Clinical and Translational Medicine最新文献

{"title":"METTL14-mediated m6A modification of ZFP14 inhibits clear cell renal cell carcinoma progression via promoting STAT3 ubiquitination","authors":"Zhuonan Liu,&nbsp;Tianshui Sun,&nbsp;Zhe Zhang,&nbsp;Chiyuan Piao,&nbsp;Chuize Kong,&nbsp;Xiaotong Zhang","doi":"10.1002/ctm2.70232","DOIUrl":"https://doi.org/10.1002/ctm2.70232","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Therapeutic options for advanced clear cell renal cell carcinoma (ccRCC) are currently inadequate. Earlier research has shown that the enzyme methyltransferase-like 14 (METTL14) can suppress ccRCC development through the modification of N6-methyladenosine (m6A). This study further explored its complex biological functions and underlying molecular mechanisms. Here, we identified zinc finger protein 14 (ZFP14) as a novel target of METTL14-mediated m6A, and its under-expression was associated with ccRCC tumourigenesis and progression. Detailed investigations revealed that METTL14 interacted directly with the 3′ untranslated region of ZFP14 mRNA, promoting m6A modification at two specific sites. These modifications were recognised by the protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which stabilised and enhanced the expression of ZFP14 mRNA. Functionally, the METTL14/ZFP14 axis suppressed in vitro growth, migration and invasiveness and in vivo proliferation and metastasis of ccRCC cells. ZFP14 potentially regulated numbers of transcripts, among which matrix metalloproteinase 1/3 (MMP1/3) were validated to be under-expressed by ZFP14. Crucially, ZFP14 interacted with the signal transducer and activator of transcription 3 (STAT3), augmenting its K48-linked ubiquitination and destabilising it via the proteasome pathway. Moreover, ZFP14 repressed ccRCC cell in vivo growth and metastasis as well as decreasing MMP1/3 levels by under-expressing STAT3. These observations confirmed that ZFP14 served as both a novel target for METTL14-mediated m6A modification and a significant tumour suppressor in ccRCC, shedding light on the cellular and molecular operations in ccRCC and opening up possibilities for novel therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>ZFP14 under-expression is associated with ccRCC tumourigenesis and progression.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>METTL14-mediated m6A enhances ZFP14 mRNA stability and expression with IGF2BP2 as the reader in ccRCC.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>ZFP14 promotes the degradation of STAT3 by enhancing its K48-linked ubiquitination, inhibiting ccRCC progression.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EpCAM deficiency causes the premature ageing of intestinal stem cells via EGFR/SP1/mTORC1 pathway","authors":"Keying Li,&nbsp;Changlong Xu,&nbsp;Lulu Liu,&nbsp;Yunjuan Wang,&nbsp;Jun Chen,&nbsp;Chunyuan Li,&nbsp;Zitong Peng,&nbsp;Xiaoqian Li,&nbsp;Gang Chang,&nbsp;Zili Lei,&nbsp;Yanhong Yang","doi":"10.1002/ctm2.70219","DOIUrl":"https://doi.org/10.1002/ctm2.70219","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We reported a precise molecular mechanism underlying the longevity of intestinal stem cells (ISCs) maintained by EpCAM via the EGFR/SP1/mTORC1 pathway. EpCAM is highly expressed in ISCs,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and most patients of congenital tufting enteropathy (CTE), caused by EpCAM mutations,&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; die of intestinal failure.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; EpCAM deficiency induces premature ageing of ISCs via downregulating TSC1 to hyperactivate the mTORC1 pathway.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, upstream signals through which EpCAM regulates the expression of TSC1 remain unknown.&lt;/p&gt;&lt;p&gt;As previous report,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; EpCAM&lt;sup&gt;−/−&lt;/sup&gt; mice showed no significant differences in appearance compared to wild type (WT) littermates at the E18.5 stage (Figure S1A,B). However, the mutant pups started to have diarrhoea after birth and most died within 1 week. The tufting and erosion of the intestinal villi were observed in mutants at both E18.5 and P3 stages (Figures S1C,D and S2A,B). &lt;i&gt;Tert&lt;/i&gt;, encoding the protein component of telomerase, was significantly downregulated but γH2AX, the DNA damage accumulation-associated protein, was considerably increased in the E18.5 mutant small intestines (Figure S1E−G), confirming the premature ageing of these tissues.