Kai Fu

Colorectal cancer is frequently driven by hyperactivation of Wnt/β-catenin signaling, which also contributes to reduced responsiveness to chemotherapy. However, how aberrant Wnt/β-catenin signaling enables colorectal cancer cells to tolerate chemotherapy-induced DNA damage remains elusive. Identifying actionable downstream effectors of this pathway may provide a more selective strategy to improve chemotherapy response while avoiding the toxicity associated with global Wnt inhibition. Here we show that TELO2-interacting protein 1 ( TTI1 ) is a direct transcriptional target of β-catenin/TCF in colorectal cancer. TTI1 expression correlates with β-catenin abundance and is elevated in tumors from patients with poor response to neoadjuvant chemotherapy. Mechanistically, TTI1 maintains the integrity of the TELO2-TTI1-TTI2 complex and stabilizes the DNA damage response kinases ATM and ATR. Genetic depletion of TTI1 destabilizes ATM and ATR, attenuates DNA damage signaling, impairs double-strand break repair, and sensitizes colorectal cancer cells to 5-fluorouracil and oxaliplatin. Conversely, restoration of TTI1 or ATM/ATR re-establishes DNA damage responses and chemo-insensitivity. Pharmacological suppression of the TTT complex by piperlongumine mimics TTI1 loss and enhances the anti-tumor activity of chemotherapy in cell lines, xenografts, Apc -mutant patient-derived organoids and Apc ^min/+ colonic adenomas. These findings define a β-catenin-TTI1-ATM/ATR axis that links Wnt/β-catenin activation to DNA damage tolerance and chemotherapy response in colorectal cancer. Targeting TTI1 is therefore a promising approach to improve chemotherapy efficacy in Wnt/β-catenin-activated colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. The classic development of CRC is a process from normal colonic mucosa to polyp to eventually adenocarcinoma. However, the critical genes regulating this process and the underlying molecular mechanisms remain elusive. Here, we identified ZNF473 as an upregulated and key functional gene in CRC progression. Specifically, comprehensive bioinformatics analyses were performed to explore the expression of ZNF473 in CRC samples and to investigate its correlation with clinicopathological characteristics, prognosis, and potential biological functions. In vitro experiments were performed to elucidate the potential role and molecular mechanisms of ZNF473 in CRC progression. Results demonstrate that ZNF473 is highly expressed in CRC and correlates with poor prognosis. Functionally, ZNF473 knockdown significantly inhibits cell viability and proliferation. Furthermore, gene function enrichment analyses reveal an association between ZNF473 and pathways related to drug metabolism (Cytochrome P450) and chemotherapy resistance. Mechanistically, ZNF473 physically interact with p53 to promote its protein degradation, consequently upregulates the Survivin expression. In summary, this study reveals the role and molecular function of ZNF473 in CRC progression, uncovering a potential novel ZNF473/p53/Survivin axis and providing a hint for targeting ZNF473 to suppress tumor growth and potential chemoresistance.

Aberrant activation of Wnt/β-catenin signaling is proposed as a major molecular mechanism underlying the occurrence and progression of colorectal cancer (CRC). However, the precise mechanisms controlling the accumulation of β-catenin protein in CRC cells remain incompletely understood. Here, we show that TRIM24 is elevated in CRC tissues and partially distributed in the cytoplasm. TRIM24 is phosphorylated at serine 1042 by Aurora kinase B (AURKB), which promotes its cytoplasmic distribution. Subsequently, TRIM24 activates Wnt/β-catenin signaling by facilitating AKT activation through interaction with and ubiquitination of its negative regulator von Hippel-Lindau (VHL), resulting in β-catenin accumulation and enhanced proliferation of CRC cells. Moreover, chemical inhibition of AURKB suppresses tumor growth in subcutaneous mouse model and exhibits particular effectiveness against tumors derived from CRC cells characterized by prominent cytoplasmic TRIM24 distribution. Together, these findings reveal a critical role of TRIM24 in CRC cell proliferation, particularly through activating Wnt/β-catenin signaling.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The hypoxic microenvironment in HCC enhances glycolysis and co-directed lactate accumulation, which leads to increased lactylation. However, the exact biological pattern remains to be elucidated. Therefore, we sought to identify hypoxia-glycolysis-lactylation (HGL) prognosis-related signatures and validate this in vitro. Methods: Transcriptomic data of patients with HCC were collected from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Differentially expressed HGL genes between HCC and normal tissues were obtained by DEseq2. The consensus clustering algorithm was employed to stratify patients into two distinct clusters. Subsequently, the single sample Gene Set Enrichment Analysis (ssGSEA), Tumor Immune Estimation Resource (TIMER) and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to assess immune infiltration and immune evasion. Least Absolute Shrinkage and Selection Operator (LASSO) and COX regression analysis were used to identify an HGL prognosis-related signature. Based on spatial transcriptome and histological data, we analyzed the expression of these genes in HCC and explored the function of Homer Scaffold Protein 1 (HOMER1) in HCC cells. Results: We identified 72 differentially expressed HGL genes and two HGL clusters. Cluster2, with better survival (p < 0.001), was significantly enriched in metabolic-related pathways. The HGL prognosis-related signature exhibited great predictive efficacy for patients in TCGA, ICGC, and GSE148355 databases (3-year area under the curve (AUC) = 0.822, 0.738, and 0.707, respectively). The elevated expression of HOMER1 in HCC was revealed by the combination of spatial transcriptome and histological data. Knocking down HOMER1 significantly inhibited the malignant progression of HCC cells. Conclusions: We identified a signature with great predictive efficacy and discovered a gene, HOMER1, that influences the malignant progression of HCC with the potential to become a novel therapeutic target.

