Cancer Communications最新文献

{"title":"AP4 induces JNK1 and a miR-22-3p/FOSL1 feed-forward loop to activate AP-1 and promote colorectal cancer metastasis","authors":"Jinjiang Chou,&nbsp;Markus Kaller,&nbsp;Matjaz Rokavec,&nbsp;Fangteng Liu,&nbsp;Heiko Hermeking","doi":"10.1002/cac2.12514","DOIUrl":"10.1002/cac2.12514","url":null,"abstract":"<p>Dear Editor,</p><p>Colorectal cancer (CRC) is the third most deadly cancer worldwide [<span>1</span>]. The mortality of CRC has remained high due to limited treatment options for metastatic CRC (mCRC) [<span>2</span>]. Epithelial-mesenchymal transition (EMT) is an important contributor to mCRC [<span>2</span>]. The c-MYC proto-oncogene (MYC)-induced transcription factor AP4 (TFAP4/AP4) is a driver of EMT, thereby presumably facilitates mCRC [<span>3, 4</span>]. The mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway has been implicated in the regulation of EMT and mCRC [<span>5</span>].</p><p>Here, we analyzed whether AP4 regulates components of the MAPK/JNK/AP-1 pathway after MYC activation using CRC cells rendered <i>AP4</i>-deficient by a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) approach. The detailed methods are shown in the Supplementary file. First, we grouped MYC-induced changes in mRNA expression observed in the CRC cell line DLD-1 <i>AP4</i> wild-type 1/pRTR-<i>c-MYC</i>-VSV (<i>AP4</i>-WT1 DLD-1/pRTR-<i>c</i>-<i>MYC-</i>VSV) into 6 non-overlapping expression clusters (Supplementary Figure S1A, left), with cluster 1 representing mRNAs down-regulated, and clusters 2-6 representing different patterns of mRNA up-regulated after MYC activation. MAPK signaling pathway components were strongly over-represented in cluster 6 (Supplementary Figure S1A, right). The AP4 targets <i>MIR22 host gene</i> (<i>MIR22HG</i>) and <i>E-</i><i>cadherin 1</i> (<i>CDH1</i>) were down-regulated after MYC activation in <i>AP4</i>-WT1 DLD-1/pRTR-<i>c-MYC</i>-VSV cells (Supplementary Figure S1B). MAPK signaling effectors, including c-<i>Fos proto-oncogene</i> (<i>FOS</i>), c-<i>Jun proto-oncogene</i> (<i>JUN</i>) and <i>c-J</i><i>unB proto-oncogene</i> (<i>JUNB</i>), were over-represented in cluster 6. Additional MAPK signaling pathway components. such as <i>c-Jun N-terminal kinase 1</i> (<i>JNK1</i>), <i>mitogen-activated protein kinase kinase kinase 1</i> (<i>MAP3K1</i>), <i>mitogen-activated protein kinase kinase kinase 13</i> (<i>MAP3K13</i>), <i>mitogen-activated protein kinase kinase 3</i> (<i>MAP2K3</i>), <i>mitogen-activated protein kinase kinase 7</i> (<i>MAP2K7</i>) and <i>FOS</i>-<i>like</i> <i>1</i> (<i>FOSL1</i>) were found in clusters 3-5 (Supplementary Figure S1B). Interestingly, <i>MAP3K13, MAP2K7, JNK1</i> and <i>FOSL1</i> were induced by MYC in an <i>AP4</i>-dependent manner (Supplementary Figure S1C-D).</p><p>Notably, <i>MAP3K13</i>, <i>FOSL1, JNK1</i> and <i>MAP2K7</i> were also up-regulated after activating <i>AP4</i> for 48 or 72 hours (Figure 1A) and showed AP4-binding sites (CAGCTG) and AP4 occupancy (Supplementary Figure S2A). Therefore, these genes presumably represent direct AP4 targets. MAP3K13 and FOSL1 protein and phosphorylated JNK1 were up-regulated after <i>AP4</i> activation, whereas JNK1 protein levels remained unch","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472306","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":"Cellular metabolism: A key player in cancer ferroptosis","authors":"Xianjie Jiang,&nbsp;Qiu Peng,&nbsp;Mingjing Peng,&nbsp;Linda Oyang,&nbsp;Honghan Wang,&nbsp;Qiang Liu,&nbsp;Xuemeng Xu,&nbsp;Nayiyuan Wu,&nbsp;Shiming Tan,&nbsp;Wenjuan Yang,&nbsp;Yaqian Han,&nbsp;Jinguan Lin,&nbsp;Longzheng Xia,&nbsp;Yanyan Tang,&nbsp;Xia Luo,&nbsp;Jie Dai,&nbsp;Yujuan Zhou,&nbsp;Qianjin Liao","doi":"10.1002/cac2.12519","DOIUrl":"10.1002/cac2.12519","url":null,"abstract":"<p>Cellular metabolism is the fundamental process by which cells maintain growth and self-renewal. It produces energy, furnishes raw materials, and intermediates for biomolecule synthesis, and modulates enzyme activity to sustain normal cellular functions. Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis is a recently discovered form of iron-dependent programmed cell death. The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression. However, the role of cellular metabolism, particularly glucose and amino acid metabolism, in cancer ferroptosis is not well understood. Here, we reviewed glucose, lipid, amino acid, iron and selenium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process. Additionally, we provided a detailed overview of agents used to induce cancer ferroptosis. We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellular redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron-induced cell death, resulting in enhanced tumor cell killing. The combination of ferroptosis inducers and cellular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2024-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139459766","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":"The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023","authors":"Feng-Hua Wang,&nbsp;Xiao-Tian Zhang,&nbsp;Lei Tang,&nbsp;Qi Wu,&nbsp;Mu-Yan Cai,&nbsp;Yuan-Fang Li,&nbsp;Xiu-Juan Qu,&nbsp;Hong Qiu,&nbsp;Yu-Jing Zhang,&nbsp;Jie-Er Ying,&nbsp;Jun Zhang,&nbsp;Ling-Yu Sun,&nbsp;Rong-Bo Lin,&nbsp;Chang Wang,&nbsp;Hao Liu,&nbsp;Miao-Zhen Qiu,&nbsp;Wen-Long Guan,&nbsp;Sheng-Xiang Rao,&nbsp;Jia-Fu Ji,&nbsp;Yan Xin,&nbsp;Wei-Qi Sheng,&nbsp;Hui-Mian Xu,&nbsp;Zhi-Wei Zhou,&nbsp;Ai-Ping Zhou,&nbsp;Jing Jin,&nbsp;Xiang-Lin Yuan,&nbsp;Feng Bi,&nbsp;Tian-Shu Liu,&nbsp;Han Liang,&nbsp;Yan-Qiao Zhang,&nbsp;Guo-Xin Li,&nbsp;Jun Liang,&nbsp;Bao-Rui Liu,&nbsp;Lin Shen,&nbsp;Jin Li,&nbsp;Rui-Hua Xu","doi":"10.1002/cac2.12516","DOIUrl":"10.1002/cac2.12516","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12516","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139063385","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":"Development of antibody-drug conjugates in cancer: Overview and prospects","authors":"Dan-Yun Ruan,&nbsp;Hao-Xiang Wu,&nbsp;Qi Meng,&nbsp;Rui-Hua Xu","doi":"10.1002/cac2.12517","DOIUrl":"10.1002/cac2.12517","url":null,"abstract":"<p>In recent years, remarkable breakthroughs have been reported on antibody-drug conjugates (ADCs), with 15 ADCs successfully entering the market over the past decade. This substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs, demonstrating their efficacy in treating a wide array of malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects of ADCs. An ADC generally comprises an antibody, a linker and a payload, and the combination has profound effects on drug structure, pharmacokinetic profile and efficacy. Hence, optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects. In this review, we comprehensively reviewed the current development and the prospects of ADC, provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China, highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies, and also discussed the new related technologies, possibility of next-generation ADCs and the directions of clinical research.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139063437","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":"NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma","authors":"Yue Yao,&nbsp;Yi Xu,&nbsp;Liang Yu,&nbsp;Ting-Mao Xue,&nbsp;Zhi-Jie Xiao,&nbsp;Pui-Chi Tin,&nbsp;Hiu-Ling Fung,&nbsp;Hoi-Tang Ma,&nbsp;Jing-Ping Yun,&nbsp;Judy Wai Ping Yam","doi":"10.1002/cac2.12515","DOIUrl":"10.1002/cac2.12515","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Small extracellular vesicles (sEVs) mediate intercellular communication that contributes to hepatocellular carcinoma (HCC) progression via multifaceted pathways. The success of cell entry determines the effect of sEV on recipient cells. Here, we aimed to delineate the mechanisms underlying the uptake of