&lt;/p&gt;&lt;p&gt;SP1 is involved in various tissue and cellular senescence processes.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; At the E18.5 stage, the expression and activity of SP1 were reduced in the mutant small intestines (Figure 1A,B). The p-SP1 was predominantly present in the nucleus of epithelial cells in the inter villi region of the duodenum and decreased in the mutants at both E18.5 and P3 stages (Figures S3A and S4A−F).&lt;/p&gt;&lt;p&gt;The SP1 inhibitor Mithramycin A (MitA) reduced the expression and activity of SP1 in Caco-2 cells (Figures 1C,D and S3B,C). With the inhibition of SP1, TSC1 and TSC2 downregulated, and the activation of the mTORC1 pathway dramatically increased (Figures 1E and S3D). The TERT significantly decreased, but γH2AX increased with the MitA administration (Figure 1F−H).&lt;/p&gt;&lt;p&gt;Subsequently, Caco-2 cells were simultaneously treated with MitA and rapamycin (RAP). The p-SP1 and SP1 were significantly decreased in MitA and MitA+RAP groups (Figures 1I,K and S3E). In the MitA+RAP group, the activation of the mTORC1 pathway was markedly lower than in the MitA group (Figures 1J and S3E). The TERT was increased but γH2AX was decreased in the MitA+RAP group compared with the MitA group (Figures 1K,L and S3E).&lt;/p&gt;&lt;p&gt;The naringenin (NAR), an effective activator of SP1,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; was administrated to the pregnant females to activate SP1 in the intestines of EpCAM&lt;sup&gt;−/−&lt;/sup&gt; embryos (Figure S5A). The duodenum and jejunum showed improved intestinal villi tufting and breakage in the NAR-treated mutants (Figure S5B). The expression and activity of SP1 were significantly restored in the small intestines of the EpCAM&lt;sup&gt;−/−&lt;/sup&gt;+NAR group (Figu","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale cluster randomised trial reveals effectiveness of Helicobacter pylori eradication for gastric cancer prevention","authors":"Zong-Chao Liu,&nbsp;Wen-Qing Li","doi":"10.1002/ctm2.70229","DOIUrl":"https://doi.org/10.1002/ctm2.70229","url":null,"abstract":"&lt;p&gt;Gastric cancer (GC) remains a critical public health concern, ranking among the most prevalent cancers and leading causes of cancer-related deaths globally.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The burden is particularly pronounced in East Asia, Latin America and Eastern Europe, with nearly half of all new cases and related deaths occurring in China alone. &lt;i&gt;Helicobacter pylori&lt;/i&gt;, classified as a Group I carcinogen, plays a crucial role in gastric carcinogenesis. &lt;i&gt;H. pylori&lt;/i&gt; infection in China accounts for approximately 340 000 new cancer cases annually,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; contributing to more than 70% of all GC cases nationwide. In 2018, the infection was responsible for 78.5% of non-cardia GC and 62.1% of cardia GC.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; While randomised trials have demonstrated the efficacy of &lt;i&gt;H. pylori&lt;/i&gt; eradication for GC prevention,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; in 2014, the International Agency for Research on Cancer highlighted a lack of data to quantify the overall benefits and risks of implementing large-scale, population-based eradication programs in real world.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Recently, the Mass Intervention Trial in Shandong (MITS), China, a community-based, cluster-randomised controlled superiority intervention trial, provided new evidence on the effectiveness of population-wide &lt;i&gt;H. pylori&lt;/i&gt; intervention in preventing GC (ChiCTR-TRC-10000979, https://www.chictr.org.cn).