Neoplasia最新文献

{"title":"Therapeutic benefit of the dual ALK/FAK inhibitor ESK440 in ALK-driven neuroblastoma","authors":"Seema Chugh ,&nbsp;Jean C. Tien ,&nbsp;Jennifer Hon ,&nbsp;Carson Kenum ,&nbsp;Rahul Mannan ,&nbsp;Yunhui Cheng ,&nbsp;Chi Chiang Li ,&nbsp;Zainab I. Taher ,&nbsp;Andrew D. Delekta ,&nbsp;Pushpinder Singh Bawa ,&nbsp;Ingrid J. Apel ,&nbsp;Stephanie J. Miner ,&nbsp;Xuhong Cao ,&nbsp;Rohit Mehra ,&nbsp;Saravana M. Dhanasekaran ,&nbsp;Yuanyuan Qiao ,&nbsp;Rajen Mody ,&nbsp;Arul M. Chinnaiyan","doi":"10.1016/j.neo.2024.100964","DOIUrl":"10.1016/j.neo.2024.100964","url":null,"abstract":"<div><div>Neuroblastoma (NB) is a predominantly pediatric cancer with greater than 90% of cases arising in children under the age of five. More than half of patients have metastases detected at diagnosis, and high-risk disease is associated with five-year survival rates of only 50–60 %. Standard therapy involves highly toxic chemotherapy, surgery, radiation, and immunotherapy, and less toxic, more specific targeted therapies are urgently needed. Genomic studies have identified common driver aberrations in high-risk NB, such as <em>MYCN</em> amplification. In addition, a proportion of high-risk patients harbor amplification or activating mutations in anaplastic lymphoma kinase (<em>ALK</em>), and co-occurrence of <em>ALK</em> mutations and <em>MYCN</em> amplification have been associated with aggressive disease. In this study, we analyzed the efficacy of a Phase Ia-cleared, orally bioavailable dual ALK and focal adhesion kinase (FAK) inhibitor, ESK440, in multiple preclinical NB models. ESK440 potently inhibited proliferation of NB cell lines, with increased sensitivity in cell lines harboring <em>ALK</em> aberrations. ALK, FAK, and downstream target activation were rapidly decreased upon ESK440 treatment, and this was associated with impaired cellular migration and invasion. Importantly, ESK440 treatment also decreased MYCN levels. NB cell line and patient-derived xenograft studies showed significant reduction in tumor growth in ESK440-treated mice with no signs of toxicity. In certain NB models, ESK440 showed comparable or enhanced efficacy to lorlatinib, another clinical ALK inhibitor, and a lorlatinib-resistant cell line (COG-N-561 LR) retained sensitivity to ESK440. These preclinical results indicate that ESK440 is a promising targeted agent for ALK-driven NB and support future clinical studies to evaluate its efficacy in NB patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 100964"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139374349","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":"Tackling ALT-positive neuroblastoma: is it time to redefine risk classification systems? A systematic review with IPD meta-analysis","authors":"Marta Avinent-Pérez ,&nbsp;Frank Westermann ,&nbsp;Samuel Navarro ,&nbsp;Amparo López-Carrasco ,&nbsp;Rosa Noguera","doi":"10.1016/j.neo.2024.101106","DOIUrl":"10.1016/j.neo.2024.101106","url":null,"abstract":"<div><h3>Background</h3><div>The heterogeneous prognosis in neuroblastoma, shaped by telomere maintenance mechanisms (TMMs), notably the alternative lengthening of telomeres (ALT) pathway, necessitates a refined risk classification for high-risk patients. Current systems often lack precision, hindering tailored treatment approaches. This individual participant data (IPD) meta-analysis of survival among ALT-positive patients aims to improve risk classification systems, enhancing therapeutic strategies and patient outcomes.</div></div><div><h3>Methods</h3><div>Following PRISMA-IPD guidelines, we conducted a comprehensive review of neuroblastoma patients retrieved from PubMed, Scopus, and Embase databases until March-2024. Patients were stratified into ALT-positive and TMM-negative subgroups. Overall and event-free survival probabilities were evaluated.</div></div><div><h3>Results</h3><div>In our cohort of 293 patients (156 ALT-positive, 137 TMM-negative) obtained from eight different studies, ALT-positive individuals displayed lower survival rates than TMM-negative patients. Non-stage 4 ALT-positive patients had reduced overall and event-free survival probabilities compared to their TMM-negative counterparts, indicating potential misclassification. Stage 4 ALT-positive patients similarly showed poorer survival outcomes than non-stage 4 TMM-negative patients, underscoring the significance of ALT in patient prognosis.