Advances in circulating tumor cells for early detection, prognosis and metastasis reduction in lung cancer.

Globally, lung cancer stands as the leading type of cancer in terms of incidence and is the major source of mortality attributed to cancer. We have outlined the molecular biomarkers for lung cancer that are available clinically. Circulating tumor cells (CTCs) spread from the original location, circulate in the bloodstream, extravasate, and metastasize, forming secondary tumors by invading and establishing a favorable environment. CTC analysis is considered a common liquid biopsy method for lung cancer. We have enumerated both in vivo and ex vivo techniques for CTC separation and enrichment, examined the advantages and limitations of these methods, and also discussed the detection of CTCs in other bodily fluids. We have evaluated the value of CTCs, as well as CTCs in conjunction with other biomarkers, for their utility in the early detection and prognostic assessment of patients with lung cancer. CTCs engage with diverse cells of the metastatic process, interfering with the interaction between CTCs and various cells in metastasis, potentially halting metastasis and enhancing patient prognosis.

Building consensus on the application of organoid-based drug sensitivity testing in cancer precision medicine and drug development.

Patient-derived organoids (PDOs) have emerged as a promising platform for clinical and translational studies. A strong correlation exists between clinical outcomes and the use of PDOs to predict the efficacy of chemotherapy and/or radiotherapy. To standardize interpretation and enhance scientific communication in the field of cancer precision medicine, we revisit the concept of PDO-based drug sensitivity testing (DST). We present an expert consensus-driven approach for medication selection aimed at predicting patient responses. To further standardize PDO-based DST, we propose guidelines for clarification and characterization. Additionally, we identify several major challenges in clinical prediction when utilizing PDOs.

In vitro vascularized liver tumor model based on a microfluidic inverse opal scaffold for immune cell recruitment investigation.

Liver cancer, characterized as a kind of malignant tumor within the digestive system, poses great health harm, and immune escape stands out as an important reason for its occurrence and development. Chemokines, pivotal in guiding immune cells' migration, is necessary to initiate and deliver an effective anti-tumor immune response. Therefore, understanding the chemotactic environment and identifying chemokines that regulate recruitment of immune cells to the tumor microenvironment (TME) are critical to improve current immunotherapy interventions. Herein, we report a well-defined inverse opal scaffold generated with a microfluidic emulsion template for the construction of a vascularized liver tumor model, offering insights into immune cells' recruitment. Due to the excellent 3D porous morphology of the inverse opal scaffold, human hepatocellular carcinoma cells can aggregate in the pores of the scaffold to form uniform multicellular tumor spheroids. More attractively, the vascularized liver tumor model can be achieved by constructing a 3D co-culture system involving endothelial cells and hepatocellular carcinoma cells. The results demonstrate that the 3D co-cultured tumor cells increase the neutrophil chemokines remarkably and recruit neutrophils to tumor tissues, then promote tumor progression. This approach opens a feasible avenue for realizing a vascularized liver tumor model with a reliable immune microenvironment close to that of a solid tumor of liver cancer.

Physical immune escape: Weakened mechanical communication leads to escape of metastatic colorectal carcinoma cells from macrophages.

The significance of biochemical cues in the tumor immune microenvironment in affecting cancer metastasis is well established, but the role of physical factors in the microenvironment remains largely unexplored. In this article, we investigated how the mechanical interaction between cancer cells and immune cells, mediated by extracellular matrix (ECM), influences immune escape of cancer cells. We focus on the mechanical regulation of macrophages' targeting ability on two distinct types of colorectal carcinoma (CRC) cells with different metastatic potentials. Our results show that macrophages can effectively target CRC cells with low metastatic potential, due to the strong contraction exhibited by the cancer cells on the ECM, and that cancer cells with high metastatic potential demonstrated weakened contractions on the ECM and can thus evade macrophage attack to achieve immune escape. Our findings regarding the intricate mechanical interactions between immune cells and cancer cells can serve as a crucial reference for further exploration of cancer immunotherapy strategies.

