GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma

Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research.In this study,the link between GDF15 and chemotherapy resistance in ESCC was further explored.The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies.ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response.GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2.Through an in vivo study,we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin.Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A.AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A,indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin.The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy,resulting in beneficial therapeutic outcomes.

Minimal residual disease in solid tumors:an overview

Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD detection to provide more accurate management for cancer patients.As new techniques and algorithms have enhanced the performance of MRD detection,the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients.In fact,MRD detection has been shown to achieve better performance than imaging methods.On this basis,rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances.This review summarizes the development of MRD biomarkers,techniques,and strategies for the detection of cancer,and emphasizes the application of MRD detection in solid tumors,particularly for the guidance of clinical treatment.

AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma

Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined.Here,we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1(AFB1)targets.Among the most significant hits was the aryl hydrocarbon receptor(AHR),a ligand-binding transcription factor regulating cell metabolism,differentiation,and immunity.

A CRISPR knockout negative screen reveals synergy between CDKs inhibitor and metformin in the treatment of human cancer in vitro and in vivo

Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent.However,the lack of a clear understanding of the indications of metformin limits its efficacy.Here,we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin.Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment(T18)compared to those of the untreated cells at day 0(T0)yielded candidate genes.Knockdown of a group of cyclin-dependent kinases(CDKs),including CDK1,CDK4,and CDK6,confirmed the results of the screen.Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo.Although cell cycle parameters were not further altered under the combination treatment,investigation of the metabolome revealed significant changes in cell metabolism,especially with regard to fatty acid oxidation,the tricarboxylic acid cycle and aspartate metabolism.Such changes appeared to be mediated through inhibition of the mTOR pathway.Collectively,our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.

Correction: AHR mediates the Aflatoxin B1 toxicity associated with hepatocellular carcinoma

Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistake occurred during the production process in Fig.7 that needs to be corrected.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.

Molecular alterations and therapeutic targets in pancreatic neuroendocrine tumors

Human pancreatic neuroendocrine tumors(PanNETs)are a rare,deadly tumor type that is sporadic or arises in the background of a hereditary syndrome.A critical genetic event in sporadic tumors is inactivation of the gene menin 1(MEN1)on chromosome 11,and indeed,PanNETs occur in patients with the hereditary syndrome multiple endocrine neoplasia type 1(MEN1)due to germline mutations in the gene.Here,we review the recent progress in the field of molecular genetics and therapeutic targets of PanNETs.The key genomic alterations,including MEN1,ATRX/DAXX,mammalian target of rapamycin(mTOR),DNA damage and repair associated genes,vascular endothelial growth factor receptor(VEGFR)and SSTRs,and epigenetic aberrations in PanNETs are discussed.In addition,the commonly used preclinical models for PanNETs are enumerated.