Neoplasia最新文献

{"title":"Clinical and genetic drivers of oligo-metastatic disease in colon cancer","authors":"Alessandro Ottaiano ,&nbsp;Mariachiara Santorsola ,&nbsp;Roberto Sirica ,&nbsp;Annabella Di Mauro ,&nbsp;Antonella Di Carlo ,&nbsp;Monica Ianniello ,&nbsp;Francesco Sabbatino ,&nbsp;Rosa Castiello ,&nbsp;Francesca Del Peschio ,&nbsp;Marco Cascella ,&nbsp;Francesco Perri ,&nbsp;Maurizio Capuozzo ,&nbsp;Nicola Martucci ,&nbsp;Edoardo Mercadante ,&nbsp;Valentina Borzillo ,&nbsp;Rossella Di Franco ,&nbsp;Francesco Izzo ,&nbsp;Vincenza Granata ,&nbsp;Carmine Picone ,&nbsp;Antonella Petrillo ,&nbsp;Giovanni Savarese","doi":"10.1016/j.neo.2024.101111","DOIUrl":"10.1016/j.neo.2024.101111","url":null,"abstract":"<div><h3>Background</h3><div>Oligo-metastatic disease (OMD) in colon cancer patients exhibits distinct clinical behavior compared to poly-metastatic disease (PMD), with a more responsive and indolent course. This study aims to identify clinical and biological factors uniquely associated with oligo-metastatic behavior.</div></div><div><h3>Methods</h3><div>Metastatic colon cancer patients from an academic center underwent genetic characterization. OMD was defined as ≤3 lesions per organ, each with a total diameter &lt;70 mm and none exceeding 25 mm. Tumor DNA sequencing by NGS utilized the TruSight Oncology 500 kit. Overall survival (OS) was determined from metastasis diagnosis until death using Kaplan–Meier analysis. Multivariate Cox regression examined prognostic links between clinicopathological and genetic factors. Associations with metastatic patterns were evaluated using Chi-square.</div></div><div><h3>Results</h3><div>The analysis involved 104 patients (44 with OMD, 60 with PMD). OMD was more prevalent in males (<em>P</em> = 0.0299) and with single organ involvement (<em>P</em> = 0.0226). Multivariate analysis adjusted for age (&gt;70 vs. &lt;70 years), gender (male vs. female), tumor side (right vs. left), metastatic involvement (more than one site vs. one site), response to first-line therapy (disease control vs. no disease control), and <em>RAS</em>/<em>BRAF</em> variants (wild-type vs. mutated) identified OMD vs. PMD as the strongest independent predictor of survival (HR: 0.14; 95 % CI: 0.06-0.33; <em>P</em>&lt;0.0001). OMD patients exhibited distinct molecular characteristics, including lower frequencies of <em>BRAF</em> p.V600E (P=0.0315) and <em>KRAS</em> mutations (P=0.0456), as well as a higher frequency of high tumor mutational burden (<em>P</em>=0.0127). Additionally, by integrating data from public datasets and our case study, we hypothesize that some gene alterations (i.e.: <em>BRAF, SMAD4, RAF1</em>, and <em>mTOR</em>) may prevent OMD occurrence.</div></div><div><h3>Conclusion</h3><div>OMD, characterized by male predominance, single-site involvement, and distinct molecular features in colon cancer, suggests the need for tailored management strategies.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101111"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incidence, mortality, and global burden of retinoblastoma in 204 countries worldwide from 1990 to 2021: Data and systematic analysis from the Global Burden of Disease Study 2021","authors":"Linyan Wang ,&nbsp;Jianing Chen ,&nbsp;Yunhan Shen ,&nbsp;Grace Loy Ming Hooi ,&nbsp;Shuohan Wu ,&nbsp;Feng Xu ,&nbsp;Hao Pei ,&nbsp;Jianpeng Sheng ,&nbsp;Tiansheng Zhu ,&nbsp;Juan Ye","doi":"10.1016/j.neo.2024.101107","DOIUrl":"10.1016/j.neo.2024.101107","url":null,"abstract":"<div><h3>Background</h3><div>Retinoblastoma (Rb), the primary intraocular malignancy in children, poses significant risks, yet its overall burden remains inadequately assessed. This study aims to analyze global Rb trends using Global Burden of Disease, Injuries, and Risk Factors study (GBD) 2021 data.</div></div><div><h3>Methods</h3><div>GBD 2021 data was analyzed to assess Rb incidence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021. Average annual percentage changes (AAPCs) were calculated across genders, age groups (0-9 years), and geographic regions categorized by socio-demographic index (SDI) quintiles.