All-trans retinoic acid pretreatment of mesenchymal stem cells enhances the therapeutic effect on acute kidney injury.

A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.

High-resolution detection of copy number alterations in single cells with HiScanner.

Improvements in single-cell whole-genome sequencing (scWGS) assays have enabled detailed characterization of somatic copy number alterations (CNAs) at the single-cell level. Yet, current computational methods are mostly designed for detecting chromosome-scale changes in cancer samples with low sequencing coverage. Here, we introduce HiScanner (High-resolution Single-Cell Allelic copy Number callER), which combines read depth, B-allele frequency, and haplotype phasing to identify CNAs with high resolution. In simulated data, HiScanner consistently outperforms state-of-the-art methods across various CNA types and sizes. When applied to high-coverage scWGS data from human brain cells, HiScanner shows a superior ability to detect smaller CNAs, uncovering distinct CNA patterns between neurons and oligodendrocytes. For 179 cells we sequenced from longitudinal meningioma samples, integration of CNAs with point mutations revealed evolutionary trajectories of tumor cells. These findings show that HiScanner enables accurate characterization of frequency, clonality, and distribution of CNAs at the single-cell level in both non-neoplastic and neoplastic cells.

Incidence Rate of Secondary Glaucoma Following Congenital Cataract Surgery: An In-Depth Systematic Review and Meta-Analysis.

PURPOSE: To assess the incidence of secondary glaucoma in children following congenital cataract surgery. DESIGN: Systematic review and meta-analysis. METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception through March 16, 2023. Studies reporting congenital cataract surgery and glaucoma were enrolled. The quality of the selected studies was assessed using the Newcastle Ottawa Scale, and data analysis was executed utilizing R software. RESULTS: A total of 36 published studies with 3151 patients (4717 eyes) were included in the analysis. The incidence rate of glaucoma following congenital cataract surgery was 6.6% (95% CI: 3.9%, 9.9%). The incidence of secondary glaucoma in the primary intraocular lens (IOL) implantation group (3.3% [95% CI: 1.5%, 5.8%]) and the secondary IOL implantation group (3.5% [95% CI: 0%, 11.4%]) were lower compared to the aphakia group (13.5% [95% CI: 7.7%, 20.6%]). The incidence rate among children with congenital cataracts from Asia (6.9% [95% CI: 4.1%, 10.4%]) was higher than that in European children (0.9% [95% CI: 0%, 3.0%]; P < .01). A correlation was identified between the age at cataract surgery and the incidence of secondary glaucoma (P = .02). CONCLUSIONS: This meta-analysis found that the incidence of secondary glaucoma following congenital cataract surgery is approximately 6.6%. Children with IOL implantation exhibit a lower incidence of secondary glaucoma, with a lower incidence noted in European children compared to their Asian counterparts. The age at cataract surgery is an important risk factor to consider.

CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer.

Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.

Associations of environmental cadmium exposure with kidney damage: Exploring mediating DNA methylation sites in Chinese adults.

Environmental exposure is widely recognized as the primary sources of Cadmium (Cd) in the human body, and exposure to Cd is associated with kidney damage in adults. Nevertheless, the role of DNA methylation in Cd-induced kidney damage remains unclear. This study aimed to investigate the epigenome-wide association of environmental Cd-related DNA methylation changes with kidney damage. We included 300 non-smoking adults from the China in 2019. DNA methylation profiles were measured with Illumina Infinium MethylationEPIC BeadChip array. Linear mixed-effect model was employed to estimate the effects of urinary Cd with DNA methylation. Differentially methylated positions (DMPs) associated with urinary Cd were then tested for the association with kidney damage indicators. The mediation analysis was further applied to explore the potential DNA methylation based mediators. The prediction model was developed using a logistic regression model, and used 1000 bootstrap resampling for the internal validation. We identified 27 Cd-related DMPs mapped to 20 genes after the adjustment of false-discovery-rate for multiple testing among non-smoking adults. 17 DMPs were found to be associated with both urinary Cd and kidney damage, and 14 of these DMPs were newly identified within the Chinese. Mediation analysis revealed that DNA methylation of cg26907612 and cg16848624 mediated the Cd-related reduced kidney damage. In addition, ten variables were selected using the LASSO regression analysis and were utilized to develop the prediction model. It found that the nomogram model predicted the risk of kidney damage caused by environmental Cd with a corrected C-index of 0.779. Our findings revealed novel DMPs associated with both environmental Cd exposure and kidney damage among non-smoking adults, and developed an easy-to-use nomogram-illustrated model using these novel DMPs. These findings could provide a theoretical basis for formulating prevention and control strategies for kidney damage from the perspective of environmental pollution and epigenetic regulation.