&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Conducted across 980 villages in 10 townships in Linqu, Shandong, the trial involved 180 284 participants, divided into three groups based on baseline &lt;i&gt;H. pylori&lt;/i&gt; infection status. &lt;i&gt;H. pylori&lt;/i&gt;-positive individuals were assigned to receive either 10-day quadruple anti-&lt;i&gt;H. pylori&lt;/i&gt; treatment (20 mg omeprazole bid, 750 mg tetracycline tid, 400 mg metronidazole tid and 300 mg bismuth citrate bid, &lt;i&gt;n&lt;/i&gt; = 52 026) or symptom alleviation treatment (a single dosage of 20 mg omeprazole and 300 mg bismuth citrate, &lt;i&gt;n&lt;/i&gt; = 50 304), while &lt;i&gt;H. pylori&lt;/i&gt;-negative individuals (&lt;i&gt;n&lt;/i&gt; = 77 954) did not receive any treatment.&lt;/p&gt;&lt;p&gt;The trial's 11.8-year follow-up (2011–2022) confirmed a 13% reduction in GC incidence among all treated participants and a 19% reduction among those with successful &lt;i&gt;H. pylori&lt;/i&gt; eradication, compared to the symptom alleviation group.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The authors also reported a more clinically informative measure: a number needed to treat (NNT) of 141 patients to prevent one GC case across all treated individuals, which was improved to 96 among those who achieved successful eradication.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; These NNT estimates from MITS were higher (indicating comparatively modest effect magnitude) than those reported in prior trials and meta-analyses,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; mainly due to the usage of a partially effective symptom alleviation treatment in MITS, which included omeprazole and bismuth rather than a pure placebo. Notably, 15.1% of participants in the","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells","authors":"Haoxian Ke,&nbsp;Peisi Li,&nbsp;Zhihao Li,&nbsp;Xian Zeng,&nbsp;Chi Zhang,&nbsp;Shuzhen Luo,&nbsp;Xiaofang Chen,&nbsp;Xinlan Zhou,&nbsp;Shichen Dong,&nbsp;Shaopeng Chen,&nbsp;Junfeng Huang,&nbsp;Ming Yuan,&nbsp;Runfeng Yu,&nbsp;Shubiao Ye,&nbsp;Tuo Hu,&nbsp;Zhonghui Tang,&nbsp;Dongbin Liu,&nbsp;Kui Wu,&nbsp;Xianrui Wu,&nbsp;Ping Lan","doi":"10.1002/ctm2.70175","DOIUrl":"https://doi.org/10.1002/ctm2.70175","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Tumour immune macroenvironment is comprised of tumour and surrounding organs responding to tumourigenesis and immunotherapy. The lack of comprehensive analytical methods hinders its application for prediction of survival and treatment response in colorectal cancer (CRC) patients.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Cytometry by time-of-flight (CyTOF) and RNA-seq was applied to characterise immune cell heterogeneity in a discovery cohort including tumour, blood and intestinal architecture comprising epithelium, lamina propria, submucosa, muscularis propria of normal bowel and tumour–adjacent bowel tissues. Immunoprofiling was also validated by a validation cohort using single-cell RNA sequencing, spatial transcription, CyTOF and multiplex immunofluorescent staining.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Based on cell phenotype and transcription, we identify distinct immunotypes in the CRC macroenvironment including blood, tumour and different intestinal architecture, showing disturbed immune cell compositions, increasing expression of immunosuppressive markers and cell–cell interactions contributing to immunosuppressive regulation. Furthermore, we evaluate immune macroenvironment influencing factors including tertiary lymphoid structures (TLSs), consensus molecular subtypes (CMSs) and immune checkpoint inhibitors (ICIs). TLS presence fuels anti-tumour immunity by promoting CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration and altering activation or suppression of T cell systematically. TLS presence correlates with patient survival, intrinsic CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in effector memory CD8&lt;sup&gt;+&lt;/sup&gt; T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our findings provide insights into the CRC immune macroenvironment, highlighting immune cell suppression and activation in tumourigenesis. Our study illustrates the potential utility of blood for predicting immunotherapy response.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Distinct immunotypes are identified in the CRC macroenvironment.