Molecular Cancer最新文献

{"title":"Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma","authors":"Jason C. Klein, Lei Wang, Douglas Strand, Chewlan Lastufka, Gregory A. Hosler, Gary C. Hon","doi":"10.1186/s12943-024-02168-8","DOIUrl":"https://doi.org/10.1186/s12943-024-02168-8","url":null,"abstract":"Undifferentiated pleomorphic sarcoma (UPS) and related tumors are the most common type of soft tissue sarcoma. However, this spectrum of tumors has different etiologies with varying rates of metastasis and survival. Two dermal-based neoplasms in this class of pleomorphic sarcomas, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS), are challenging to differentiate at initial biopsy but vary significantly in prognosis. We performed single-cell transcriptomics on five AFX and PDS biopsy specimens as well as both single-cell and spatial transcriptomics on one PDS excision specimen to better characterize these tumors. The top differential genes between AFX and PDS were predictive of overall survival in 17 other cancers included in the Human Protein Atlas. Of these genes, COL6A3 and BGN predicted overall survival and metastasis-free survival in independent cohorts of 46 and 38 UPS tumors, respectively. COL6A3 was most predictive of overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel at predicting metastasis in UPS.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"162 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer.","authors":"Mei Peng, Jun Deng, Xiangping Li","doi":"10.1186/s12943-024-02167-9","DOIUrl":"10.1186/s12943-024-02167-9","url":null,"abstract":"<p><p>Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":"256"},"PeriodicalIF":27.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624131","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 dynamics shaping pre-metastatic and metastatic niches in liver metastases: from molecular mechanisms to therapeutic strategies","authors":"Chang Zhu, Jing-Yu Liao, Yi-Yang Liu, Ze-Yu Chen, Rui-Zhi Chang, Xiao-Ping Chen, Bi-Xiang Zhang, Jun-Nan Liang","doi":"10.1186/s12943-024-02171-z","DOIUrl":"https://doi.org/10.1186/s12943-024-02171-z","url":null,"abstract":"Liver metastases are commonly detected in the advanced stages of various malignant tumors, representing a significant clinical challenge. Throughout the process of liver metastases formation, immune cells play a pivotal role, particularly in the pre-metastatic and metastatic niches within the liver. Immune cells establish extensive and intricate interactions with tumor cells and other components in the liver, collectively promoting and sustaining the growth of liver metastases. Despite the limited efficacy of existing therapeutic modalities against some advanced liver metastases, novel immune-based treatment approaches are continuously being explored and validated. Building on the systematic elucidation of the immunosuppressive characteristics of liver metastases, we explored the potential of novel immunotherapies applicable to patients with liver metastases from multiple dimensions.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"98 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer","authors":"Qi Xie, Xiaolin Liu, Rengyun Liu, Jingxuan Pan, Jing Liang","doi":"10.1186/s12943-024-02166-w","DOIUrl":"https://doi.org/10.1186/s12943-024-02166-w","url":null,"abstract":"PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer","authors":"W. J. McDaid, L. Wilson, H. Adderley, A. Martinez-Lopez, M. J. Baker, J. Searle, L. Ginn, T. Budden, M. Aldea, A. Marinello, J. V. Aredo, A. Viros, B. Besse, H. A. Wakelee, F. Blackhall, S. Castillo-Lluva, C. R. Lindsay, A. Malliri","doi":"10.1186/s12943-024-02157-x","DOIUrl":"https://doi.org/10.1186/s12943-024-02157-x","url":null,"abstract":"KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC. KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"10 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cells in immune checkpoint blockade antitumor therapy","authors":"An Zhang, Tao Fan, Yixiao Liu, Guanhua Yu, Chunxiang Li, Zheng Jiang","doi":"10.1186/s12943-024-02156-y","DOIUrl":"https://doi.org/10.1186/s12943-024-02156-y","url":null,"abstract":"Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group of T lymphocytes with the ability to suppress immune responses and maintain immune homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity and facilitate cancer progression by weakening functions of effector T cells (Teffs). Consequently, targeting Tregs to eliminate them from tumor microenvironments to improve Teffs’ activity could emerge as an effective strategy for cancer immunotherapy. This review outlines the biology of Tregs, detailing their origins, classification, and crucial markers. Our focus lies on the complex role of Tregs in cancer’s development, progression and treatment, particularly on their suppressive role upon antitumor responses via multiple mechanisms. We delve into Tregs’ involvement in immune checkpoint blockade (ICB) therapy, their dual effect on cancer immunotherapy and their potential biomarkers for ICB therapy effectiveness. We also summarize advances in the therapies that adjust Tregs to optimize ICB therapy, which may be crucial for devising innovative cancer treatment strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"18 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Traditional Chinese medicine in treating upper digestive tract cancers","authors":"Alexis Shiying