Utility of contrast-enhanced MRI radiomics features combined with clinical indicators for predicting induction chemotherapy response in primary central nervous system lymphoma.

PURPOSE: To assess the utility of combining contrast-enhanced magnetic resonance imaging (CE-MRI) radiomics features with clinical variables in predicting the response to induction chemotherapy (IC) for primary central nervous system lymphoma (PCNSL). METHODS: A total of 131 patients with PCNSL (101 in the training set and 30 in the testing set) who had undergone contrast-enhanced MRI scans were retrospectively analyzed. Pyradiomics was utilized to extract radiomics features, and the clinical variables of the patients were gathered. Radiomics prediction models were developed using different combinations of feature selection methods and machine learning models, and the best combination was ultimately chosen. We screened clinical variables associated with treatment outcomes and developed clinical prediction models. The predictive performance of radiomics model, clinical model, and combined model, which integrates the best radiomics model and clinical characteristics, was independently assessed and compared using Receiver Operating Characteristic (ROC) curves. RESULTS: In total, we extracted 1598 features. The best radiomics model we selected as the best utilized T-test and Recursive Feature Elimination (RFE) for feature selection and logistic regression for model building. Serum Interleukin 2 Receptor (IL-2R) and Eastern Cooperative Oncology Group (ECOG) Score were utilized to develop a clinical predictive model for assessing the response to induction chemotherapy. The results of the testing set revealed that the combined prediction model (radiomics and IL-2R) achieved the highest area under the ROC curve at 0.868 (0.683, 0.967), followed by the radiomics model at 0.857 (0.681, 0.957), and the clinical prediction model (IL-2R and ECOG) at 0.618 (0.413, 0.797). The combined model was significantly more accurate than the clinical model, with an AUC of 0.868 compared to 0.618 (P < 0.05). While the radiomics model had slightly better predictive power than the clinical model, this difference was not statistically significant (AUC, 0.857 vs. 0.618, P > 0.05). CONCLUSIONS: Our prediction model, which combines radiomics signatures from CE-MRI with serum IL-2R, can effectively stratify patients with PCNSL before high-dose methotrexate (HD-MTX) -based chemotherapy.

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification.

Existing studies have underscored the pivotal role of N-acetyltransferase 10 (NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squamous cell carcinoma (HNSCC) remain unexplored. In this study, we identified a significant upregulation of RNA-binding protein with serine-rich domain 1 (RNPS1) in HNSCC, where RNPS1 inhibits the ubiquitination degradation of NAT10 by E3 ubiquitin ligase, zinc finger SWIM domain-containing protein 6 (ZSWIM6), through direct protein interaction, thereby promoting high NAT10 expression in HNSCC. This upregulated NAT10 stability mediates the enhancement of specific tRNA ac4C modifications, subsequently boosting the translation process of genes involved in pathways such as IL-6 signaling, IL-8 signaling, and PTEN signaling that play roles in regulating HNSCC malignant progression, ultimately influencing the survival and prognosis of HNSCC patients. Additionally, we pioneered the development of TRMC-seq, leading to the discovery of novel tRNA-ac4C modification sites, thereby providing a potent sequencing tool for tRNA-ac4C research. Our findings expand the repertoire of tRNA ac4C modifications and identify a role of tRNA ac4C in the regulation of mRNA translation in HNSCC.