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;TLS and immunotherapy exert influence on the immune macroenvironment.&lt;/li&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the FOXM1/CMA/ER stress axis in regulating the progression of nonalcoholic steatohepatitis","authors":"Shuoyi Ma,&nbsp;Erzhuo Xia,&nbsp;Miao Zhang,&nbsp;Yinan Hu,&nbsp;Siyuan Tian,&nbsp;Xiaohong Zheng,&nbsp;Bo Li,&nbsp;Gang Ma,&nbsp;Rui Su,&nbsp;Keshuai Sun,&nbsp;Qingling Fan,&nbsp;Fangfang Yang,&nbsp;Guanya Guo,&nbsp;Changcun Guo,&nbsp;Yulong Shang,&nbsp;Xinmin Zhou,&nbsp;Xia Zhou,&nbsp;Jingbo Wang,&nbsp;Ying Han","doi":"10.1002/ctm2.70202","DOIUrl":"https://doi.org/10.1002/ctm2.70202","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background/aims&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The molecular mechanisms driving nonalcoholic steatohepatitis (NASH) progression are poorly understood. This research examines the involvement of chaperone-mediated autophagy (CMA) in NASH progression.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Hepatic CMA activity was analysed in NASH mice and patients. Lysosome-associated membrane protein 2A (LAMP2A) was knocked down or overexpressed to assess the effects of hepatocyte-specific CMA on NASH progression. Mice received a high-fat diet or a methionine and choline-deficient diet to induce NASH. Palmitic acid was employed to mimic lipotoxicity-induced hepatocyte damage in vitro. The promoter activity of FOXM1 was evaluated via ChIP and dual-luciferase reporter assays.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Hepatic CMA activity was substantially low in NASH mice and patients. LAMP2A knockdown resulted in hepatocyte-specific CMA deficiency, which promoted fibrosis and hepatic inflammation in NASH mice. Both in vitro and in vivo, CMA deficiency also exacerbated hepatocyte damage and endoplasmic reticulum (ER) stress. Mechanistically, CMA deficiency in hepatocytes increased cholesterol accumulation by blocking the degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCR), a key cholesterol synthesis-related enzyme, and the accumulated cholesterol subsequently induced ER stress and hepatocyte damage. The restoration of hepatocyte-specific CMA activity effectively ameliorated diet-induced NASH and ER stress in vivo and in vitro. FOXM1 directly bound to LAMP2A promoter and negatively regulated its transcription. The upregulation of FOXM1 expression impaired CMA and enhanced ER stress, which in turn increased FOXM1 expression, resulting in a vicious cycle and promoting NASH development.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study highlights the significance of the FOXM1/CMA/ER stress axis in NASH progression and proposes novel therapeutic targets for NASH.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Chaperone-mediated autophagy (CMA) deficiency in hepatocytes promotes hepatic inflammation and fibrosis in mice with nonalcoholic steatohepatitis (NASH) by inducing cholesterol accumulation and endoplasmic reticulum (ER) stress.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Upregulated FOXM1 impairs CMA by suppressing the transcription of lysosome-associated ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone","authors":"Jiayan Yan,&nbsp;Zhifeng Jiang,&nbsp;Shiyu Zhang,&nbsp;Qichao Yu,&nbsp;Yijun Lu,&nbsp;Runze Miao,&nbsp;Zhaoyou Tang,&nbsp;Jia Fan,&nbsp;Liang Wu,&nbsp;Dan G. Duda,&nbsp;Jian Zhou,&nbsp;Xinrong Yang","doi":"10.1002/ctm2.70224","DOIUrl":"https://doi.org/10.1002/ctm2.70224","url":null,"abstract":"<p>Solid tumours are intricate and highly heterogeneous ecosystems, which grow in and invade normal organs. Their progression is mediated by cancer cells’ interaction with different cell types, such as immune cells, stromal cells and endothelial cells, and with the extracellular matrix. Owing to its high incidence, aggressive growth and resistance to local and systemic treatments, liver cancer has particularly high mortality rates worldwide. In recent decades, spatial heterogeneity has garnered significant attention as an unfavourable biological characteristic of the tumour microenvironment, prompting extensive research into its role in liver tumour development. Advances in spatial omics have facilitated the detailed spatial analysis of cell types, states and cell‒cell interactions, allowing a thorough understanding of the spatial and temporal heterogeneities of tumour microenvironment and informing the development of novel therapeutic approaches. This review illustrates the latest discovery of the invasive zone, and systematically introduced specific macroscopic spatial heterogeneities, pathological spatial heterogeneities and tumour microenvironment heterogeneities of liver cancer.