Yutong Shen

A drug-induced resistant cancer cell is different from its parent cell in transcriptional response to drug treatment. The distinct transcriptional response pattern of a drug-induced resistant cancer cell to drug treatment might be introduced by acquired DNA methylation aberration in the cell exposing to sustained drug stimulation. In this study, we performed both transcriptional and DNA methylation profiles of the HCT-8 wild-type cells (HCT-8/WT) for human colorectal cancer (CRC) and the 5-fluorouracil (5-FU)-induced resistant cells (HCT-8/5-FU) after treatment with 5-FU for 0, 24 and 48 h. Integrated analysis of transcriptional and DNA methylation profiles showed that genes with promoter hypermethylation and concordant expression silencing in the HCT-8/5-FU cells are mainly involved in pathways of pyrimidine metabolism and drug metabolism-cytochrome P450. Transcriptional analysis confirmed that genes with transcriptional differences between a drug-induced resistant cell and its parent cell after drug treatment for a certain time, rather than their primary transcriptional differences, are more likely to be involved in drug resistance. Specifically, transcriptional differences between the drug-induced resistant cells and parental cells after drug treatment for 24 h were significantly consistent with the differentially expressed genes (termed as CRG5-FU) between the tissues of nonresponders and responders of CRCs to 5-FU-based therapy and the consistence increased after drug treatment for 48 h (binomial test, P-value=1.88E−06). This study reveals a major epigenetic mechanism inducing the HCT-8/WT cells to acquire resistance to 5-FU and suggests an appropriate time interval (24–48 h) of 5-FU exposure for identifying clinically relevant drug resistance signatures from drug-induced resistant cell models.

Until recently, few prognostic signatures for colorectal cancer (CRC) patients receiving 5-fluorouracil (5-FU)-based chemotherapy could be used in clinical practice. Here, using transcriptional profiles for a panel of cancer cell lines and three cohorts of CRC patients, we developed a prognostic signature based on within-sample relative expression orderings (REOs) of six gene pairs for stage II-III CRC patients receiving 5-FU-based chemotherapy. This REO-based signature had the unique advantage of being insensitive to experimental batch effects and free of the impractical data normalization requirement. After stratifying 184 CRC samples with multi-omics data from The Cancer Genome Atlas into two prognostic groups using the REO-based signature, we further revealed that patients with high recurrence risk were characterized by frequent gene copy number aberrations reducing 5-FU efficacy and DNA methylation aberrations inducing distinct transcriptional alternations to confer 5-FU resistance. In contrast, patients with low recurrence risk exhibited deficient mismatch repair and carried frequent gene mutations suppressing cell adhesion. These results reveal the multi-omics landscapes determining prognoses of stage II-III CRC patients receiving 5-FU-based chemotherapy.

BACKGROUND: Forkhead box (FOX) proteins belong to one of the largest transcription factor families and play crucial roles in the initiation and progression of cancer. Prior research has linked several FOX genes, such as FOXA1 and FOXM1, to the crucial process of carcinogenesis. However, the overall picture of FOX gene family across human cancers is far from clear. METHODS: To investigate the broad molecular signatures of the FOX gene family, we conducted study on multi-omics data (including genomics, epigenomics and transcriptomics) from over 11,000 patients with 33 different types of human cancers. RESULTS: Pan-cancer analysis reveals that FOX gene mutations were found in 17.4% of tumor patients with a substantial cancer type-dependent pattern. Additionally, high expression heterogeneity of FOX genes across cancer types was discovered, which can be partially attributed to the genomic or epigenomic alteration. Co-expression network analysis reveals that FOX genes may exert functions by regulating the expression of both their own and target genes. For a clinical standpoint, we provided 103 FOX gene-drug target-drug predictions and found FOX gene expression have potential survival predictive value. All of the results have been included in the FOX2Cancer database, which is freely accessible at http://hainmu-biobigdata.com/FOX2Cancer. CONCLUSION: Our findings may provide a better understanding of roles FOX genes played in the development of tumors, and help to offer new avenues for uncovering tumorigenesis and unprecedented therapeutic targets.

Lymph node metastasis contributed to the leading cause and treatment failure in nasopharyngeal carcinoma (NPC). The microenvironment and the cellular communications of lymph node metastasized tumours determine the tumour progression and therapeutic effect, but the ecosystems about the lymph node metastasis (LNM) for NPC patients remain poorly characterized. Here, we integrated the transcriptomes of 47,618 single cells from eight samples related to NPC LNM. The dynamic immune ecosystems and immunosuppressive microenvironment including T cells, myeloid cells and B cells were observed in the lymph node metastatic samples compared with primary tumours. Additionally, the heterogeneity of epithelial cells was also revealed, and several clusters with expression programs that were associated with the progression-free survival of NPC patients were identified. Additionally, our data revealed the complex intercellular communications from primary to lymph node metastasis. The rewiring of CCL signalling which plays an important role in tumour metastasis was further identified. Altogether, we systematically characterized the ecosystem of NPC primary and lymph node metastasized tumours, which may shed light on the development of a therapeutic strategy to improve clinical outcomes of NPC patients with lymph node metastasis.