Ligands and receptors in human cytomegalovirus entry: Current therapies and new directions.

The demand for human cytomegalovirus (HCMV) vaccines was first raised by a committee convened during the 1990s. A comprehensive investigation into the mechanism of viral infection supports the prioritization of developing drugs or vaccines that specifically target receptors and ligands involved in the infection process. As primary targets for neutralizing antibodies to combat HCMV, viral ligands (trimer, pentamer, and glycoprotein B) have crucial roles and exhibit substantial antiviral potential, which could be exploited for breakthroughs in antiviral research.

Knockdown of ADAMDEC1 ameliorates ox-LDL-induced endothelial cell injury and atherosclerosis progression.

This study was designed to investigate the role of a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC-1) in atherosclerosis (AS). The Gene Expression Omnibus (GEO) database was utilized to identify differentially expressed genes (DEGs) between carotid atheroma plaque and carotid tissue adjacent atheroma plaque obtained from AS patients. Gene functional enrichment analysis was conducted on DEGs using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). QRT-PCR was employed to quantify mRNAs expression. AS animal model was established using ApoE-/- mice; serum triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were detected. Aortic sinus atherosclerotic lesions were observed using H&E staining and Oil Red O staining. ADAMDEC-1 was silenced using small interfering RNAs (siRNAs) in human vascular smooth muscle cells (HVSMCs). Cell proliferation, migration, and cell cycle progression were detected by cell count kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EDU), wound scratch healing assay, transwell assay, and flow cytometry, respectively. Western blot was used to evaluate various protein expression levels. Our results showed that ADAMDEC-1 was highly expressed in the serum of AS patients, consistent with the in silico results. The elevated TG, LDL-C, and HDL-C levels along with H&E and Oil Red O staining confirmed the successful establishment of the AS mouse model. ADAMDEC-1 expression was also elevated in AS mice. ADAMDEC-1 knockdown in HVSMCs suppressed cell proliferation, inhibited the expression of proliferating cell nuclear antigen (PCNA), and reduced the levels of matrix metalloproteinases (MMP2 and MMP9) proteins. Protein-protein interaction (PPI) analysis indicated that ADAMDEC-1 was associated with CXCL9, CCR5, TNF-α, TNFR1, and NF-κB-p50. The expression levels of CXCL9, CCR5, TNF-α, TNFR1, and NF-κB-p50 increased, while ADAMDEC-1 knockdown attenuated the expression of these proteins. Our study findings substantiate that ADAMDEC-1 may represent a novel target for AS.

A CRISPR-Cas9 library screening identifies CARM1 as a critical inhibitor of ferroptosis in hepatocellular carcinoma cells.

Ferroptosis is an iron-catalyzed form of regulated cell death that results from the accumulation of lipid peroxidation products and reactive oxygen species to a lethal content. However, the transcriptional regulation of ferroptosis is not well understood. Sorafenib, a standard drug for hepatocellular carcinoma (HCC), induces ferroptosis in HCC cells. In this study, we conducted a CRISPR-Cas9 library screening targeting epigenetic factors and identified coactivator-associated arginine methyltransferase 1 (CARM1) as a critical inhibitor of ferroptosis. CARM1 depletion intensified Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione level, increased lipid peroxidation, and altered mitochondrial crista structure. Additionally, we investigated a CARM1 inhibitor (CARM1i) as a potential ferroptosis inducer. Combining the CARM1i with Sorafenib enhanced the induction of ferroptosis. Notably, both CARM1 knockdown and CARM1i showed cooperative effects with Sorafenib in inhibiting HCC growth in mice. The underlying mechanism involves CARM1-catalyzed H3R26me2a on the promoter of glutathione peroxidase 4, leading to its transcriptional activation and subsequent ferroptosis inhibition. Furthermore, Sorafenib treatment induced the transcription of CARM1 through the MDM2-p53 axis. In summary, our findings establish CARM1 as a critical ferroptosis inhibitor and highlight the potential of CARM1is as novel ferroptosis inducers, providing promising therapeutic strategies for HCC treatment.