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paclitaxel biological synthesis promotes the innovation of anti-cancer drugs","authors":"Xiaolin Zhang,&nbsp;Gang Liu,&nbsp;Jianbin Yan","doi":"10.1002/ctm2.70230","DOIUrl":"https://doi.org/10.1002/ctm2.70230","url":null,"abstract":"&lt;p&gt;Paclitaxel, as a star natural drug with significant anti-tumour activity, has become the frontline chemotherapy medication to treat various cancers since its advent in 1992.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Different from other anticarcinogens, paclitaxel uniquely promotes the assembly of tubulin subunits into stable, non-dynamic states that impede cancer cell proliferation, thereby effectively controlling the development of the disease. With the increasing number of cancer patients worldwide and the continuous advancement of medical technology, the market demand for paclitaxel is expected to expand continually. The market for the paclitaxel injection alone is estimated to reach 15.8 billion USD by 2032.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Furthermore, integrating multiple disciplines, including medicine, biology and materials science, has the potential to expand the applications of paclitaxel significantly into medical devices. As an active pharmaceutical ingredient in drug-coated balloons and stents, paclitaxel is crucial in inhibiting intimal proliferation and preventing in-stent restenosis, thus providing a novel treatment option for patients with cardiovascular disease. This application improves the efficacy of paclitaxel and expands its clinical applications.&lt;/p&gt;&lt;p&gt;As precision medicine continues to advance, the personalisation of paclitaxel treatment is set to become a key focus for the future.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Utilising advanced genomic and phenomic analysis techniques enables the precise identification of tumour types in patients. This capability allows for the development of tailored treatment plans, which can significantly enhance the therapeutic efficacy of the medication and improve the overall quality of life for patients. The ongoing optimisation of paclitaxel in combination with other medications and therapies will continue to advance, with an emphasis on enhancing treatment efficacy and targeting capability while minimising adverse effects. The advancement of paclitaxel precision medicine necessitates the enhancement of its yield and purity (Figure 1A). More crucially, it involves developing new paclitaxel derivatives that improve patient compliance with medication regimens.&lt;/p&gt;&lt;p&gt;The rapid development of synthetic biology makes it possible to efficiently synthesise and directly generate novel paclitaxel derivatives tailored to different medical needs. It is reported that 600 taxoids have been identified from various &lt;i&gt;Taxus&lt;/i&gt; species,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; among which about 24 taxoids exhibit cytotoxicity to tumour cells, thus providing a promising resource for discovering new agents with potent cytotoxic properties and reduced susceptibility to resistance. Recent breakthroughs in paclitaxel biosynthesis open new avenues for developing paclitaxel derivatives.