Yunyan Gu

Pan‐cancer multi‐omics analyses reveal crosstalk between the Hippo and immune signaling pathways in the tumor microenvironment

The Hippo signaling pathway is critical for carcinogenesis. However, the roles of the Hippo signaling pathway in the tumor immune microenvironment have been rarely investigated. This study systematically analyzed the relationship between the Hippo signaling pathway and immune cell infiltration across 32 cancer types. Both bioinformatics analyses and biological experiments revealed that the downstream effector of Hippo signaling YAP1 might inhibit CD8+ T cell infiltration by upregulating the expression of the transcription factor CREB1 in uterine corpus endometrial carcinoma. In addition, esophageal carcinoma (ESCA) patients were classified into three subtypes based on the Hippo–immune gene panel. The subtypes of ESCA had distinct characteristics in immune cell infiltration, immune pathways, and prognosis. Thus, this study also reveals a new classification of the immune subtypes with prognostic characteristics in ESCA.

Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade

Mutations in BRCA1 or BRCA2 (BRCA1/2) cause homologous recombination deficiency (HRD). Ovarian cancer (OvCa) patients harbouring HRD beyond BRCA1/2 mutation result in a state referred to as "BRCAness". OvCa with BRCAness could benefit from PARP inhibitors. This study aims to identify a signature to detect the BRCAness population at the transcriptome level. We used a rank-based algorithm to develop a qualitative BRCAness signature for OvCa. Upregulation of CXCL1 with downregulation of SV2A and upregulation of LY9 with downregulation of CHRNB3 were constructed as the BRCAness signature (2 gene pairs, 2-GPS) for OvCa. OvCa samples that were classified as BRCAness by 2-GPS showed improved overall survival, progression-free survival and exhibited increased multi-omics alterations in homologous recombination genes and enhanced sensitivity to immune checkpoint blockade. BRCAness cells were sensitive to PARP inhibitors. By biological experiments, we validated SKOV3 cells and patients with HRD exhibited higher expression of CXCL1 than SV2A and higher expression of LY9 than CHRNB3 at mRNA level. Both SKOV3 and A2780 with HRD were sensitive to mitomycin C, cisplatin and olaparib. In conclusion, 2-GPS could robustly predict BRCAness OvCa at the individual level and extend the population who may benefit from PARP inhibitors.