Organoid models have the potential to recapitulate the biological and pharmacotypic features of parental tumors. Nevertheless, integrative pharmaco-proteogenomics analysis for drug response features and biomarker investigation for precision therapy of patients with liver cancer are still lacking. We established a patient-derived liver cancer organoid biobank (LICOB) that comprehensively represents the histological and molecular characteristics of various liver cancer types as determined by multiomics profiling, including genomic, epigenomic, transcriptomic, and proteomic analysis. Proteogenomic profiling of LICOB identified proliferative and metabolic organoid subtypes linked to patient prognosis. High-throughput drug screening revealed distinct response patterns of each subtype that were associated with specific multiomics signatures. Through integrative analyses of LICOB pharmaco-proteogenomics data, we identified the molecular features associated with drug responses and predicted potential drug combinations for personalized patient treatment. The synergistic inhibition effect of mTOR inhibitor temsirolimus and the multitargeted tyrosine kinase inhibitor lenvatinib was validated in organoids and patient-derived xenografts models. We also provide a user-friendly web portal to help serve the biomedical research community. Our study is a rich resource for investigation of liver cancer biology and pharmacological dependencies and may help enable functional precision medicine.

KRAS mutations are causally linked to protumor inflammation and are identified as driving factors in tumorigenesis. Here, using multiomics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS-mutant iCCA. In KRAS-mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant antitumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti–PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS-mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in patients with KRAS-mutant iCCA were significantly associated with superior response to anti–PD-1 immunotherapy. Significance: This work describes a novel inflammatory checkpoint mediated by IL1RN alternative splicing variants that may serve as a promising basis to develop therapeutic options for KRAS-mutant iCCA and other cancers. This article is featured in Selected Articles from This Issue, p. 2109

Estrogen impacts neural development; meanwhile, it has a protective effect on the brain. Bisphenols, primarily bisphenol A (BPA), can exert estrogen-like or estrogen-interfering effects by binding with estrogen receptors. Extensive studies have suggested that neurobehavioral problems, such as anxiety and depression, can be caused by exposure to BPA during neural development. Increasing attention has been paid to the effects on learning and memory of BPA exposure at different developmental stages and in adulthood. Further research is required to elucidate whether BPA increases the risk of neurodegenerative diseases and the underlying mechanisms, as well as to assess whether BPA analogs, such as bisphenol S and bisphenol F, influence the nervous system.

Numerous studies reported that dyslipidemia was associated with cancer risk. However, few studies investigated the associations between dyslipidemia and non-small cell lung cancer (NSCLC). Four hundred twenty-four histologically confirmed NSCLC cases and 414 controls, matched for age and sex, were enrolled to examine the relationship between dyslipidemia and NSCLC. Demographic and clinical data were obtained from patients’ medical records and telephone interviews. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Abnormal triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels showed statistically significant coexistence with NSCLC compared with controls. Higher levels of TG were associated with a higher risk of NSCLC (OR = 1.541, 95% CI, (1.072–2.215)). The odds ratios (ORs) for NSCLC for normal and high levels of HDL-C versus those with a low level of HDL-C were 0.337(95% CI, (0.242–0.468)) and 0.288(95% CI, (0.185–0.448)), respectively. After adjustment for age, sex, smoking status, hypertension, body mass index, diabetes and lipid profiles, the adjusted OR for normal and high levels of HDL-C were 0.320(95% CI, (0.218–0.470)) and 0.233(95% CI, (0.134–0.407)), respectively. However, after adjustment, high levels of TG increased the risk of NSCLC but not significantly (OR = 1.052, 95% CI (0.671–1.649)). This study provided evidence that dyslipidemia increased the risk of NSCLC in Chinese population.

Objective: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high mortality-to-incidence ratios. Apolipoprotein M (ApoM), a member of the apolipoprotein family, is mainly synthesized in the liver, whereas its role in HCC has not been elucidated. Here, we examined the effect of ApoM on the biological behavior of HCC cells and the possible mechanisms. Methods: We used CRISPR/Cas9 technology to knock out ApoM in SMMC7721 cells. Differentially expressed genes before and after ApoM knockout (KO) were analyzed by GeneChip microarrays and confirmed by qRT-PCR. Cell assays of proliferation, apoptosis, migration and invasion were performed in SMMC7721 cells, and the expression of epithelial–mesenchymal transition (EMT) markers was performed by western blot. And we performed functional recovery experiments by overexpressing vitamin D receptor (VDR) in SMMC7721. Results: The ApoM-KO SMMC7721 cell line was successfully constructed using the CRISPR/Cas9 technology. Our results showed that silencing ApoM suppressed apoptosis and promoted proliferation, migration, invasion and EMT of SMMC7721 cells. The microarray data revealed that a total of 1,868 differentially expressed genes were identified, including VDR. The qRT-PCR and western blot verification results demonstrated that knocking out ApoM could significantly reduce the expression of VDR. The functional recovery experiments indicated that VDR overexpression could offset the inhibition of cell apoptosis and the promotion of cell proliferation, migration, invasion and EMT caused by knocking out ApoM in SMMC7721 cells. Conclusion: ApoM could function as a tumor suppressor to inhibit the growth and metastasis of SMMC7721 cells via VDR signaling in HCC.

Numerous studies have demonstrated that serum high-density lipoprotein cholesterol (HDL-C) levels correlate strongly with cancer patient survival. However, other studies have had the opposite results. We therefore conducted a systematic review and meta-analysis to assess the prognostic value of HDL-C levels in people with cancer. We searched PubMed, Embase, and the Cochrane Library (last update by December 28, 2017) for studies evaluating the effect of serum HDL-C levels on cancer patient prognosis. Data from 25 studies covering13,140 patients were included. Combined hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were assessed using fixed-effects and random-effects models. High serum HDL-C levels were associated with better OS (pooled HR = 0.70; 95% confidence interval (CI) (0.60–0.82). In the subgroup, the relative high level of HDL-C yielded a favorable outcome in most of tumor types. However, in the nasopharyngeal carcinoma subgroup, the correlation was not significant (combined HR = 1.31; 95% CI (0.91–1.90)). High serum HDL-C levels were associated with better DFS (pooled HR = 0.64; 95% confidence interval (CI) (0.50–0.81)). This meta-analysis demonstrates that high serum HDL-C levels are associated with better OS in patients with solid tumors, but not nasopharyngeal carcinoma; and high serum HDL-C levels are associated with better DFS.