Neoplasia最新文献

{"title":"New horizons in B-cell lymphoma immunotherapy: From immune checkpoints to precision medicine","authors":"RuiXin Zheng ,&nbsp;YuXiao Li ,&nbsp;KaiXin Shi ,&nbsp;YuanYuan Pan ,&nbsp;KaiYi Liu ,&nbsp;JinCheng Song ,&nbsp;Li Li","doi":"10.1016/j.neo.2025.101206","DOIUrl":"10.1016/j.neo.2025.101206","url":null,"abstract":"<div><div>B-cell lymphoma, a malignancy in hematology with high heterogeneity, has its genesis and progression intricately associated with immune system regulation. Over the past three decades, transformative breakthroughs in B-cell malignancy investigations have emerged through paradigm-shifting molecular discoveries. Nevertheless, numerous hurdles persist in attaining a comprehensive understanding and effective treatment of this disease. Novel chemotherapeutic strategies demonstrate promising potential in B-cell lymphoma management, particularly through targeting immune checkpoints such as PD-1 (Programmed Cell Death Protein 1), LAG-3 (Lymphocyte-activation Gene 3), TIM-3 (T-cell Immunoglobulin and Mucin-domain containing-3), and TIGIT (T-cell Immunoreceptor with Ig and ITIM Domains) play pivotal regulatory roles within the immune system. These molecules critically orchestrate immune cell activation dynamics, proliferative capacity, and effector functions, thereby preserving immunological homeostasis. Deciphering the functional architecture of co-inhibitory checkpoints (e.g., PD-1/CTLA-4) in lymphomagenesis serves dual imperatives: deconstructing tumor immune evasion programs while establishing conceptual frameworks for precision immunotherapeutics development. PD-1 engagement with PD-L1/PD-L2 impairs T lymphocyte activation, facilitating tumor immune evasion. Deciphering these molecular processes enables therapeutic agents to employ targeted blockade strategies to restore antitumor immunity in lymphomas. Moreover, in-depth research on these checkpoints holds great promise for the discovery of novel biomarkers. These biomarkers may help predict responses to immunotherapy in lymphoma patients. This would enable clinicians to tailor personalized treatment plans for each patient, maximizing the therapeutic efficacy while minimizing unnecessary side-effects. Certain genetic signatures related to these immune checkpoints might be identified as predictors of a favorable response to PD-1 inhibitor-based immunotherapy. This analysis systematically deciphers the molecular interplay of PD-1/LAG-3/TIM-3/TIGIT immune checkpoint axes, delineating their regulatory dynamics in B-cell lymphomagenesis. It systematically summarizes the current research achievements, delves into the existing problems, and explores the future research directions. This approach seeks to advance dual contributions to fundamental science and clinical application in B-cell lymphoma immunotherapy, thereby facilitating therapeutic innovations while deepening mechanistic comprehension of disease pathogenesis. By doing so, it aims to provide valuable insights for both basic research and clinical translation in the field of B-cell lymphoma immunotherapy, ultimately enabling advancements in patient care and deeper insights into this multifaceted condition.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101206"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory mechanisms of the Hippo/YAP axis by G-protein coupled estrogen receptor in gastric signet-ring cell carcinoma","authors":"Yufei Wang ,&nbsp;Yuanlin Sun ,&nbsp;Weizhu Zhao ,&nbsp;Jiazi Zhang ,&nbsp;Xiaofeng Wang ,&nbsp;Fangqi Hu ,&nbsp;Zhifei Han ,&nbsp;Longgang Wang ,&nbsp;Luguang Liu ,&nbsp;Bing Liu ,&nbsp;Liqing Liu ,&nbsp;Bo Bi ,&nbsp;Dong Sun ,&nbsp;Bingtian Liu ,&nbsp;Jie Chai","doi":"10.1016/j.neo.2025.101199","DOIUrl":"10.1016/j.neo.2025.101199","url":null,"abstract":"<div><div>Although aberrant activation of the Hippo/YAP axis has been implicated in the development of gastric cancer, functional studies of this cascade in the context of gastric signet-ring cell carcinoma (GSRC) remain absent. Our previous single-cell sequencing results showed that G protein-coupled estrogen receptor (GPER) is overexpressed in GSRC, and this overexpression is associated with aberrant activation of the Hippo/YAP axis. In this study, we integrated <em>in vitro</em> cytological functional assays with GSRC