FGFR3-driven gene regulatory network analysis reveals a protumoral role for p63 in luminal bladder tumors

FGFR2 fusion-driven cholangiocarcinoma is characterized by a distinct neutrophil-enriched tumor microenvironment in a syngeneic murine model.

The syngeneic murine Ff-iCCA model is introduced, providing a platform for functional investigation of cancer cell-TME crosstalk in this molecular subtype, and overcoming the key limitation of prior models relying on human transgenes in immunodeficient hosts.

Mut-p53 acts as a synthetic lethal partner with E2F3 inhibition in gastric cancer under FGFR1 inhibitor.

BACKGROUND Gastric cancer frequently harbors TP53 mutations, posing a challenge for therapies directly targeting mutant p53. Fibroblast growth factor receptor 1 (FGFR1) is a potential therapeutic target, but its interaction with mutant p53 in gastric cancer remains poorly understood. METHODS We evaluated our newly designed FGFR1 inhibitor, S29, across multiple gastric cancer cell lines. Synthetic lethal partners of mutant p53 were identified using the Synthetic Lethality Online Analysis Database and validated through molecular assays, including overexpression and knockdown of p53 and E2F3. Clinical tissue samples were analyzed to confirm the pathological relevance of the FGFR1-E2F3-p53 axis. RESULTS S29 effectively suppressed gastric cancer cell growth while concurrently increasing mutant p53 expression and downregulating E2F3. We identified E2F3 as a synthetic lethal partner of mutant p53. While p53 knockdown abolished S29's inhibitory effects, the combination of mutant p53 accumulation and FGFR1-mediated E2F3 inhibition significantly triggered G2/M cell cycle arrest and programmed cell death. These findings were consistent with expression patterns observed in clinical samples. CONCLUSIONS Our study demonstrates that FGFR1 inhibition induces synthetic lethality in mutant p53 gastric cancer by targeting the E2F3 axis. These results suggest that S29 provides a strategic therapeutic approach for patients with TP53 mutations.

Genetic Ablation and Multi‐Omics Profiling Reveal CEP55 as a Key Driver of Tumorigenesis in Diverse Cancer Models

ABSTRACT CEP55, a centrosomal protein frequently overexpressed in multiple cancers, is implicated in regulation of genomic instability and PI3K/AKT pathway activation, yet its role in tumor progression and the tumor microenvironment remains incompletely defined. Here, we developed an inducible Cep55 knockout (KO) mouse model and complementary primary, immortalized, and transformed mouse embryonic fibroblast (MEF) systems and employ integrative multi‐omics analyses to define CEP55‐driven mechanisms and validated findings in human cancer datasets. Cep55 deletion is well tolerated in adult tissues but significantly delays tumor onset and progression in E1A/Ras‐driven models and prolongs survival in PTEN‐deficient cancer models. Mechanistically, spatial transcriptomic and proteomic analyses revealed that CEP55 regulates extracellular matrix (ECM) remodeling, integrin signaling, and cell adhesion pathways, AKT/ERK signaling and cellular stress responses. Importantly, loss of Cep55 also reprograms the tumor immune microenvironment, reducing tumor‐supportive macrophage polarization and enhancing antigen‐specific CD8+ T‐cell responses in vitro. Collectively, these findings demonstrate that CEP55 is dispensable for adult tissue homeostasis but plays a critical role in tumor progression by coordinating oncogenic signaling, extracellular matrix dynamics, and tumor–immune interactions and highlight it as a potential therapeutic target in aggressive and immune‐resistant cancers.

Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling

Results provide experimental support for targeting the PI3K/AKT/mTOR axis as a potential therapeutic strategy in cervical cancer through functional and mechanistic link between recurrent PIK3CA-E545K-MUT and aggressive tumor behavior in cervical cancer via AKT/mTOR pathway activation.

Comprehensive Analyses of SOX7 Provide Novel Insights on Its Tumor Suppressor Role and Its Target Genes with Therapeutic Implications in Multiple Myeloma

Multiple myeloma (MM) is an incurable hematological malignancy. SOX7, located within the recurrently deleted 8p23.1 region in MM, is suggested to act as a tumor suppressor. We characterized SOX7 through genetic, epigenetic, and functional analyses in MM cell lines. SOX7 was frequently silenced due to deletion and/or promoter hypermethylation. Ectopic SOX7 expression in KMS-18 and MM.1S cell lines caused a progressive decline in SOX7-transduced cells and induced G1 cell cycle arrest and/or apoptosis. Although SOX7 re-expression did not enhance bortezomib efficacy, treatment with the pan-histone deacetylase inhibitor panobinostat induced G1 arrest, promoted apoptosis, and increased SOX7 expression in MM.1S cells. Whole-transcriptome sequencing identified G1/S progression-related Wnt/β-catenin pathway genes as major SOX7-regulated targets, while ChIP-Seq analysis revealed widespread genomic SOX7 occupancy in MM.1S. Flow cytometric analysis of permeabilized bone marrow tumor cells from newly diagnosed and relapsed MM patients demonstrated generally low SOX7 protein expression. Collectively, these results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression. The anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction.

Single-cell transcriptomics and functional analyses identified SPIN.DOC as a regulator for Wnt signaling and cancer stemness in colorectal cancer