</div></div><div><h3>Conclusions</h3><div>Our study highlights poorer outcomes in ALT-positive neuroblastoma patients, emphasizing the need to integrate TMM status into international risk classification guidelines. Standardizing TMM assessment is key for refining treatment strategies, considering the unique biology of ALT-positive patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101106"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904047","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":"Kinomic profiling to predict sunitinib response of patients with metastasized clear cell Renal Cell Carcinoma","authors":"Jeannette C. Oosterwijk-Wakka ,&nbsp;Liesbeth Houkes ,&nbsp;Loes F.M. van der Zanden ,&nbsp;Lambertus A.L.M. Kiemeney ,&nbsp;Kerstin Junker ,&nbsp;Anne Y Warren ,&nbsp;Tim Eisen ,&nbsp;Ulrich Jaehde ,&nbsp;Marius T Radu ,&nbsp;Rob Ruijtenbeek ,&nbsp;Egbert Oosterwijk","doi":"10.1016/j.neo.2024.101108","DOIUrl":"10.1016/j.neo.2024.101108","url":null,"abstract":"<div><h3>Introduction</h3><div>Treatment with Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor (TKI) has increased the progression-free survival (PFS) and overall-survival (OS) of patients with metastasized renal cell carcinoma (mRCC). With modest OS improvement and variable response and toxicity predictive and/or prognostic biomarkers are needed to personalize patient management: Prediction of individual TKI therapy response and resistance will increase successful treatment outcome while reducing unnecessary drug use and expense. The aim of this study was to investigate whether kinase activity analysis can predict sunitinib response and/or toxicity using tissue samples obtained from primary clear cell RCC (ccRCC) from a cohort of clinically annotated patients with mRCC receiving sunitinib as first-line treatment.</div></div><div><h3>Materials and Methods</h3><div>EuroTARGET partners collected ccRCC and matched normal kidney tissue samples immediately after surgery, snap-frozen and stored at -80°C until use. Phosphotyrosine-activity profiling was performed using PamChip® peptide microarrays (144 peptides derived from known phosphorylation sites in Protein Tyrosine Kinase substrates) of lysed tissue samples (5 µg protein input) of 163 mRCC patients. Evolve software Was used to analyze kinome profiles and Bionavigator was used for unsupervised and supervised clustering. The kinexus kinase predictor (<span><span>www.phosphonet.ca</span><svg><path></path></svg></span>) was used to analyze the peptide lists within the clusters.</div></div><div><h3>Results</h3><div>Kinome data was available from 94 patients who received sunitinib as 1st-line treatment and had complete follow-up of their clinical data (PFS, OS and toxicity) for at least 6 months. Matched normal tissue was available from 14 mRCC patients. Supervised clustering of basal kinome activity could correctly classify mRCC patients with PFS &gt;9 months <em>versus</em> PFS&lt;9 months with an accuracy of 61 %. Unsupervised hierarchical clustering revealed 3 major clusters related to immune signaling, VEGF pathway, and immune signaling/cell adhesion. Basal kinase activity levels of patients with short PFS were substantially higher compared to patients who experienced extended PFS.</div></div><div><h3>Discussion/Conclusion</h3><div>Based on kinase levels ccRCC tumors can be subdivided into 3 clusters which may reflect the aggressiveness of these tumors. The accuracy of response prediction of 61 % based on basal kinase levels is too low to justify implementation. STK assays may help to predict sunitinib toxicity and guide clinical management. Additionally, it is possible that mRCC patients with an immune kinase signature are better checkpoint inhibitor candidates, but this needs to be studied.