Postoperative clinical outcomes with and without short-term intravenous tranexamic acid after posterior lumbar interbody fusion: A prospective cohort study.

The use of tranexamic acid (TXA) in posterior lumbar interbody fusion (PLIF) surgery is believed to be beneficial for reducing intraoperative blood loss, postoperative drainage volume (PDV), and length of hospital stay (LOS). However, whether continued administration of intravenous TXA within 24 hours after surgery is more beneficial to patients has not yet been studied. This study prospectively analyzed the perioperative outcomes of patients who received and did not receive intravenous TXA within 24 hours after PLIF (≥2 segments) surgery from January 2018 to December 2021. A total of 78 and 69 patients were included in the TXA (receive intravenous TXA intraoperatively and within 24 hours postoperatively) and non-TXA (only receive intravenous TXA intraoperatively) groups, respectively. No significant differences were observed in the intraoperative blood loss and operative time between the 2 groups. The postoperative drainage volume, postoperative drainage time, and length of hospital stay in the TXA group were significantly lower than those in the non-TXA group. The rates and volumes of postoperative blood and albumin transfusions were significantly lower in the TXA group than those in the non-TXA group. No significant differences were observed in the perioperative complication rates between the 2 groups. No increase in thrombosis-related complications was observed with postoperative TXA administration. Short-term TXA use after PLIF (≥2 segments) surgery is safe. In addition to intraoperative use of TXA, additionally administration of intravenous TXA within 24 hours postoperatively can improve the perioperative clinical outcomes of patients without increasing the risk of thrombotic events.

Preparation and anti-tumor effects of mesoporous silica nanoparticles loaded with trifluoperazine.

We have developed a targeted nano-drug delivery system that effectively harnesses the anti-tumor properties of trifluoperazine (TFP), while concurrently mitigating its side effects on the central nervous system. The manufacturing process entailed the preparation of mesoporous silica nanoparticles (MSN-NH2), followed by the loading of trifluoperazine into the pores of MSN-NH2 and then surface modification with polyethylene glycol (PEG) and anisamide (AA), resulting in the formation of TFP@MSN@PEG-AA (abbreviated as TMPA) nanoparticles. In vitro and in vivo anti-tumor activity and hemolysis experiments showed that TMPA had an excellent safety profile and a good anti-tumor effect. Importantly, the drug content of the TMPA nanoparticle group was found to be significantly lower than that of the TFP group in the mouse brain tissue as determined by High Performance Liquid Chromatography (HPLC) detection. Therefore, the developed drug delivery system achieved the goal of maintaining TFP's anti-tumor action while avoiding its negative effects on the central nervous system.

Pyruvate kinase M in germ cells is essential for sperm motility and male fertility but not spermatogenesis.

ABSTRACT: Male germ cells employ specific metabolic pathways throughout their developmental stages. In a previous study, we discovered heightened expression of pyruvate kinase M (PKM), a pivotal glycolytic enzyme, in spermatogonia and spermatids. To gain deeper insights into PKM's roles in spermatogenesis, sperm function, and male fertility, we engineered a conditional-knockout mouse model (Pkm-vKO mice) to selectively disrupt the Pkm gene within germ cells. Despite maintaining regular testicular histology and sperm morphology, the male Pkm-vKO mice were infertility, characterized by significant impairments in sperm motility and adenosine triphosphate (ATP) generation. In addition, Pkm-null spermatozoa exhibited similar deficits in protein tyrosine phosphorylation linked to capacitation, as well as compromised performance in in vitro fertilization experiments. To conclude, PKM's presence is not obligatory for the entirety of spermatogenesis in male germ cells; however, it emerges as a critical factor influencing sperm motility and overall male fertility.

Identification of a Non-Invasive Urinary Exosomal Biomarker for Diabetic Nephropathy Using Data-Independent Acquisition Proteomics.