Background: Intratumoral tertiary lymphoid structures (iTLS) in hepatocellular carcinoma (HCC) are associated with improved survival and may influence treatment decisions. However, their non-invasive detection remains challenging in HCC. We aim to develop a non-invasive model using baseline contrast-enhanced MRI to predict the iTLS status. Methods: A total of 660 patients with HCC who underwent surgery were retrospectively recruited from four centers between October 2015 and January 2023 and divided into training, internal test, and external validation sets. After features dimensionality and selection, corresponding features were used to construct transfer learning radiomic (TLR) models for diagnosing iTLS, and model interpretability was explored with pathway analysis in The Cancer Genome Atlas-Liver HCC. The performances of models were assessed using the area under the receiver operating characteristic curve (AUC). The log-rank test was used to evaluate the prognostic value of the TLR model. The combination therapy set of 101 patients with advanced HCC treated with first-line anti-programmed death 1 or ligand 1 plus antiangiogenic treatment between January 2021 and January 2024 was used to investigate the value of the TLR model for evaluating the treatment response. Results: The presence of iTLS was identified in 46.0% (n=308) patients. The TLR model demonstrated excellent performance in predicting the presence of iTLS in training (AUC=0.91, 95% CI: 0.87, 0.94), internal test (AUC=0.85, 95% CI: 0.77, 0.93) and external validation set (AUC=0.85, 95% CI: 0.81, 0.90). The TLR model-predicted iTLS group has favorable overall survival (HR=0.66; 95% CI: 0.48, 0.90; p=0.007) and relapse-free survival (HR=0.64; 95% CI: 0.48, 0.85; p=0.001) in the external validation set. The model-predicted iTLS status was associated with inflammatory response and specific tumor-associated signaling activation (all p<0.001). The proportion of treatment responders was significantly higher in the model-predicted group with iTLS than in the group without iTLS (36% vs 13.73%, p=0.009). Conclusion: The TLR model has indicated accurate prediction of iTLS status, which may assist in the risk stratification for patients with HCC in clinical practice.

Background Tertiary lymphoid structures (TLS) within the tumor microenvironment have been associated with cancer prognosis and therapeutic response. However, the immunological pattern of a high peritumoral TLS (pTLS) density and its clinical potential in hepatocellular carcinoma (HCC) remain poor. This study aimed to elucidate biological differences related to pTLS density and develop a radiomic classifier for predicting pTLS density in HCC, offering new insights for clinical diagnosis and treatment. Methods Spatial transcriptomics (n=4) and RNA sequencing data (n=952) were used to identify critical regulators of pTLS density and evaluate their prognostic significance in HCC. Baseline MRI images from 660 patients with HCC who had undergone surgery treatment between October 2015 and January 2023 were retrospectively recruited for model development and validation. This included training (n=307) and temporal validation (n=76) cohorts from Xiangya Hospital, and external validation cohorts from three independent hospitals (n=277). Radiomic features were extracted from intratumoral and peritumoral regions of interest and analyzed using machine learning algorithms to develop a predictive classifier. The classifier’s performance was evaluated using the area under the curve (AUC), with prognostic and predictive value assessed across four independent cohorts and in a dual-center outcome cohort of 41 patients who received immunotherapy. Results Patients with HCC and a high pTLS density experienced prolonged median overall survival (pConclusion We identified key regulators of pTLS density in patients with HCC and proposed a non-invasive radiomic classifier capable of assisting in stratification for prognosis and treatment.