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101108"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899599","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":"Recent advances of photodiagnosis and treatment for head and neck squamous cell carcinoma","authors":"Yining Zhang ,&nbsp;Zhenfang Li ,&nbsp;Chengchi Zhang ,&nbsp;Chengying Shao ,&nbsp;Yanting Duan ,&nbsp;Guowan Zheng ,&nbsp;Yu Cai ,&nbsp;Minghua Ge ,&nbsp;Jiajie Xu","doi":"10.1016/j.neo.2024.101118","DOIUrl":"10.1016/j.neo.2024.101118","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma (HNSCC) are the most common type of head and neck tumor that severely threatens human health due to its highly aggressive nature and susceptibility to distant metastasis. The diagnosis of HNSCC currently relies on biopsy and histopathological examination of suspicious lesions. However, the early mucosal changes are subtle and difficult to detect by conventional oral examination. As for treatment, surgery is still the primary treatment modality. Due to the complex anatomy and the lack of intraoperative modalities to accurately determine the incision margins, surgeons are in a dilemma between extensive tumor removal and improving the quality of patient survival. As more knowledge is gained about HNSCC, the increasing recognition of the value of optical imaging has been emphasized. Optical technology offers distinctive possibilities for early preoperative diagnosis, intraoperative real-time visualization of tumor margins, sentinel lymph node biopsies, phototherapy. Fluorescence imaging, narrow-band imaging, Raman spectroscopy, optical coherence tomography, hyperspectral imaging, and photoacoustic imaging have been reported for imaging HNSCC. This article provides a comprehensive overview of the fundamental principles and clinical applications of optical imaging in the diagnosis and treatment of HNSCC, focusing on identifying its strengths and limitations to facilitate advancements in this field.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101118"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899671","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":"β-Catenin mediated TAM phenotype promotes pancreatic cancer metastasis via the OSM/STAT3/LOXL2 axis","authors":"Yijia Zhang ,&nbsp;Xinya Zhu ,&nbsp;Liyuan Chen ,&nbsp;Tianyu Gao ,&nbsp;Guang Chen ,&nbsp;Jin Zhu ,&nbsp;Guoyu Wang ,&nbsp;Daiying Zuo","doi":"10.1016/j.neo.2024.101096","DOIUrl":"10.1016/j.neo.2024.101096","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and dismal prognosis, largely attributed to its unique tumor microenvironment. However, the molecular mechanisms by which tumor-associated macrophages (TAMs) promote PDAC progression, particularly the role of β-catenin signaling in regulating TAM phenotype and function, remain incompletely understood.</div><div>Initially, we performed comprehensive analyses of RNA-seq and single-cell RNA-seq (scRNA-seq) datasets to investigate OSM and LOXL2 expression patterns in PDAC. Subsequently, the regulatory relationship between β-catenin and OSM in TAMs was examined using THP-1-derived macrophages. Furthermore, the functional impact of TAM-derived OSM on PDAC progression was evaluated through <em>in vitro</em> co-culture systems and an <em>in vivo</em> Panc02 lung metastasis model. Additionally, mechanistic studies employed pharmacological inhibitors and genetic approaches targeting β-catenin, OSM, and STAT3 signaling.</div><div>Notably, elevated expression of OSM and LOXL2 in PDAC specimens significantly correlated with poor patient survival. Intriguingly, scRNA-seq analysis revealed that β-catenin signaling was uniquely activated in TAMs among immune cells, which consequently regulated both TAM polarization and OSM expression. These OSM-expressing TAMs exhibited a distinct hybrid M1/M2 phenotype. Besides, our transcriptional profiling of TAMs revealed concurrent activation of both pro- and anti-inflammatory programs, with enrichment in Wnt signaling pathways. RNA-seq analysis of PDAC cells exposed to TAM-derived factors demonstrated enhanced mesenchymal transition and stemness properties, with direct enrichment of OSM signaling and extracellular matrix remodeling pathways. Mechanistically, β-catenin activation directly regulated both TAM phenotype and OSM expression, while TAM-conditioned medium enhanced PDAC cell migration, invasion, and lung metastasis. Importantly, inhibition of β-catenin signaling simultaneously altered TAM polarization and reduced OSM expression, which substantially attenuated epithelial-mesenchymal transition (EMT) in co-cultured PDAC cells. Moreover, STAT3 inhibition abolished OSM-induced LOXL2 expression and subsequent EMT programming.