Huang, Jiaying Wu, Aftab AMIN, Xiu-Qiong Fu, Zhi-Ling Yu","doi":"10.1186/s12943-024-02149-x","DOIUrl":"https://doi.org/10.1186/s12943-024-02149-x","url":null,"abstract":"Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"2 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variability in non-tumor areas of colorectal cancer patients as revealed by endoscopic intestinal step biopsies","authors":"Shoko Ikuta, Yutaka Saito, So Takata, Yoichiro Nakatani, Izumi Nagatomo, Satoshi Shiba, Yoshito Takeda, Yasushi Totoki, Sayaka Mizutani, Hironori Sunakawa, Hiroaki Ikematsu, Hiroyuki Takamaru, Atsushi Kumanogoh, Shinichi Yachida","doi":"10.1186/s12943-024-02159-9","DOIUrl":"https://doi.org/10.1186/s12943-024-02159-9","url":null,"abstract":"A comprehensive endoscopic small and large intestinal untargeted step biopsy procedure was conducted to compare gene expression between the normal intestinal mucosa of healthy individuals and that of patients with colorectal tumors. From 78 participants (healthy individuals [n = 17], patients with colorectal conventional adenomas [n = 6], patients with Tis–T1 colorectal cancer [n = 41], patients with T2–4 colorectal cancer [n = 14]), biopsies of normal mucosa of the terminal ileum, right-sided colon (cecum and ascending colon), and left-sided colorectum (descending colon, sigmoid colon, and rectum) were obtained using a lower gastrointestinal endoscope. RNA was extracted from all samples, and total transcriptome sequencing was performed. Transcriptome data from 388 samples was analyzed. DNA was also extracted from tumor biopsy tissues and analyzed for whole-exome sequencing. In healthy individuals, gene expression differed significantly among the terminal ileum, right-sided colon, and left-sided colorectum, presumably linked to embryological factors. There were differences in gene expression in the normal mucosa in colorectal cancer patients, compared to healthy controls. Patients with tumors, especially T2–4 colorectal cancer, showed considerable variation in gene expression in non-tumor tissues, even in the terminal ileum distant from the tumor site. Based on endoscopic biopsies, the results imply cancer-predisposing conditions in seemingly normal tissues. The present study points to the importance of small intestine and cancer-predisposing conditions in the colon of colorectal cancer patients, with possible implications for developing novel immunotherapy and other therapeutic modalities.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"243 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A prospective multi-cohort study identifies and validates a 5-gene peripheral blood signature predictive of immunotherapy response in non-small cell lung cancer","authors":"Shaoqiu Chen, Fangfang Liu, Yuanyuan Fu, Chris K. Deng, Jeffrey A. Borgia, Abdul-Ghani Ayman, Masaki Nasu, Mayumi Jijiwa, Hua Yang, Ting Gong, Junlong Wang, Zhougui Ling, Xiaoyan Wang, Hongwei Wang, Qian Chu, Youping Deng","doi":"10.1186/s12943-024-02160-2","DOIUrl":"https://doi.org/10.1186/s12943-024-02160-2","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC. We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS). In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80–0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07–0.58, p = 0.005). Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"109 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 nucleocapsid protein interaction with YBX1 displays oncolytic properties through PKM mRNA destabilization","authors":"Xin Chen, Baohong Jiang, Yu Gu, Zhaoyang Yue, Ying Liu, Zhiwei Lei, Ge Yang, Minhua Deng, Xuelong Zhang, Zhen Luo, Yongkui Li, Qiwei Zhang, Xuepei Zhang, Jianguo Wu, Chunyu Huang, Pan Pan, Fangjian Zhou, Ning Wang","doi":"10.1186/s12943-024-02153-1","DOIUrl":"https://doi.org/10.1186/s12943-024-02153-1","url":null,"abstract":"SARS-CoV-2, a highly contagious coronavirus, is responsible for the global pandemic of COVID-19 in 2019. Currently, it remains uncertain whether SARS-CoV-2 possesses oncogenic or oncolytic potential in influencing tumor progression. Therefore, it is important to evaluate the clinical and functional role of SARS-CoV-2 on tumor progression. Here, we integrated bioinformatic analysis of COVID-19 RNA-seq data from the GEO database and performed functional studies to explore the regulatory role of SARS-CoV-2 in solid tumor progression, including lung, colon, kidney and liver cancer. Our results demonstrate that infection with SARS-CoV-2 is associated with a decreased expression of genes associated with cancer proliferation and metastasis in lung tissues from patients diagnosed with COVID-19. Several cancer proliferation or metastasis related genes were frequently downregulated in SARS-CoV-2 infected intestinal organoids and human colon carcinoma cells. In vivo and in vitro studies revealed that SARS-CoV-2 nucleocapsid (N) protein inhibits colon and kidney tumor growth and metastasis through the N-terminal (NTD) and the C-terminal domain (CTD). The molecular mechanism indicates that the N protein of SARS-CoV-2 interacts with YBX1, resulting in the recruitment of PKM mRNA into stress granules mediated by G3BP1. This process ultimately destabilizes PKM expression and suppresses glycolysis. Our study reveals a new function of SARS-CoV-2 nucleocapsid protein on tumor progression.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"8 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}