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; The enzymes that play a pivotal role in paclitaxel synthesis, especially those belonging to the cytochrome P450 family (CYP450s), demonstrate impr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-Methyladenosine modification mediated by METTL3 promotes DNA-PKcs expression to induce anlotinib resistance in osteosarcoma","authors":"Yining Zhang,&nbsp;Guohong Shen,&nbsp;Dan Zhang,&nbsp;Tingting Meng,&nbsp;Zhaorui Lv,&nbsp;Lei Chen,&nbsp;Jianmin Li,&nbsp;Ka Li","doi":"10.1002/ctm2.70228","DOIUrl":"https://doi.org/10.1002/ctm2.70228","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Acquired anlotinib resistance is still a key challenge in osteosarcoma treatment. Unravelling the mechanisms underlying anlotinib resistance is the key to optimising its efficacy for treating osteosarcoma. Previous studies have explored the pivotal function of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) with regard to osteosarcoma chemoresistance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We used bioinformatics analysis to predict DNA-PKcs and Beclin-1 interactions, confirmed through immunofluorescence (IF) and co-immunoprecipitation (co-IP). Dual-luciferase analyses and Methylated RNA immunoprecipitation (MeRIP) were implemented to detect the detected m&lt;sup&gt;6&lt;/sup&gt;A modifications. RNA fluorescence in situ hybridisation (FISH)—IF co-localisation and RNA immunoprecipitation (RIP) were conducted to explore the interplay between PRKDC mRNA and the indicated proteins.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Anlotinib-treated osteosarcoma cells exhibited increased DNA-PKcs levels, and silencing DNA-PKcs augmented osteosarcoma sensitivity to anlotinib. DNA-PKcs affects anlotinib-induced autophagy by interacting with Beclin-1 and regulating its ubiquitination. Notably, PRKDC mRNA, encoding DNA-PKcs, underwent N&lt;sup&gt;6&lt;/sup&gt;-Methyladenosine (m&lt;sup&gt;6&lt;/sup&gt;A) modification. Methyltransferase-like 3 (METTL3) positively regulated DNA-PKcs expression. Functionally, METTL3 enhances anlotinib resistance in osteosarcoma, which is reversed by PRKDC knockdown. Mechanistically, METTL3 binds to PRKDC mRNA and facilitates m&lt;sup&gt;6&lt;/sup&gt;A methylation. Additionally, m&lt;sup&gt;6&lt;/sup&gt;A methylated PRKDC mRNA is identified via YTH N&lt;sup&gt;6&lt;/sup&gt;-methyladenosine RNA-binding protein 1 (YTHDF1), augmenting its expression.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings revealed that DNA-PKcs promotes anlotinib resistance by regulating protective autophagy, while METTL3 induces PRKDC m&lt;sup&gt;6&lt;/sup&gt;A modification, enhancing its expression. Thus, targeting METTL3/PRKDC may be a novel strategy for improving therapeutic efficacy in human osteosarcoma.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;DNA-PKcs knockdown heightens osteosarcoma sensitivity to anlotinib.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;DNA-PKcs modulates anlotinib-induced pr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNF31 induces paclitaxel resistance by sustaining ALYREF cytoplasmic–nuclear shuttling in human triple-negative breast cancer","authors":"Shumei Huang,&nbsp;Dongni Shi,&nbsp;Shuqin Dai,&nbsp;Xingyu Jiang,&nbsp;Rui Wang,&nbsp;Muwen Yang,&nbsp;Boyu Chen,&nbsp;Xuwei Chen,&nbsp;Lingzhi Kong,&nbsp;Lixin He,&nbsp;Pinwei Deng,&nbsp;Xiangfu Chen,&nbsp;Chuyong Lin,&nbsp;Yue Li,&nbsp;Jun Li,&nbsp;Libing Song,&nbsp;Yawei Shi,&nbsp;Weidong Wei","doi":"10.1002/ctm2.70203","DOIUrl":"https://doi.org/10.1002/ctm2.70203","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Resistance to paclitaxel-based chemotherapy is the major obstacle in triple-negative breast cancer (TNBC) treatment. However, overcoming paclitaxel resistance remains an unsolved problem. The present study aimed to determine whether paclitaxel treatment impairs Aly/REF export factor (ALYREF) cytoplasmic–nuclear shuttling, its mechanism, and the role of ubiquitinated ALYREF in paclitaxel resistance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The subcellular proportion of ALYREF was detected in samples from patients with TNBC using immunohistochemistry to analyze the relationship between ALYREF distribution and paclitaxel response. Cell viability assays, immunofluorescence assays, quantitative real-time reverse transcription PCR assays, western blotting, and terminal deoxynucleotidyl transferase nick-end-labelling assays were conducted to measure the biological function of the subcellular proportion of ALYREF and E3 ligase ring finger protein 31 (RNF31) on paclitaxel sensitivity in TNBC. The synergistic effects of an RNF31 inhibitor plus paclitaxel on TNBC were evaluated. Cox regression models were adopted to assess the prognostic role