</div><div>Collectively, we identified a novel β-catenin/OSM-STAT3/LOXL2 signaling axis mediating TAM-induced PDAC progression. This pathway not only elucidates a previously unrecognized mechanism of β-catenin-mediated regulation of TAM function and phenotype but also presents potential therapeutic targets for intervention.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101096"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911030","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":"Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer","authors":"Xumin Zhou ,&nbsp;Shilong Cheng ,&nbsp;Zhongjie Chen ,&nbsp;Jinming Zhang ,&nbsp;Jiaqi Wang ,&nbsp;Qiang Li ,&nbsp;Xumin Zhou","doi":"10.1016/j.neo.2024.101109","DOIUrl":"10.1016/j.neo.2024.101109","url":null,"abstract":"<div><div>Immunotherapy with checkpoint inhibitors produced significant clinical responses in a subset of cancer patients who were resistant to prior therapies. However, Castration-resistant prostate cancer (CRPC) is seriously lack of T cell infiltration, which greatly limits the clinical application of immunotherapy, but the mechanism is unclear. In the present study, in silico analyses and experimental data show that HnRNP L was significantly negatively correlated with CD4+ and CD8+ <em>T</em> cells infiltration in patients; besides, we found deficiency of HnRNP L recruites CD4+ and CD8+ <em>T</em> cells infiltration and impairs tumorigenesis. Mechanically, HnRNP L enhanced the translation of c-Myc and then promoted CXCL8 secretion via alternative splicing of EIF4G1. In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP <span>l</span>-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101109"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899620","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":"USP14 inhibition by degrasyn induces YAP1 degradation and suppresses the progression of radioresistant esophageal cancer","authors":"Fang Yuan ,&nbsp;Juan Xu ,&nbsp;Lingmei Xuan ,&nbsp;Chan Deng ,&nbsp;Wei Wang ,&nbsp;Rong Yang","doi":"10.1016/j.neo.2024.101101","DOIUrl":"10.1016/j.neo.2024.101101","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Radiotherapy is a major modality for esophageal cancer (ESCA) treatment, yet radioresistance severely hampers its therapeutic efficacy. Ubiquitin-specific peptidase 14 (USP14) is a novel deubiquitinase and can mediate cancer cells’ response to irradiation, although the underlying mechanism remains unclear, including in ESCA.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;To evaluate the expression of USP14 in ESCA tissues or cells, we used RNA-Seq, immunoblotting, co-immunoprecipitation (Co-IP), ubiquitination, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence assays in this investigation. Additionally, we used CCK8, cloning, and migration tests to examine the proliferation and migration of ESCA cells. We also used transplantation tumor mouse model to investigate the course of the cancer cell growth. Finally, we looked into the biological processes linked to USP14 using gene set enrichment analysis (GSEA), which was later verified.