</div></div><div><h3>Results</h3><div>From 1990 to 2021, the global Rb age-standardized incidence rate (ASIR) increased from 0.08 (per 100,000, range: 0.05 to 0.10) to 0.09 (per 100,000, range: 0.06 to 0.13). ASIR was not significantly correlated with SDI (R = -0.095, P = 0.18), while age-standardized DALYs rate (R = -0.693, P &lt; 0.001) and age-standardized mortality rate (ASMR) (R = -0.71, P &lt; 0.001) were significantly and negatively correlated with SDI. Increases in ASIR were concentrated in Asia, Europe, and northern and southern Africa. The highest standardized DALYs and ASMR were noted in certain countries in Asia, Europe, and South Africa. Among age groups, the highest disease burdens were observed in the “0-6 days” and “2-4 years” groups. There were no significant gender differences in Rb burden globally.</div></div><div><h3>Conclusions</h3><div>Despite global progress, regions with lower SDI face elevated Rb burden and mortality. Females exhibit higher burdens during infancy, necessitating further investigation. Effective Rb management in resource-limited areas requires international collaboration focused on health education, early diagnosis, and prenatal screening for high-risk families.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101107"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"True cancer stem cells exhibit relative degrees of dormancy and genomic stability","authors":"Sanford H. Barsky ,&nbsp;Krista Mcphail ,&nbsp;Justin Wang ,&nbsp;Jordan Dillard ,&nbsp;Crystal J. Beard ,&nbsp;Yin Ye","doi":"10.1016/j.neo.2025.101127","DOIUrl":"10.1016/j.neo.2025.101127","url":null,"abstract":"<div><h3>Background</h3><div>Cancer stem cells in human tumors have been defined by stem cell markers, embryonal signaling pathways and characteristic biology, ie., namely the ability to repopulate the proliferating population. However, even if these properties can be demonstrated within a tumor cell subpopulation, it does not mean that they are truly hierarchical stem cells because they could have been derived from the proliferating population in a reversible manner.</div></div><div><h3>Methods</h3><div>Using a human PDX, Mary-X, that overall expressed a strong cancer stem cell phenotype, the study conducted both GPP-labelled retroviral transfection and fluorescent microsphere uptake studies to distinguish proliferating from dormant cells and array CGH to identify regions of amplifications (gains) and deletions (losses) on the overall Mary-X population and then applied derived probes by FISH on individual cells to identify a genomically stable subpopulation.</div></div><div><h3>Results</h3><div>Whereas 97-99 % of the cells expressed retroviral GFP and not fluorescent particles and showed numerous gene amplifications and deletions, approximately 1-3 % of the cells showed the opposite. The subpopulation with the retained fluorescent microspheres and exhibiting genomic stability was significantly smaller in size than their GFP-expressing and genomically unstable counterparts. Sorting Mary-X spheroids on the basis of either CD133 or ALDH positivity further enriched for this subpopulation.</div></div><div><h3>Conclusions</h3><div>These studies indicate that a truly biological cancer stem cell subpopulation exists that exhibits both dormancy and genomic stability. This subpopulation could not have been derived from the proliferating and resulting genomically unstable population and therefore represents a truly hierarchical stem cell subpopulation capable of only unidirectional differentiation.