of RNF31 in TNBC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Herein, we showed that regulation of ALYREF cytoplasmic–nuclear shuttling is associated with the paclitaxel response in TNBC. In paclitaxel-sensitive TNBC, ALYREF was trapped in the cytoplasm by paclitaxel, while in paclitaxel-resistant TNBC, ALYREF was efficiently transported into the nucleus to exert its function, allowing the export of the mRNAs encoding paclitaxel-resistance-related factors, including tubulin beta 3 class III (TUBB3), stathmin 1 (STMN1), and microtubule-associated protein Tau (TAU), ultimately inducing paclitaxel resistance in TNBC. Mechanistically, we found that RNF31 interacts with and ubiquitinates ALYREF, which facilitates ALYREF nuclear transportation via importin 13 (IPO13) under paclitaxel treatment. Notably, the RNF31 inhibitor and paclitaxel synergistically repressed tumour growth in vivo and in TNBC patient-derived organoids. In addition, analysis of patients with TNBC showed that elevated RNF31 levels correlated with poor prognosis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These data indicated that RNF31-mediated ALYREF ubiquitylation could represent a potent target to reverse paclitaxel resistance in TNBC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HSPG2 could promote normal haematopoiesis in acute myeloid leukaemia patients after complete remission by repairing bone marrow endothelial progenitor cells","authors":"Chen-Yuan Li,&nbsp;Zhen-Kun Wang,&nbsp;Tong Xing,&nbsp;Meng-Zhu Shen,&nbsp;Xin-Yan Zhang,&nbsp;Dan-Dan Chen,&nbsp;Yu Wang,&nbsp;Hao Jiang,&nbsp;Qian Jiang,&nbsp;Xiao-Jun Huang,&nbsp;Yuan Kong","doi":"10.1002/ctm2.70220","DOIUrl":"https://doi.org/10.1002/ctm2.70220","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Even after achieving complete remission (CR), many acute myeloid leukaemia (AML) patients suffer from poor haematopoietic recovery after chemotherapy. Previous studies have shown that the damage of bone marrow endothelial progenitor cell (BM EPC) hinders haematopoietic recovery after chemotherapy in mice. Therefore, elucidation of the mechanism and repair strategy of chemotherapy-induced BM EPC damage is urgent needed.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The prospective case–control study enrolled 40 AML patients after CR (CR patients), who received idarubicin and cytarabine (IA) regimen (&lt;i&gt;n&lt;/i&gt; = 20), or homoharringtonine, aclarubicin and cytarabine (HAA) regimen (&lt;i&gt;n&lt;/i&gt; = 20) as induction chemotherapy, and their age-matched healthy controls (HCs, &lt;i&gt;n&lt;/i&gt; = 20). The HSPG2 expression level in BM EPCs and BM plasma were determined via flow cytometry and enzyme-linked immunosorbent assays. The BM EPC's functions were evaluated by apoptosis, reactive oxygen species (ROS) level, migration and tube formation assays. The haematopoiesis-supporting ability and leukaemia cell-supporting ability of BM EPCs were assessed through coculture assay. Moreover, RNA sequencing and qPCR were performed to further explore the underlying mechanism.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;HSPG2 levels decreased in both the BM plasma and BM EPCs of CR patients after IA and HAA induction chemotherapy. Moreover, the BM EPC's functions of CR patients were reduced. In vitro experiments demonstrated that the &lt;i&gt;HSPG2&lt;/i&gt; gene knockdown or cytosine arabinoside treatment led to BM EPC dysfunction, whereas the HSPG2 treatment promoted repair of the BM EPC function in vitro. In addition, we found that the HSPG2 treatment restored the BM EPC function from CR patients without affecting their leukaemia cell-supporting ability. Mechanistically, BM EPC functions and haematopoietic regulation-related genes were significantly decreased after the &lt;i&gt;HSPG2&lt;/i&gt; gene knockdown.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our findings demonstrate a significant role of HSPG2 in BM EPC functions. This discovery uncovers that HSPG2 is a potential therapeutic target for promoting the BM EPC function of AML-CR patients after chemotherapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The HSPG2 level in the BM EPCs of AML-CR patien","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}