sEV in HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Macropinocytosis was examined by the ability of cells to internalize dextran and sEV. Macropinocytosis was analyzed in Na(+)/H(+) exchanger 7 (<i>NHE7</i>)-knockdown and -overexpressing cells. The properties of cells were studied using functional assays. pH biosensor was used to evaluate the intracellular and endosomal pH. The expression of NHE7 in patients’ liver tissues was examined by immunofluorescent staining. Inducible silencing of NHE7 in established tumors was performed to reveal the therapeutic potential of targeting NHE7.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The data revealed that macropinocytosis controlled the internalization of sEVs and their oncogenic effect on recipient cells. It was found that metastatic HCC cells exhibited the highest efficiency of sEV uptake relative to normal liver cells and non-metastatic HCC cells. Attenuation of macropinocytic activity by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) limited the entry of sEVs and compromised cell aggressiveness. Mechanistically, we delineated that high level of NHE7, a sodium-hydrogen exchanger, alkalized intracellular pH and acidized endosomal pH, leading to the maturation of macropinosomes. Inducible inhibition of NHE7 in established tumors developed in mice delayed tumor development and suppressed lung metastasis. Clinically, NHE7 expression was upregulated and linked to dismal prognosis of HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study advances the understanding that NHE7 enhances sEV uptake by macropinocytosis to promote the malignant properties of HCC cells. Inhibition of sEV uptake via macropinocytosis can be exploited as a treatment alone or in combination with conventional therapeutic approaches for HCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139048366","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":"Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance","authors":"Chen Ming-Kun,&nbsp;Chen Zi-Xian,&nbsp;Cai Mao-Ping,&nbsp;Chen Hong,&nbsp;Chen Zhuang-Fei,&nbsp;Zhao Shan-Chao","doi":"10.1002/cac2.12518","DOIUrl":"10.1002/cac2.12518","url":null,"abstract":"<p>Targeted delivery of anti-tumor drugs and overcoming drug resistance in malignant tumor cells remain significant clinical challenges. However, there are only few effective methods to address these issues. Extracellular vesicles (EVs), actively secreted by cells, play a crucial role in intercellular information transmission and cargo transportation. Recent studies have demonstrated that engineered EVs can serve as drug delivery carriers and showed promising application prospects. Nevertheless, there is an urgent need for further improvements in the isolation and purification of EVs, surface modification techniques, drug assembly processes, and precise recognition of tumor cells for targeted drug delivery purposes. In this review, we summarize the applications of engineered EVs in cancer treatment and overcoming drug resistance, and current challenges associated with engineered EVs are also discussed. This review aims to provide new insights and potential directions for utilizing engineered EVs as targeted delivery systems for anti-tumor drugs and overcoming drug resistance in the near future.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139058139","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":"Association of previously irradiated stable brain metastases with outcomes of atezolizumab-treated non-small cell lung cancer: A pooled analysis of individual patient data from three randomized trials","authors":"Tiantian Guo,&nbsp;Yue Zhou,&nbsp;Fei Liang,&nbsp;Zezhou Wang,&nbsp;Vincent Bourbonne,&nbsp;Lukas Käsmann,&nbsp;Nora Sundahl,&nbsp;Abraham Jing-Ching Wu,&nbsp;Jianjiao Ni,&nbsp;Zhengfei Zhu","doi":"10.1002/cac2.12512","DOIUrl":"10.1002/cac2.12512","url":null,"abstract":"<p>Brain metastasis (BM) has long been recognized as a