Zhuo Wang

Deciphering ovarian cancer heterogeneity through spatial transcriptomics, single-cell profiling, and copy number variations

High-grade serous ovarian carcinoma (HGSOC) poses a formidable clinical challenge due to multidrug resistance (MDR) caused by tumor heterogeneity. To elucidate the intricate mechanisms underlying HGSOC heterogeneity, we conducted a comprehensive analysis of five single-cell transcriptomes and eight spatial transcriptomes derived from eight HGSOC patients. This study provides a comprehensive view of tumor heterogeneity across the spectrum of gene expression, copy number variation (CNV), and single-cell profiles. Our CNV analysis revealed intratumor heterogeneity by identifying distinct tumor clones, illuminating their evolutionary trajectories and spatial relationships. We further explored the homogeneity and heterogeneity of CNV across tumors to pinpoint the origin of heterogeneity. At the cellular level, single-cell RNA sequencing (scRNA seq) analysis identified three meta-programs that delineate the functional profile of tumor cells. The communication networks between tumor cell clusters exhibited unique patterns associated with the meta-programs governing these clusters. Notably, the ligand-receptor pair MDK - NCL emerged as a highly enriched interaction in tumor cell communication. To probe the functional significance of this interaction, we induced NCL overexpression in the SOVK3 cell line and observed enhanced tumor cell proliferation. These findings indicate that the MDK - NCL interaction plays a crucial role in promoting HGSOC tumor growth and may represent a promising therapeutic target. In conclusion, this study comprehensively unravels the multifaceted nature of HGSOC heterogeneity, providing potential therapeutic strategies for this challenging malignancy.

FOXA1 Leads to Aberrant Expression of SIX4 Affecting Cervical Cancer Cell Growth and Chemoresistance

Cervical cancer (CC) is among the most prevalent cancers among female populations with high recurrence rates all over the world. Cisplatin (DDP) is the first-line treatment for multiple cancers, including CC. The main problem associated with its clinical application is drug resistance. This study is aimed at investigating the function and downstream regulation mechanism of forkhead-box A1 (FOXA1) in CC, which was verified as an oncogene in several cancers. Using GEO database and bioinformatics analysis, we identified FOXA1 as a possible oncogene in CC. Silencing of FOXA1 inhibited CC cell growth, invasion, and chemoresistance. Afterwards, the downstream gene of FOXA1 was predicted using a bioinformatics website and validated using ChIP and dual-luciferase assays. SIX4, a possible target of FOXA1, promoted CC cell malignant aggressiveness and chemoresistance. In addition, overexpression of SIX4 promoted phosphorylation of PI3K and AKT proteins and activated the PI3K/AKT signaling pathway. Further overexpression of SIX4 reversed the repressive effects of FOXA1 knockdown on CC cell growth, invasion, and chemoresistance in DDP-resistant cells. FOXA1-induced SIX4 facilitates CC progression and chemoresistance, highlighting a strong potential for FOXA1 to serve as a promising therapeutic target in CC.

Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation

Abstract An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing cancer cells to levels comparable with niraparib as a single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme catalyzing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of the cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism. Significance: The presented data indicate, to our knowledge, for the first time, the potential benefit of concomitant modulation of cholesterol biosynthesis pathway and PARP inhibition and highlight the need for further investigation to assess its translational relevance.