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;We observed a significant upregulation of USP14 in human ESCA tissues and cell lines, especially in those with radioresistance. Moreover, USP14 knockdown significantly restrained the proliferation and inhibited the radiation tolerance of ESCC cells. Here, we identified a potential inhibitor of USP14, Degrasyn (DGS), and investigated its regulatory effects on ESCA radioresistance and progression. We found that DGS had marked antiproliferative effects in radiosensitive ESCA cell lines. Notably, a low dose of DGS significantly enhanced the sensitivity of radioresistant ESCA cells to irradiation, as shown by the significantly reduced cell proliferation, migration, and invasion. Furthermore, the combination of DGS and X-ray irradiation strongly induced DNA damage in radioresistant ESCA cell lines by increasing the phosphorylation levels of H2AX (γ-H2AX) and checkpoint kinase 1/ataxia-telangiectasia-mutated-and-Rad3-related kinase (CHK1/ATR) signaling. Animal experiments confirmed the effective role of the DGS and X-ray combined treatment in reducing tumor growth and irradiation tolerance of ESCA &lt;em&gt;in vivo&lt;/em&gt; with undetectable toxicity. Importantly, the promotive and malignant biological behaviors of ESCA cells suppressed by the DGS/X-ray combination treatment were almost eliminated by USP14 overexpression, along with the abolished DNA damage process. Mechanistically, we found that USP14 could interact with Yes-associated protein 1 (YAP1) and induce its deubiquitination in radioresistant ESCA cells. Interestingly, we discovered that DGS/X-ray co-therapy significantly reduced the stability of YAP1 and induced its ubiquitination in radioresistant ESCA cells. More importantly, the proliferation, epithelial-mesenchymal tansition (EMT) process, and DNA damage regulated by DGS/X-ray and USP14 knockdown were significantly eliminated when YAP1 was overexpressed in radioresistant ESCA cells.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;These data","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101101"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830520","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":"Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function","authors":"Annat Raiter ,&nbsp;Yael Barhum ,&nbsp;Julia Lipovetsky ,&nbsp;Chen Menachem ,&nbsp;Sharona Elgavish ,&nbsp;Shmuel Ruppo ,&nbsp;Yehudit Birger ,&nbsp;Shai Izraeli ,&nbsp;Orna Steinberg-Shemer ,&nbsp;Rinat Yerushalmi","doi":"10.1016/j.neo.2024.101117","DOIUrl":"10.1016/j.neo.2024.101117","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype that accounts for 10-15 % of breast cancer. Current treatment of high-risk early-stage TNBC includes neoadjuvant chemo-immune therapy. However, the substantial variation in immune response prompts an urgent need for new immune-targeting agents. This requires a comprehensive understanding of TNBC's tumor microenvironment. We recently demonstrated that Galectin-3 (Gal-3) binding protein/Gal-3 complex secreted by TNBC cells induces immunosuppression, through inhibiting CD45 signaling in T cells. Here, we further investigated the interaction between secreted Gal-3 and T cells in TNBC.</div><div>Using CRISPR/Cas9 gene editing of the TNBC MDA-MB-231 cell-line, we obtained Gal-3 negative^(neg) clones. We studied these in an <em>in-vitro</em> model, co-cultured with peripheral blood mononuclear cells (PBMC) to imitate immune-tumor interaction, and in an <em>in-vivo</em> model, when implanted in mice.</div><div>Gal-3^neg tumors in mice had decelerated tumor growth after PBMC inoculation. In contrast, the Gal-3 positive^(pos) tumors continued growing despite PBMC inoculation, and tumor T regulatory cell (CD4/FoxP3+) infiltration increased. RNA sequencing of T cells from women with TNBC with elevated plasma levels of Gal-3 revealed significantly lower expression of oxidative phosphorylation genes than in T cells from healthy women. Similarly, in our <em>in-vitro</em> model, the decreased expression of oxidative phosphorylation genes and mitochondrial dysfunction resulted in a significant increase in CD8 intracellular reactive oxygen species. Consequently, T exhausted cells (CD8/PD1/Tim3/Lag3+) significantly increased in PBMC co-cultured with Gal-3^pos TNBCs.</div><div>To conclude, we revealed a novel TNBC-related Gal-3 suppressor mechanism that involved upregulation of CD4 T regulatory and of CD8 T exhausted cells.