cell lines and <em>in vivo</em> xenograft nude mice models to elucidate the functional implications of GPER in GSRC. The overexpression of GPER was identified as being associated with more unfavorable outcomes in GSRC. Its activation facilitated tumor proliferation by YAP nuclear translocation and subsequent transcriptional activation. Mechanistically, GPER inhibited LATS1-mediated YAP phosphorylation by competitively binding to ARRB2, thereby enhancing YAP activity. Moreover, YAP was shown to bind to the GPER promoter, forming a positive feedback loop that reinforced oncogenic signaling. Pharmacological inhibition of GPER using G-15 reduced YAP activation and effectively attenuated tumor aggressiveness, highlighting the GPER-YAP feedback loop as a potential therapeutic target for GSRC. This study underscores the pivotal role of the GPER-YAP positive feedback loop in GSRC and proposes dual inhibition of GPER and YAP as a promising therapeutic strategy for GSRC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101199"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Twist1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of Twist1","authors":"Audrey Lafargue ,&nbsp;Hailun Wang ,&nbsp;Sivarajan T. Chettiar ,&nbsp;Rajendra P. Gajula ,&nbsp;Amol C. Shetty ,&nbsp;Yang Song ,&nbsp;Brian W. Simons ,&nbsp;Muhammad Ajmal Khan ,&nbsp;Triet Nguyen ,&nbsp;Hwai-Wei Tseng ,&nbsp;Jinhee Chang ,&nbsp;Danielle N. Waters ,&nbsp;Aaron Chan ,&nbsp;Christine Lam ,&nbsp;Francesca A. Carrieri ,&nbsp;Caleb Smack ,&nbsp;Nick Connis ,&nbsp;Dipanwita Dutta Chowdhury ,&nbsp;Katriana Nugent ,&nbsp;Ismaeel Siddiqui ,&nbsp;Phuoc T. Tran","doi":"10.1016/j.neo.2025.101179","DOIUrl":"10.1016/j.neo.2025.101179","url":null,"abstract":"<div><div>Non-small cell lung carcinoma (NSCLC) is a major cause of cancer mortality. High expression of the epithelial-to-mesenchymal transition transcription factor (EMT-TF) Twist1 is strongly associated with metastatic cancers and with treatment resistance. Twist1 can also upregulate O-GlcNAcylation to suppress fail-safe programs such as Kras^G12D oncogene-induced senescence (OIS) that accelerates NSCLC tumorigenesis. We wanted to decipher the critical domains and transcriptional targets required for Twist1 acceleration of lung tumorigenicity. We created a novel genetically-engineered mouse model for autochthonous lung cancer through lung epithelial expression of <em>Kras^G12D</em> oncogene (CR) concomitantly with <em>Twist1</em>^wt (CRT) or a <em>Twist1^F191G</em> transactivation-deficient mutant (CRF191G). Compared to CR and CRF191G, CRT mice had shorter tumor-free survival and more aggressive tumors histologically. CRT lung tumors also showed higher proliferation and lower cell-cycle arrest suggesting that the Twist1 transactivation-domain is important for OIS suppression. Supporting these data, we observed in non-cancer human bronchial epithelial cells (HBECs) that the co-expression of human <em>TWIST1^wt</em> enhanced tumorigenic/invasive programs and could suppress <em>HRas^G12V</em>-induced senescence while co-expressing <em>TWIST1^F187G</em> transactivation-deficient mutant could not. <em>TWIST1^wt</em> co-expression with <em>HRas^G12V</em> in HBECs differentially modulated MYC downstream transcriptional programs. Finally, OIS induction in HBEC<img><em>HRas^G12V-TWIST1^wt</em> was rescued by O-GlcNAcylation inhibition or by treatment with a novel MYC inhibitor MYCi975 or by MYC knockdown. Altogether, these results indicate that the Twist1 transactivation domain is required for Twist1-dependent acceleration of lung tumorigenesis via MYC and nominate MYCi975 as a means to activate latent OIS programs. MYC targeting strategies could limit pro-tumorigenic programs and serve as a therapeutic for TWIST1-overexpressing NSCLCs.