitivity to 20S and 19S proteasome inhibitors, we suggest a new mode of proteasome targeting by interference with a proteasome ATPase. Overall, a link between PSMC6 and ovarian carcinoma aggressiveness is envisioned, highlighting PSMC6 as a potential diagnostic and therapeutic target. Show less

This study used a deidentified nationwide (US-based) high-grade serous ovarian cancer (HGSOC) clinicogenomic database (CGDB) to enrich our understanding of HGSOC's genomic heterogeneity and assess the utility of comprehensive genomic profiling (CGP) in clinical settings. We conducted a retrospective observational analysis on 856 patients with HGSOC profiled with CGP genomic tests, retrieved from CGDB from January 2011 to September 2023. In addition to Overall, our study provides evidence that CGP significantly improves the identification of molecular targets in HGSOC, supporting its importance in the clinical practice to provide patients with more therapeutic options. Show less

Progression to stage IV disease remains the main cause of breast cancer-related deaths. Increasing knowledge on the hematogenous phase of metastasis is key for exploiting the entire window of opportunity to interfere with early dissemination and to achieve a more effective disease control. Recent evidence suggests that circulating tumor cells (CTCs) possess diverse adaptive mechanisms to survive in blood and eventually metastasize, encouraging research into CTC-directed therapies. On the hypothesis that the distinguishing molecular features of CTCs reveal useful information on metastasis biology and disease outcome, we compared the transcriptome of CTCs, primary tumors, lymph-node and lung metastases of the MDA-MB-231 xenograft model, and assessed the biological role of a panel of selected genes, by in vitro and in vivo functional assays, and their clinical significance in M0 and M+ breast cancer patients. We found that hematogenous dissemination is governed by a transcriptional program and identified a CTC signature that includes 192 up-regulated genes, mainly related to cell plasticity and adaptation, and 282 down-regulated genes, involved in chromatin remodeling and transcription. Among genes up-regulated in CTCs, FADS3 was found to increases cell membrane fluidity and promote hematogenous diffusion and lung metastasis formation. TFF3 was observed to be associated with a subset of CTCs with epithelial-like features in the experimental model and in a cohort of 44 breast cancer patients, and to play a role in cell migration, invasion and blood-borne dissemination. The analysis of clinical samples with a panel of CTC-specific genes (ADPRHL1, ELF3, FCF1, TFF1 and TFF3) considerably improved CTC detection as compared with epithelial and tumor-associated markers both in M0 and stage IV patients, and CTC kinetics informed disease relapse in the neoadjuvant setting. Our findings provide evidence on the potential of a CTC-specific molecular profile as source of metastasis-relevant genes in breast cancer experimental models and in patients. Thanks to transcriptome analysis we generated a novel CTC signature in the MDA-MB-231 xenograft model, adding a new piece to the current knowledge on the key players that orchestrate tumor cell hematogenous dissemination and breast cancer metastasis, and expanding the list of CTC-related biomarkers for future validation studies. Show less