Ferroptosis is a cell death modality triggered by excessive lipid peroxidation. Two recent studies (Zou et al., 2020; Cui et al., 2021) not only reveal critical roles of ether-linked phospholipids as an additional source for providing polyunsaturated fatty acid-containing phospholipids in driving ferroptosis but also suggest a context-dependent role of TMEM189-mediated vinyl-ether phospholipid (plasmalogen) synthesis in ferroptosis.

Fructose metabolism and fructose kinase KHK-C/A are key factors in the development of lipid oversynthesis-promoted metabolic disorders and cancer. Here, we summarize and discuss the current knowledge about the specific features of fructose metabolism and the distinct roles of KHK-C and KHK-A in metabolic liver diseases and their relevant metabolic disorders and cancer, and we highlight the specific protein kinase activity of KHK-A in tumor development. In addition, different approaches that have been used to inhibit KHK and the exploration of KHK inhibitors in clinical treatment are introduced.

Cancer is an evolutionary process fueled by genetic or epigenetic alterations in the genome. Understanding the evolutionary dynamics that are operative at different stages of tumor progression might inform effective strategies in early detection, diagnosis, and treatment of cancer. However, our understanding on the dynamics of tumor evolution through time is very limited since it is usually impossible to sample patient tumors repeatedly. The recent advances in in vitro 3D organoid culture technologies have opened new avenues for the development of more realistic human cancer models that mimic many in vivo biological characteristics in human tumors. Here, we review recent progresses and challenges in cancer genomic evolution studies and advantages of using tumor organoids to study cancer evolution. We propose to establish an experimental evolution model based on continuous passages of patient-derived organoids and longitudinal sampling to study clonal dynamics and evolutionary patterns over time. Development and integration of population genetic theories and computational models into time-course genomic data in tumor organoids will help to pinpoint the key cellular mechanisms underlying cancer evolutionary dynamics, thus providing novel insights on therapeutic strategies for highly dynamic and heterogeneous tumors.

The response rate of most anti-cancer drugs is limited because of the high heterogeneity of cancer and the complex mechanism of drug action. Personalized treatment that stratifies patients into subgroups using molecular biomarkers is promising to improve clinical benefit. With the accumulation of preclinical models and advances in computational approaches of drug response prediction, pharmacogenomics has made great success over the last 20 years and is increasingly used in the clinical practice of personalized cancer medicine. In this article, we first summarize FDA-approved pharmacogenomic biomarkers and large-scale pharmacogenomic studies of preclinical cancer models such as patient-derived cell lines, organoids, and xenografts. Furthermore, we comprehensively review the recent developments of computational methods in drug response prediction, covering network, machine learning, and deep learning technologies and strategies to evaluate immunotherapy response. In the end, we discuss challenges and propose possible solutions for further improvement.

The use of tree shrews as experimental animals for biomedical research is a new practice. Several recent studies suggest that tree shrews are suitable for studying cancers, including breast cancer, glioblastoma, lung cancer, and hepatocellular carcinoma. However, the telomeres and the telomerase of tree shrews have not been studied to date. Here, we characterize telomeres and telomerase in tree shrews. The telomere length of tree shrews is approximately 23 kb, which is longer than that of primates and shorter than that of mice, and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization (FISH) analyses. Tree shrew spleen, bone marrow, testis, ovary, and uterus show high telomerase activities, which are increased in breast tumor tissues by telomeric repeat amplification protocol assays. The telomere length becomes shorter, and telomerase activity decreases with age. The tree shrew TERT and TERC are more highly similar to primates than to rodents. These findings lay a solid foundation for using tree shrews to study aging and cancers.

The identification and application of the Von Hippel-Lindau (VHL) gene is a seminal breakthrough in kidney cancer research. VHL and its protein pVHL are the root cause of most kidney cancers, and the cascading pathway below them is crucial for understanding hypoxia, in addition to the aforementioned tumorigenesis routes and treatments. We reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor (HIF), their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a transcription factor, respectively, as well as their non-canonical functions revealed recently. Additionally, we discussed how their dysregulation promotes tumorigenesis: beginning with chromosome 3 p-arm (3p) loss/epigenetic methylation, followed by two-allele knockout, before the loss of complimentary tumor suppressor genes leads cells down predictable oncological paths. These different pathways can ultimately determine the grade, outcome, and severity of the deadliest genitourinary cancer. We finished by investigating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma (ccRCC) by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor (VEGF) inhibitors, mammalian target of rapamycin complex 1 (mTORC1) inhibitors, small molecule HIF inhibitors, immune checkpoint blockade therapy, and synthetic lethality.