Diabetic nephropathy (DN), as the one of most common complications of diabetes, is generally diagnosed based on a longstanding duration, albuminuria, and decreased kidney function. Some patients with the comorbidities of diabetes and other primary renal diseases have similar clinical features to DN, which is defined as non-diabetic renal disease (NDRD). It is necessary to distinguish between DN and NDRD, considering they differ in their pathological characteristics, treatment regimes, and prognosis. Renal biopsy provides a gold standard; however, it is difficult for this to be conducted in all patients. Therefore, it is necessary to discover non-invasive biomarkers that can distinguish between DN and NDRD. In this research, the urinary exosomes were isolated from the midstream morning urine based on ultracentrifugation combined with 0.22 µm membrane filtration. Data-independent acquisition-based quantitative proteomics were used to define the proteome profile of urinary exosomes from DN (n = 12) and NDRD (n = 15) patients diagnosed with renal biopsy and Type 2 diabetes mellitus (T2DM) patients without renal damage (n = 9), as well as healthy people (n = 12). In each sample, 3372 ± 722.1 proteins were identified on average. We isolated 371 urinary exosome proteins that were significantly and differentially expressed between DN and NDRD patients, and bioinformatic analysis revealed them to be mainly enriched in the immune and metabolic pathways. The use of least absolute shrinkage and selection operator (LASSO) logistic regression further identified phytanoyl-CoA dioxygenase domain containing 1 (PHYHD1) as the differential diagnostic biomarker, the efficacy of which was verified with another cohort including eight DN patients, five NDRD patients, seven T2DM patients, and nine healthy people. Additionally, a concentration above 1.203 µg/L was established for DN based on the ELISA method. Furthermore, of the 19 significantly different expressed urinary exosome proteins selected by using the protein-protein interaction network and LASSO logistic regression, 13 of them were significantly related to clinical indicators that could reflect the level of renal function and hyperglycemic management.

The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma.

PCIF1 can mediate the methylation of N6,2'-O-dimethyladenosine (m6Am) in mRNA. Yet, the detailed interplay between PCIF1 and the potential cofactors and its pathological significance remain elusive. Here, we demonstrated that PCIF1-mediated cap mRNA m6Am modification promoted head and neck squamous cell carcinoma progression both in vitro and in vivo. CTBP2 was identified as a cofactor of PCIF1 to catalyze m6Am deposition on mRNA. CLIP-Seq data demonstrated that CTBP2 bound to similar mRNAs as compared with PCIF1. We then used the m6Am-Seq method to profile the mRNA m6Am site at single-base resolution and found that mRNA of TET2, a well-known tumor suppressor, was a major target substrate of the PCIF1-CTBP2 complex. Mechanistically, knockout of CTBP2 reduced PCIF1 occupancy on TET2 mRNA, and the PCIF1-CTBP2 complex negatively regulated the translation of TET2 mRNA. Collectively, our study demonstrates the oncogenic function of the epitranscriptome regulator PCIF1-CTBP2 complex, highlighting the importance of the m6Am modification in tumor progression.

Tumour follower cells: A novel driver of leader cells in collective invasion (Review).

Collective cellular invasion in malignant tumours is typically characterized by the cooperative migration of multiple cells in close proximity to each other. Follower cells are led away from the tumour by specialized leader cells, and both cell populations play a crucial role in collective invasion. Follower cells form the main body of the migration system and depend on intercellular contact for migration, whereas leader cells indicate the direction for the entire cell population. Although collective invasion can occur in epithelial and non­epithelial malignant neoplasms, such as medulloblastoma and rhabdomyosarcoma, the present review mainly provided an extensive analysis of epithelial tumours. In the present review, the cooperative mechanisms of contact inhibition locomotion between follower and leader cells, where follower cells coordinate and direct collective movement through physical (mechanical) and chemical (signalling) interactions, is summarised. In addition, the molecular mechanisms of follower cell invasion and metastasis during remodelling and degradation of the extracellular matrix and how chemotaxis and lateral inhibition mediate follower cell behaviour were analysed. It was also demonstrated that follower cells exhibit genetic and metabolic heterogeneity during invasion, unlike leader cells.