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101127"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “p85α Inactivates MMP-2 and Suppresses Bladder Cancer Invasion by Inhibiting MMP-14 Transcription and TIMP-2 Degradation” [Neoplasia (2019) 21, 908–920]","authors":"Jingjing Wang ,&nbsp;Ning Zhang ,&nbsp;Minggang Peng ,&nbsp;Xiaohui Hua ,&nbsp;Chao Huang ,&nbsp;Zhongxian Tian ,&nbsp;Qipeng Xie ,&nbsp;Junlan Zhu ,&nbsp;Jingxia Li ,&nbsp;Haishan Huang ,&nbsp;Chuanshu Huang","doi":"10.1016/j.neo.2024.101095","DOIUrl":"10.1016/j.neo.2024.101095","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101095"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling","authors":"Thomas M.B. Ware ,&nbsp;Adilson Fonseca Teixeira ,&nbsp;Josephine Iaria ,&nbsp;Rodney B. Luwor ,&nbsp;Hong-Jian Zhu","doi":"10.1016/j.neo.2024.101110","DOIUrl":"10.1016/j.neo.2024.101110","url":null,"abstract":"<div><div>Glioblastoma is the most aggressive type of brain cancer, but treatment improvements for glioblastoma patients remain stagnated for over 20 years. This is despite the large number of clinical trials that have attempted to replicate the success of therapeutics developed for other cancer types. This discrepancy highlights the urgent need to decipher the unique biology of glioblastomas. Here, we show that glioblastoma tumour cells are highly plastic, integrating into blood vessel walls to disseminate throughout the brain. This relies on the transdifferentiation of glioblastoma tumor cells into endothelial-like cells in a process we termed endothelialisation. Mechanistically, in addition to TGF-β-ALK5-Smad2/3 signaling, glioblastoma tumour cells also activate TGF-β-ALK1-Smad1/5 signaling – a mechanism previously thought to be limited to endothelial cells. Consequently, therapeutic targeting of TGF-β-ALK1-Smad1/5 activity impaired endothelialisation-driven glioblastoma progression. This study identifies a previously unknown component of glioblastoma biology and establishes a therapeutic approach to reduce the progression of this disease.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101110"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat","authors":"Tamara Zenz ,&nbsp;Robert Jenke ,&nbsp;Denys Oliinyk ,&nbsp;Sandra Noske ,&nbsp;René Thieme ,&nbsp;Tim Kahl ,&nbsp;Ines Gockel ,&nbsp;Florian Meier-Rosar ,&nbsp;Achim Aigner ,&nbsp;Thomas RH Büch","doi":"10.1016/j.neo.2024.101121","DOIUrl":"10.1016/j.neo.2024.101121","url":null,"abstract":"<div><h3>Introduction</h3><div>Histone deacetylase inhibitors (HDACi) have shown promising preclinical activity in gastric cancer cells; unfortunately, however, these could not be confirmed in clinical trials. This highlights the need for the identification of underlying reasons, which may also provide the basis for possible combination therapies. Here, we delineated the effects of HDACi on components of EGFR signalling in gastric cancer cells.</div></div><div><h3>Methods</h3><div>We investigated entinostat effects on EGFR and amphiregulin (AREG) expression in various cell line- and primary patient tumor-based <em>in vitro, ex vivo</em> and <em>in vivo</em> models, on the mRNA and protein level. Based on these results, a combined entinostat plus EGFR inhibitor erlotinib treatment <em>in vitro</em> and <em>in vivo</em> was studied.</div></div><div><h3>Results</h3><div>Proteomics analyses in gastric cancer cells treated with entinostat revealed a marked upregulation of EGFR in the majority of cell lines and an even more robust induction of the EGFR ligand AREG. This was confirmed in a panel of different cell lines <em>in vitro</em>, in tumor tissue-slice cultures <em>ex vivo</em> and in cell line- or patient-derived tumor xenografts in mice. Since previous studies in other tumor entities showed a downregulation of EGFR by HDACi, our findings thus indicate essential differences in the adaptive response of gastric carcinoma cells. Moreover, our results provided the basis for combined entinostat + EGFR inhibitor (erlotinib) treatment, and indeed we demonstrate synergistic effects in combination therapy studies.</div></div><div><h3>Conclusion</h3><div>Our findings establish the profound upregulation of the EGFR/AREG axis by entinostat as starting point for a rational combination therapy in gastric carcinoma.