Genetic, epigenetic, and metabolic alterations are all hallmarks of cancer. However, the epigenome and metabolome are both highly complex and dynamic biological networks in vivo. The interplay between the epigenome and metabolome contributes to a biological system that is responsive to the tumor microenvironment and possesses a wealth of unknown biomarkers and targets of cancer therapy. From this perspective, we first review the state of high-throughput biological data acquisition (i.e. multiomics data) and analysis (i.e. computational tools) and then propose a conceptual in silico metabolic and epigenetic regulatory network (MER-Net) that is based on these current high-throughput methods. The conceptual MER-Net is aimed at linking metabolomic and epigenomic networks through observation of biological processes, omics data acquisition, analysis of network information, and integration with validated database knowledge. Thus, MER-Net could be used to reveal new potential biomarkers and therapeutic targets using deep learning models to integrate and analyze large multiomics networks. We propose that MER-Net can serve as a tool to guide integrated metabolomics and epigenomics research or can be modified to answer other complex biological and clinical questions using multiomics data.

Small cell lung cancer (SCLC) is the most aggressive lung cancer with high heterogeneity. Mouse SCLC cells derived from the Rb1L/L/Trp53L/L (RP) autochthonous mouse model grew as adhesion or suspension in cell culture, and the adhesion cells are defined as non-neuroendocrine (non-NE) SCLC cells. Here, we uncover the heterogenous subpopulations within the non-NE cells and referred to them as mesenchymal-like (Mes) and epithelial-like (Epi) SCLC cells. The Mes cells have increased capability to form colonies in soft agar and harbored stronger metastatic capability in vivo when compared with the Epi cells. Gene Set Enrichment Analysis reveals that the transforming growth factor (TGF)-β signaling is enriched in the Mes cells. Importantly, inhibition of the TGF-β signaling through ectopic expression of dominant-negative Tgfbr2 (Tgfbr2-DN) or treatment with Tgfbr1 inhibitor SD-208 consistently abrogates tumor metastasis in nude mouse allograft assays. Moreover, genetic deletion of Tgfbr2 or Smad4, the key components of the TGF-β signaling pathway, dramatically attenuates SCLC metastasis in the RP autochthonous mouse model. Collectively, our results uncover the high heterogeneity in non-NE SCLC cells and highlight an important role of TGF-β signaling in promoting SCLC metastasis.

Small cell lung cancer (SCLC) is a phenotypically heterogeneous disease with an extremely poor prognosis, which is mainly attributed to the rapid development of resistance to chemotherapy. However, the relation between the growth phenotypes and chemo-resistance of SCLC remains largely unclear. Through comprehensive bioinformatic analyses, we found that the heterogeneity of SCLC phenotype was significantly associated with different sensitivity to chemotherapy. Adherent or semiadherent SCLC cells were enriched with activation of the PI3K/Akt/mTOR pathway and were highly chemoresistant. Mechanistically, activation of the PI3K/Akt/mTOR pathway promotes the phenotypic transition from suspension to adhesion growth pattern and confers SCLC cells with chemo-resistance. Such chemo-resistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors. Our findings support that the PI3K/Akt/mTOR pathway plays an important role in SCLC phenotype transition and chemo-resistance, which holds important clinical implications for improving SCLC treatment.