prognostic factor associated with poor prognosis for non-small cell lung cancer (NSCLC) in the era of conventional chemotherapy and targeted therapy [<span>1</span>]. In the era of immunotherapy, controversial findings have been reported regarding the prognostic significance of BM in patients with NSCLC treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Several studies have shown that the presence of BM did not impact overall survival (OS) or progression-free survival (PFS) [<span>2, 3</span>], whereas other studies have identified BM as a negative prognostic factor [<span>4, 5</span>]. These previous works were mostly based on small sample sizes, and the prognostic significance of BM in patients treated with PD-1/PD-L1 inhibitors warrants further investigation.</p><p>In the present study, we used Vivli, a global, neutral data-sharing platform that enables access to anonymized individual patient data from trials, to evaluate the association between previously irradiated stable BM (iBM) and treatment outcomes of atezolizumab-containing regimens using pooled data from prospective phase III trials. Three clinical trials, IMpower130 (NCT02367781) [<span>6</span>], IMpower131 (NCT02367794) [<span>7</span>], and IMpower150 (NCT02366143) [<span>8</span>], were identified. Supplementary Table S1 provides an overview of the included three clinical trials. The study design and methods are described in the Supplementary Material.</p><p>Supplementary Figure S1 shows the patient disposition for the per-protocol population. In the per-protocol population (<i>n</i> = 2,700), only 10 (3.3%) of 316 patients with baseline BM did not undergo previous irradiation, who were excluded due to difficulties in statistical analyses. Among the 2,690 patients finally included, 210 (11.8%) of 1,778 patients in the atezolizumab-containing arm and 96 (10.5%) of 912 patients in the chemotherapy alone arm had iBM. Baseline demographics and clinical characteristics for patients without baseline BM and patients with iBM are shown in Supplementary Table S2. In patients without BM, OS and PFS were improved with atezolizumab-containing regimens compared with chemotherapy alone (Supplementary Figure S2). In patients with iBM, adding atezolizumab significantly improved OS and PFS compared with chemotherapy alone (Supplementary Figure S3).</p><p>We utilized propensity score matching (PSM) to control for the heterogeneity between patients with iBM and those without BM (Supplementary Table S3). A total of 11 patients in the atezolizumab-containing arm and 10 in the chemotherapy alone arm were excluded due to missing relevant baseline characteristic data. We compared the OS of patients with iBM and those without baseline BM before and after PSM (Figure 1). In the atezolizumab-containing arm, OS was longer in patients with iBM than in those without BM in the original cohort (unadjusted hazard ratio [HR] = ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12512","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139037363","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":"Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma","authors":"Weiren Liu,&nbsp;Huqiang Wang,&nbsp;Qianfu Zhao,&nbsp;Chenyang Tao,&nbsp;Weifeng Qu,&nbsp;Yushan Hou,&nbsp;Run Huang,&nbsp;Zimei Sun,&nbsp;Guiqi Zhu,&nbsp;Xifei Jiang,&nbsp;Yuan Fang,&nbsp;Jun Gao,&nbsp;Xiaoling Wu,&nbsp;Zhixiang Yang,&nbsp;Rongyu Ping,&nbsp;Jiafeng Chen,&nbsp;Rui Yang,&nbsp;Tianhao Chu,&nbsp;Jian Zhou,&nbsp;Jia Fan,&nbsp;Zheng Tang,&nbsp;Dong Yang,&nbsp;Yinghong Shi","doi":"10.1002/cac2.12513","DOIUrl":"10.1002/cac2.12513","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed integrated multiomics analysis in 116 iCCA samples, including whole-exome sequencing, bulk RNA-sequencing and proteome analysis. Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Three metabolic subtypes (S1-S3) with subtype-specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune-suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>)/AT-rich interactive domain 1A (<i>ARID1A</i>) mutations. Among the S2 subtype-specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen-activated protein kinase (MAPK) signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12513","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032184","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":"Rescue of p53 functions by in vitro-transcribed mRNA impedes the growth of high-grade serous ovarian cancer","authors":"Monika Raab,&nbsp;Izabela Kostova,&nbsp;Samuel Peña-Llopis,&nbsp;Daniela Fietz,&nbsp;Monika Kressin,&nbsp;Seyed Mohsen Aberoumandi,&nbsp;Evelyn Ullrich,&nbsp;Sven Becker,&nbsp;Mourad Sanhaji,&nbsp;Klaus Strebhardt","doi":"10.1002/cac2.12511","DOIUrl":"10.1002/cac2.12511","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The cellular tumor protein p53 (<i>TP53</i>) is a tumor suppressor gene that is frequently mutated in human cancers. Among various cancer types, the very aggressive high-grade serous ovarian carcinoma (HGSOC) exhibits the highest prevalence of <i>TP53</i> mutations, present in &gt;96% of cases. Despite intensive efforts to reactivate p53, no clinical drug has been approved to rescue p53 function. In this study, our primary objective was to administer in vitro-transcribed (IVT) wild-type (WT) p53-mRNA to HGSOC cell lines, primary cells, and orthotopic mouse models, with the aim of exploring its impact on inhibiting tumor growth and dissemination, both in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To restore the activity of p53, WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system. Moreover, IVT WT p53 mRNA was delivered into different HGSOC model systems (primary cells and patient-derived organoids) using liposomes and studied for proliferation, cell cycle progression, apoptosis, colony formation, and chromosomal instability. Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells, followed by ingenuity pathway analysis. In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Reactivation of the <i>TP53</i> tumor suppressor gene was explored in different HGSOC model systems using newly designed IVT mRNA-based methods. The introduction of WT p53 mRNA triggered dose-dependent apoptosis, cell cycle arrest, and potent long-lasting inhibition of HGSOC cell proliferation. Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling, such as apoptosis, cell cycle regulation, and DNA damage. Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells, underscoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress. Furthermore, in various mouse models, treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC, providing valuable insights into ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138884486","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":"Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites","authors":"Ji Eon Kim,&nbsp;So-Young Park,&nbsp;Chulhwan Kwak,&nbsp;Yoonji Lee,&nbsp;Dae-Geun Song,&nbsp;Jae Woo Jung,&nbsp;Haesong Lee,&nbsp;Eun-Ae Shin,&nbsp;Yangie Pinanga,&nbsp;Kyung-hee Pyo,&nbsp;Eun Hae Lee,&nbsp;Wonsik Kim,&nbsp;Soyeon Kim,&nbsp;Chang-Duck Jun,&nbsp;Jeanho Yun,&nbsp;Sun Choi,&nbsp;Hyun-Woo Rhee,&nbsp;Kwang-Hyeon Liu,&nbsp;Jung Weon Lee","doi":"10.1002/cac2.12510","DOIUrl":"10.1002/cac2.12510","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Transmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Upon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho-dynamic-related protein I (DRP1) and certain mitophagy receptors at TM4SF5-enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and β-oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings suggested that TM4SF5-enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":16.2,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12510","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138828322","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}