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101121"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic and proteomic profiling identifies feline fibrosarcoma as clinically amenable model for aggressive sarcoma subtypes","authors":"Mikiyo Weber ,&nbsp;Daniel Fuchs ,&nbsp;Amiskwia Pöschel ,&nbsp;Erin Beebe ,&nbsp;Zuzana Garajova ,&nbsp;Armin Jarosch ,&nbsp;Laura Kunz ,&nbsp;Witold Wolski ,&nbsp;Lennart Opitz ,&nbsp;Franco Guscetti ,&nbsp;Mirja C. Nolff ,&nbsp;Enni Markkanen","doi":"10.1016/j.neo.2024.101104","DOIUrl":"10.1016/j.neo.2024.101104","url":null,"abstract":"<div><div>Fibrosarcomas (FSA) are malignant mesenchymal tumors characterized by low chemo- and radiosensitivity. Development of novel treatment strategies for human adult FSA is hindered by the low incidence and the absence of suitable clinical models. Interestingly, aggressive FSA occur more frequently in domestic cats, hence potentially representing a clinically amenable model to assess novel therapies such as targeted imaging or theranostics. However, a lack of molecular characterization of FSA and adjacent normal tissue (NT) in both species hinders identification of tumor-specific targets and undermines the translational potential of feline FSA. Combining laser-capture microdissection, RNAsequencing and liquid chromatography-tandem mass spectrometry, we perform comprehensive profiling of 30 feline FSA and matched skeletal muscle, adipose and connective tissue. Clear inter-tissue differences allow identification of significantly upregulated and tumor-exclusive features that represent potential targets for diagnostic and therapeutic approaches. While feline FSA are characterized by hyperactive EIF2, TP53 and MYC signaling, immune-related and neuronal pathways emerge as modulators of tumor aggressiveness and immunosuppression. A high degree of molecular similarity with canine and adult FSA allows identification of tumor targets that are conserved across species. Significant enrichment in DNA repair pathways in feline FSA correlate with aggressive clinical behavior in human soft-tissue sarcoma. Finally, we leverage the molecular profiles to identify vulnerabilities, including sensitivity to ATR and PARP inhibition as potential treatment for feline FSA. In conclusion, this detailed landscape provides a rich resource to identify target candidates and therapeutic vulnerabilities within and across species and supports feline FSA as relevant models for the human disease.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101104"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11713505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Informatics strategies for early detection and risk mitigation in pancreatic cancer patients","authors":"Di Jin ,&nbsp;Najeeb Ullah Khan ,&nbsp;Wei Gu ,&nbsp;Huijun Lei ,&nbsp;Ajay Goel ,&nbsp;Tianhui Chen","doi":"10.1016/j.neo.2025.101129","DOIUrl":"10.1016/j.neo.2025.101129","url":null,"abstract":"<div><div>This review provides a comprehensive overview of the current landscape in pancreatic cancer (PC) screening, diagnosis, and early detection. This emphasizes the need for targeted screening in high-risk groups, particularly those with familial predispositions and genetic mutations, such as BRCA1, BRCA2, and PALB2. This review highlights the sporadic nature of most PC cases and significant risk factors, including smoking, alcohol consumption, obesity, and diabetes. Advanced imaging techniques, such as Endoscopic Ultrasound (EUS) and Contrast-Enhanced Harmonic Imaging (CEH-EUS), have been discussed for their superior sensitivity in early detection. This review also explores the potential of novel biomarkers, including those found in body fluids, such as serum, plasma, urine, and bile, as well as the emerging role of liquid biopsy technologies in analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes. AI-driven approaches, such as those employed in Project Felix and CancerSEEK, have been highlighted for their potential to enhance early detection through deep learning and biomarker discovery. This review underscores the importance of universal genetic testing and the integration of AI with traditional diagnostic methods to improve outcomes in high-risk individuals. Additionally, this review points to future directions in PC diagnostics, including next-generation imaging, molecular biomarkers, and personalized medicine, aiming to overcome current diagnostic challenges and improve survival rates. Ultimately, the review advocates the adoption of informatics and AI-driven strategies to