Epigenetic regulators have been implicated in tumorigenesis of many types of cancer; however, their roles in endothelial cell cancers such as canine hemangiosarcoma (HSA) have not been studied. In this study, we find that lysine-specific demethylase 2b (KDM2B) is highly expressed in HSA cell lines compared with normal canine endothelial cells. Silencing of KDM2B in HSA cells results in increased cell death in vitro compared with the scramble control by inducing apoptosis through the inactivation of the DNA repair pathways and accumulation of DNA damage. Similarly, doxycycline-induced KDM2B silencing in tumor xenografts results in decreased tumor sizes compared with the control. Furthermore, KDM2B is also highly expressed in clinical cases of HSA. We hypothesize that pharmacological KDM2B inhibition can also induce HSA cell death and can be used as an alternative treatment for HSA. We treat HSA cells with GSK-J4, a histone demethylase inhibitor, and find that GSK-J4 treatment also induces apoptosis and cell death. In addition, GSK-J4 treatment decreases tumor size. Therefore, we demonstrate that KDM2B acts as an oncogene in HSA by enhancing the DNA damage response. Moreover, we show that histone demethylase inhibitor GSK-J4 can be used as a therapeutic alternative to doxorubicin for HSA treatment.

The tumor suppressor p53 transactivates the expression of multiple genes to exert its multifaceted functions and ultimately maintains genome stability. Thus, cancer cells develop various mechanisms to diminish p53 expression and bypass the cell cycle checkpoint. In this study, we identified the gene encoding RNA-binding protein cytoplasmic polyadenylation element-binding protein 2 (CPEB2) as a p53 target. In turn, CPEB2 decreases p53 messenger RNA stability and translation to fine-tune p53 level. Specifically, we showed that CPEB2 binds the cytoplasmic polyadenylation elements in the p53 3'-untranslated region, and the RNA recognition motif and zinc finger (ZF) domains of CPEB2 are required for this binding. Furthermore, we found that CPEB2 was upregulated in renal cancer tissues and promotes the renal cancer cell proliferation and migration. The oncogenic effect of CPEB2 is partially dependent on negative feedback regulation of p53. Overall, we identify a novel regulatory feedback loop between p53 and CPEB2 and demonstrate that CPEB2 promotes tumor progression by inactivating p53, suggesting that CPEB2 is a potential therapeutic target in human renal cancer.

RNA binding motif proteins (RBMs) have been widely implicated in the tumorigenesis of multiple human cancers but scarcely studied in nasopharyngeal carcinoma (NPC). Here, we compare the mRNA levels of 29 RBMs between 87 NPC and 10 control samples. We find that RBM47 is frequently upregulated in NPC specimens, and its high expression is associated with the poor prognosis of patients with NPC. Biological experiments show that RBM47 plays an oncogenic role in NPC cells. Mechanically, RBM47 binds to the promoter and regulates the transcription of BCAT1, and its overexpression partially rescues the inhibitory effects of RBM47-knockdown on NPC cells. Moreover, transcriptome analysis reveals that RBM47 regulates alternative splicing of pre-mRNA, including those cancer-related, to a large extent in NPC cells. Furthermore, RBM47 binds to hnRNPM and cooperatively regulates multiple splicing events in NPC cells. In addition, we find that knockdown of hnRNPM inhibits proliferation and migration of NPC cells. Our study, taken together, shows that RBM47 promotes the progression of NPC through multiple pathways, acting as a transcriptional factor and a modulator of alternative splicing in cooperation with hnRNPM. Our study also highlights that RBM47 and hnRNPM could be prognostic factors and potential therapeutic targets for NPC.

Anlotinib, a novel multitarget tyrosine kinase inhibitor, has shown promising results in the management of various carcinomas. This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma (OSCC) and the underlying molecular mechanism. A retrospective clinical study revealed that anlotinib improved the median progression-free survival (mPFS) and median overall survival (mOS) of patients with recurrent and metastatic (R/M) OSCC, respectively. Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patient-derived xenograft models. Mechanistically, RNA-sequencing identified that oxidative stress, oxidative phosphorylation and AKT/mTOR signaling were involved in anlotinib-treated OSCC cells. Anlotinib upregulated NADPH oxidase 5 (NOX5) expression, elevated reactive oxygen species (ROS) production, impaired mitochondrial respiration, and promoted apoptosis. Moreover, anlotinb also inhibited phospho-Akt (p-AKT) expression and elevated p-eIF2α expression in OSCC cells. NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells. Collectively, we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC. The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/eIF2α pathway.