Furin sustains tumor-promoting signals in KRAS- and BRAF-mutated colorectal cancer by engaging the TGF-β1-COX-2 axis in a reciprocal regulatory network

CAF-derived TGF-β1 activates an LBH-mediated β-catenin stabilization program to drive gastric cancer progression

Aberrant Wnt/β-catenin signaling is frequently observed in gastric cancer (GC); however, the mechanisms sustaining this pathway in the absence of canonical genetic mutations remain incompletely understood. Here we show that the transcriptional cofactor LBH drives mutation-independent Wnt activation and malignant progression in GC via a tumour microenvironment-regulated post-translational stabilization mechanism. By integrating single-cell transcriptomics with multicentre clinical cohorts, we identify LBH as a principal regulator of epithelial–mesenchymal transition and peritoneal metastasis, and its elevated expression independently predicts poor patient survival. Mechanistically, fi broblast activation protein (FAP)-positive cancer-associated fi broblasts (CAFs) secrete TGF-β1, which selectively induces LBH expression in adjacent GC cells via the SMAD2/3 signaling cascade. Crucially, LBH physically interacts with β-catenin, providing steric hindrance that prevents destruction complex-mediated phosphorylation and subsequent ubiquitin-proteasomal degradation. This FAP⁺ CAF–TGF-β1–LBH–β-catenin paracrine axis continuously sustains global Wnt transcriptional output without requiring intrinsic genetic mutations. Our findings elucidate a critical tumour–stroma crosstalk mechanism and establish the targeted disruption of the LBH–β-catenin interaction interface as a clinically relevant therapeutic strategy for advanced gastric cancer.

RASA2 Promotes Pancreatic Cancer Metastasis by Activating TGFβ-Dependent Non-canonical Hedgehog Signaling.

KRAS mutations are a major driver of pancreatic ductal adenocarcinoma (PDAC). RASA2, a RAS GTPase-activating protein, modulates KRAS protein levels in wild-type contexts, suggesting it could play a potential role in PDAC. Here, we systematically investigated the biological function and molecular mechanisms of RASA2 in PDAC. Integrative analyses of multiple datasets and clinical samples demonstrated that RASA2 was consistently upregulated in KRAS-mutant PDAC and significantly associated with poor prognosis and metastatic progression. Gain- and loss-of-function studies revealed that RASA2 markedly enhanced PDAC cell migration and invasion in both KRAS-mutant and KRAS-wild-type models, suggesting that its pro-metastatic activity is largely independent of KRAS mutational status. Transcriptomic and mechanistic analyses revealed that RASA2 activated GLI1 through a TGFβ2-dependent, non-canonical Hedgehog pathway. Mechanistically, RASA2 interacted with RTF1 to promote H2BK120 ubiquitination at the TGFB2 promoter, thereby enhancing TGFβ2 transcription and activating downstream GLI1 signaling. Pharmacological inhibition of TGFβ signaling or genetic silencing of GLI1 effectively suppressed RASA2-driven migratory, invasive, and metastatic phenotypes in vitro and in vivo. Collectively, these findings reveal a mechanism by which RASA2-dependent epigenetic and transcriptional reprogramming promotes metastatic progression and nominate the RASA2- TGFβ2-GLI1 axis as a potential therapeutic target in PDAC.

Targeting the ANKRD54/ELOVL6 axis suppresses malignancy in BRAF mutant colorectal cancer by disrupting fatty acid metabolism and promoting ferroptosis

BRAF-mutant (BRAF-MT) colorectal cancer (CRC) represents a clinically aggressive subtype characterized by distinct biological features and significantly worse prognosis compared to BRAF wild-type (BRAF-WT) CRC, with median survival reduced by approximately 40%. The therapeutic resistance of BRAF-MT CRC stems primarily from BRAF-driven dysregulation of tumor cell proliferation. However, the molecular mechanisms underlying the aggressive phenotype and potential therapeutic vulnerabilities remain incompletely understood. Bioinformatic analyses were employed to identify candidate genes. A combination of in vitro (cell proliferation, clonal formation), ex vivo (patient-derived and mouse intestinal organoids), and in vivo (xenograft models) assays were used to assess oncogenic function. Mechanistic investigations included Western blotting, qRT-PCR, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays to delineate the regulatory axis. Fatty acid metabolism and ferroptosis were evaluated by a combination of metabolomic, biochemical, and cellular assays. Bioinformatic screening identified ankyrin repeat domain 54 (ANKRD54) as selectively overexpressed in BRAF-MT CRC and significantly associated with adverse prognosis. Inhibition of ANKRD54 markedly suppressed clonogenic potential, cellular proliferation in vitro, organoid formation in both PDOs and cKI mouse-derived organoids, and tumor growth in vivo. Mechanistically, lysine acetyltransferase 2 A (KAT2A) promoted ANKRD54 transcriptional activation through H3K27 acetylation. ANKRD54 subsequently formed a functional complex with CCAAT/enhancer binding protein beta (CEBPB), cooperatively inducing ELOVL fatty acid elongase 6 (ELOVL6) expression. This KAT2A-mediated ANKRD54/CEBPB/ELOVL6 transcriptional axis reprogrammed fatty acid metabolism, selectively suppressing ferroptosis in BRAF-MT CRC. Pharmacological targeting of either ANKRD54 or ELOVL6 substantially enhanced the therapeutic efficacy of Vemurafenib-based treatment in BRAF-MT CRC models. Clinical data corroborated that elevated ANKRD54 expression promoted malignant progression and predicted poor outcomes through this ELOVL6-dependent metabolic pathway. This study elucidates a novel KAT2A-mediated ANKRD54/CEBPB/ELOVL6 axis driving aggressive tumor behavior through regulating fatty acid metabolic and ferroptosis evasion. These findings establish ANKRD54 and ELOVL6 as promising therapeutic targets for combination strategies to overcome therapeutic resistance in BRAF-MT CRC patients.

Targeting JOSD2 degrades β-catenin to suppress colorectal cancer metastasis by disrupting RAS/ERK/β-catenin axis.

FOXD3 Is Functionally Linked to NF-κB Signaling in KRAS G12C-Mutant NSCLC Cells

KRAS G12C mutation is a clinically relevant driver in non-small cell lung cancer (NSCLC), yet the signaling networks that modulate malignant behavior in this context remain incompletely defined. In this study, we examined the functional role of FOXD3 and its relationship with NF-κB signaling in KRAS G12C-mutant NSCLC models. Stable FOXD3 overexpression was established in SW1573 and LU65 cells. FOXD3 reduced cell viability, migration, and invasion while increasing caspase 3/7 activity in both cell lines. Transcriptomic profiling in LU65 cells followed by Hallmark enrichment analysis identified TNFα signaling via NF-κB as a prominently altered pathway associated with FOXD3 overexpression. Consistently, NF-κB dual-luciferase assays showed reduced basal NF-κB transcriptional activity in FOXD3-overexpressing cells. TNFα stimulation partially reversed the inhibitory effects of FOXD3 on proliferation, migration, and invasion and attenuated FOXD3-induced apoptosis. In addition, stable FOXD3 overexpression suppressed xenograft growth in vivo. Collectively, these findings support a functional association between FOXD3 overexpression and reduced NF-κB-related transcriptional activity in KRAS G12C-mutant NSCLC models, although the present data do not establish direct causal mediation by NF-κB.

WNT-driven immune evasion promotes malignant transformation of BRAF-mutant colorectal cancer.

Functional assays demonstrated that WNT activation enhances tumor progression in immunocompetent settings, indicating immune evasion as a key driver of malignant progression.