enhance early detection, reduce morbidity, and save lives in the fight against pancreatic cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101129"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The chemokine CX3CL1 promotes intraperitoneal tumour growth despite enhanced T-cell recruitment in ovarian cancer","authors":"Stefanie Seitz ,&nbsp;Tobias F. Dreyer ,&nbsp;Christoph Stange ,&nbsp;Katja Steiger ,&nbsp;Dirk Wohlleber ,&nbsp;Martina Anton ,&nbsp;Thuý An Pham ,&nbsp;Dominique Sauter-Peschke ,&nbsp;Ute Reuning ,&nbsp;Gabriele Multhoff ,&nbsp;Wilko Weichert ,&nbsp;Marion Kiechle ,&nbsp;Viktor Magdolen ,&nbsp;Holger Bronger","doi":"10.1016/j.neo.2025.101130","DOIUrl":"10.1016/j.neo.2025.101130","url":null,"abstract":"<div><div>T-cell recruiting chemokines are required for a successful immune intervention in ovarian cancer, and also for the efficacy of modern anticancer agents such as PARP inhibitors. The chemokine CX3CL1 recruits tumour-suppressive T-cells into solid tumours, but also mediates cell–cell adhesions, e.g. of tumour cells, through its membrane-bound form. So far, its role in ovarian cancer has only been rudimentarily addressed. We show that high CX3CL1 expression significantly correlates with worsened survival in human high-grade serous ovarian cancer (n=219). In preclinical ovarian cancer, CX3CL1 plays a dual role, as it enhances the adaptive anti-tumour response, but overall still promotes tumour growth, the latter as a feature of the intraperitoneal environment. Moreover, PARP inhibitors are able to increase CX3CL1 release from human ovarian cancer cells. Collectively, our study shows that CX3CL1 is a driver of intraperitoneal tumour growth in ovarian cancer, a feature that may compromise the anticancer effect of CX3CL1-inducing PARP inhibitors.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101130"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of TUBB3 as an immunotherapy target in lung cancer by genome wide in vivo CRISPR screening","authors":"Dan Zhao ,&nbsp;Ravindra Deshpande ,&nbsp;Kerui Wu ,&nbsp;Abhishek Tyagi ,&nbsp;Sambad Sharma ,&nbsp;Shih-Ying Wu ,&nbsp;Fei Xing ,&nbsp;Stacey O'Neill ,&nbsp;Jimmy Ruiz ,&nbsp;Feng Lyu ,&nbsp;Kounosuke Watabe","doi":"10.1016/j.neo.2024.101100","DOIUrl":"10.1016/j.neo.2024.101100","url":null,"abstract":"<div><div>Recent development of immune checkpoint inhibitors has revolutionized cancer immunotherapy. Although these drugs show dramatic effects on a subset of cancer patients, many other tumors are non-responsive and the pathological mechanism of the resistance is largely unknown. To identify genes underlying anti-PD-1 immunotherapy resistance using a systematic approach, we performed an <em>in vivo</em> genome wide CRISPR screening in lung cancer cells. We integrated our results with multi-omics clinical data and performed both <em>in vitro</em> and <em>in vivo</em> assays to evaluate the role of the top candidate in regulating cytotoxic T cell killing. We identified TUBB3 as a potential target to overcome the resistance and enhance the efficacy of anti-PD-1 immunotherapy. TUBB3 expression is upregulated in lung cancer patients, and its higher expression correlates with poorer patients’ survival. We found that TUBB3 expression was significantly elevated in the non-responders compared to responders in our patient cohort that received immunotherapies. Importantly, the results of our preclinical experiments showed that inhibition of TUBB3 with a small molecule inhibitor synergized with anti-PD-1 treatment and enhanced tumor cell killing by cytotoxic T cells. Consistently, anti-PD-1 resistant cells showed significantly higher expression of TUBB3; however, TUBB3 inhibition rendered the resistant cells more susceptible to T cell killing. Mechanistic studies revealed that blocking TUBB3 suppressed the expression of PD-L1 through the EMT-related SNAI1 gene. Our results provide a rationale for a novel combination therapy consisting of the TUBB3 inhibition and anti-PD-1 immunotherapy for lung cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101100"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}