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101117"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899594","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":"Global, regional, and national burden of very early-onset colorectal cancer and its risk factors from 1990 to 2019: A systematic analysis for the global burden of disease study 2019","authors":"Zhen Junhai ,&nbsp;Meng Yang ,&nbsp;Tan Zongbiao ,&nbsp;Yan Wenxuan ,&nbsp;Li Tiange ,&nbsp;Wu Yanrui ,&nbsp;Liu Chuan ,&nbsp;Dong Weiguo","doi":"10.1016/j.neo.2024.101114","DOIUrl":"10.1016/j.neo.2024.101114","url":null,"abstract":"<div><h3>Aims</h3><div>Very early-onset colorectal cancer (EOCRC) was defined as CRC diagnosed before the age of 35 proposed by the latest EOCRC management guideline. Until now, the disease burden of very EOCRC has never been reported. This study aimed to explore the burden of very EOCRC across the past three decades.</div></div><div><h3>Methods</h3><div>We extracted the data from Global Burden of Disease Study to analyze the disease burden of very EOCRC. Risk factors for the burden of deaths and disability-adjusted life years (DALYs) due to very EOCRC were also explored in this study. Additionally, decomposition analysis and frontier analysis were also conducted.</div></div><div><h3>Results</h3><div>Despite regional and gender variations, the global very EOCRC incidence cases increased from 21,874 (95 % UI: 20,386-23,470) to 41,545 (95 % UI: 37,978-45,523). Besides, the deaths cases also increased from 11,445 (95 % UI: 10,545-12,374) to 15,486 (95 % UI: 14,289-16,803), and the DALYs cases increased from 718,136 (95 % UI: 659,858-778,283) to 961,460 (95 % UI: 886,807-1,042,734). Decomposition analysis revealed the epidemiological change contributed most to the incidence burden of very EOCRC. Countries or regions with Sociodemographic Index (SDI) between 0.4 and 0.8 had greater disease burden improvement potential through frontier analysis. Diet low in milk, diet low in calcium, alcohol use, and high body-mass index were the main contributors to deaths and DALYs.</div></div><div><h3>Conclusions</h3><div>The increase in CRC burden among populations younger than 35 years globally requires vigilance from policy makers, physicians, and young individuals themselves, especially those regions experiencing faster growth burden of very EOCRC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101114"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911028","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":"Microbial molecules, metabolites, and malignancy","authors":"Ryan M. Thomas","doi":"10.1016/j.neo.2025.101128","DOIUrl":"10.1016/j.neo.2025.101128","url":null,"abstract":"<div><div>Research elucidating the role of the microbiome in carcinogenesis has grown exponentially over the past decade. Initially isolated to associative studies on colon cancer development, the field has expanded to encompass nearly every solid and liquid malignancy that may afflict the human body. Investigations are rapidly progressing from association to causation and one particular area of causal effect relates to microbial metabolites and how they influence cancer development, progression, and treatment response. These metabolites can be produced <em>de novo</em> from individual members of the microbiome, whether that be bacteria, fungi, archaea, or other microbial organisms, or they can be through metabolic processing of dietary compounds or even host-derived molecules. In this review, contemporary research elucidating mechanisms whereby microbial-derived molecules and metabolites impact carcinogenesis and cancer treatment efficacy will be presented. While many of the examples focus on bacterial metabolites in colon carcinogenesis, this simply illustrates the accelerated nature of these investigations that occurred early in microbiome research but provides an opportunity for growth in other cancer areas. Indeed, research into the interaction of microbiome-derived metabolites in other malignancies is growing as well as investigations that involve non-bacterial metabolites. This review will provide the reader a framework to expand their knowledge regarding this complex and exciting field of cancer research.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101128"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014464","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}