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Cardone, L.

Publications and source records attributed to Cardone, L..

2 recordsLinked to original sources
bioRxiv2026

Urothelial-lineage master transcription factor hub proteomics shows mechanisms impeding urothelial cancer cell differentiation

Urothelial cancer (UC) cells of the luminal subtype exhibit partial, incomplete differentiation towards umbrella cells that line bladder lumen, seen by morphology and gene expression. Differentiation is stalled even though the cells express master transcription factors (MTFs) that drive luminal urothelial differentiation, e.g., FOXA1 and CEBPB, at levels seen in normal differentiated urothelium. We therefore analyzed the FOXA1/CEBPB MTF hub by mass spectrometry. SWI/SNF coactivator complex (CoA) components, e.g., SMARCA4, ARID1A, that read the epigenetic activation mark histone 3 lysine 27 acetylation (H3K27ac) and use ATP-hydrolysis to open chromatin, were the most abundant proteins pulled-down with FOXA1/CEBPB. However, genes for these and other CoA, e.g., CREBBP, EP300 that write H3K27ac, were mutated/deleted in >95% of UCs in clinical series. Also contained in the hub were corepressors (CoR) that erase H3K27ac and close chromatin, e.g., HDAC1, CHD4 - genes for these CoR were recurrently gained in UCs. Chromatin analyses showed H3K27ac-centered remodeling was needed to activate umbrella but not constitutively accessible cell growth/division/housekeeping genes. Restoring ARID1A into ARID1A-mutated UC cells using lentiviral transduction, or inhibiting CoR with siRNA or small molecules, activated umbrella genes and terminated replications. In summary, UC-genesis selects for loss- and gain-of-function of CoA and CoR respectively in the urothelial-lineage MTF hub; small molecule CoR-inhibitors are candidate remedies to renew maturation towards terminal differentiated-fates. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/744501v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@bda7e5org.highwire.dtl.DTLVardef@159ea57org.highwire.dtl.DTLVardef@28132borg.highwire.dtl.DTLVardef@1028bee_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2024

Enhancing PDAC Therapy: Decitabine-Olaparib Synergy Targets KRAS-Dependent Tumors

Current chemotherapies provide limited clinical benefits to patients with pancreatic ductal adenocarcinoma (PDAC), partly due to the lack of effective biomarkers for personalized therapy. KRAS activating mutations occur in almost 90% of PDAC cases, leading to a subset of tumors dependent on KRAS for survival (dKRAS). Assessing dKRAS in PDAC can be achieved using gene expression signature scores, independent of specific KRAS mutations, allowing for personalized therapies. Previous studies have shown that dKRAS-PDAC cells are more sensitive to the FDA-approved drug decitabine (DEC), although the mechanism remains unclear. While DEC is approved for hematological tumors, its repurposing in solid tumors poses challenges due to high-dose hematological side effects. Identifying optimal pharmacological approaches and response biomarkers is crucial for the successful clinical implementation of DEC in PDAC and other solid tumors. Our investigation revealed that low-dose DEC combined with the PARP inhibitor olaparib (OLA) enhances antitumor activity in dKRAS-PDAC. Mechanistically, DEC induces DNA damage and activates an ATR/ATM-mediated DNA damage response (DDR), with PARP1-mediated DNA repair playing a crucial role. Inhibiting PARP activity with OLA enhances antitumor activity, even in BRCA1/2wild-type and homologous recombination (HR)-proficient tumors, but it is ineffective in KRAS-independent tumors. Thus, transcriptomic-based KRAS dependency scores effectively predict the efficacy of combined therapy. Additionally, in dKRAS-PDAC tumors carrying a BRCA2 mutation, low-dose DEC enhances OLAs antitumor activity, completely inhibiting metastasis growth compared to single-drug treatments. Our findings support further clinical evaluation of DEC+OLA combination therapy in PDAC, particularly in dKRAS-positive tumors, irrespective of BRCA1/2 status. This approach extends the clinical benefit of OLA beyond BRCA status, addressing a limitation in targeted PARP inhibitor therapies. Furthermore, we highlight DDR as a key mechanism of action for DEC, beyond its role in gene expression regulation, underscoring the mode of action of this widely used anticancer drug.

cancer biology↗