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101179"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144106682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential prognostic association of systemic inflammatory biomarkers on survival outcomes in head and neck squamous cell carcinoma patients by human papillomavirus status","authors":"Pardis Noormohammadpour ,&nbsp;Katrina Hueniken ,&nbsp;Martha Pienkowski ,&nbsp;Shao Hui Huang ,&nbsp;Baijiang Yuan ,&nbsp;Benjamin Grant ,&nbsp;Christopher Yao ,&nbsp;Andrew Hope ,&nbsp;Jillian Tsai ,&nbsp;Andrew McPartlin ,&nbsp;David Goldstein ,&nbsp;Ali Hosni ,&nbsp;John R. de Almeida ,&nbsp;Robert C. Grant ,&nbsp;Geoffrey Liu ,&nbsp;Yuchen Li","doi":"10.1016/j.neo.2025.101178","DOIUrl":"10.1016/j.neo.2025.101178","url":null,"abstract":"<div><div>Systemic inflammatory response (SIR) markers are prognostic in various cancers. In a prospective cohort study (2006-2019) involving 2044 head and neck squamous cell carcinomas (HNSCC) patients, we assessed the prognostic associations of SIR markers at diagnosis, including NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio), LMR (lymphocyte-to-monocyte ratio), NMR (neutrophil-to-monocyte ratio), SII (systemic immune-inflammation index), eosinophil and WBC (white blood cell) levels, with progression-free (PFS) and overall survival (OS). Training (two-thirds randomly selected patients) and withheld test sets were created. Separate multivariable Cox regression models by HPV status were created for each of the seven SIR markers for the training set, and validated in the withheld test set. We found that the majority of SIR markers are strongly and significantly associated with OS and PFS in HPV-positive HNSCC patients, while the results were less significant or of lesser magnitude of association in the HPV-negative HNSCC patients. Despite validating these prognostic associations, the addition of SIR markers to a clinical prognostic model did not significantly improve predictive performance for PFS/OS. Our study demonstrates that SIR markers may have a greater impact on the survival of HPV-positive HNSCC, and less so for HPV-negative HNSCCs. These results suggest differential prognostic impact of inflammation between HPV-driven HNSCCs and non-HPV-driven HNSCCs. Although biologically relevant, these associations do not improve survival prognostication in the clinical setting.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101178"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144070897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “DNA-methylation eraser TET2 activates WTIP expression to suppress an AKT-dependent chemoresistance of gastric cancer” [Neoplasia volume 2025 Apr 24:65:101166]","authors":"Yan Guo ,&nbsp;Hongyang Yu ,&nbsp;Jinyang Li ,&nbsp;Kewei Liu ,&nbsp;Mengyi Han ,&nbsp;Yuxin Tang ,&nbsp;Li Su ,&nbsp;Xianfeng Li ,&nbsp;Haixia Wu ,&nbsp;Dongfeng Chen","doi":"10.1016/j.neo.2025.101191","DOIUrl":"10.1016/j.neo.2025.101191","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101191"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the full potential of Pyrotinib in HER2-positive metastatic breast cancer","authors":"Wei-Zhen Tang,&nbsp;Kang-jin Huang,&nbsp;Tai-Hang Liu","doi":"10.1016/j.neo.2025.101172","DOIUrl":"10.1016/j.neo.2025.101172","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101172"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The deubiquitinase USP7 stabilizes HER2 expression and promotes breast cancer progression","authors":"Xiaoyue He ,&nbsp;Xiaohong Xia ,&nbsp;Ziying Lei ,&nbsp;Mengfan Tang ,&nbsp;Jiangyu Zhang ,&nbsp;Yuning Liao ,&nbsp;Hongbiao Huang","doi":"10.1016/j.neo.2025.101192","DOIUrl":"10.1016/j.neo.2025.101192","url":null,"abstract":"<div><div>The overexpression and amplification of HER2 occurs in breast cancer. However, the mechanism of HER2 action in tumor has not yet been elucidated. HER2 can be degraded by the UPS system, and several HER2-associated E3s have been identified, but the DUB for HER2 has not yet been uncovered. Targeted therapy against HER2 has achieved impressive efficacy in patients with HER2-positive breast cancer. Herein, using MTS, Western blot, Co-IP, colony formation, RT‒qPCR, EdU, flow cytometry, immunofluorescence assays and xenograft model, we elucidated that USP7 deletion inhibited the growth of HER2-positive breast cancer cell by decreasing HER2 protein abundance. We found that USP7 was highly expressed in HER2-positive breast cancer and the expression of USP7 and HER2 was positively correlated. USP7 overexpression accelerated cell cycle progression. Mechanistically, USP7 interacted with HER2 and decreased HER2 ubiquitination to stabilize its expression. Moreover, USP7 knockdown inhibited tumor growth in vivo and in vitro. In addition, HER2 overexpression partially reversed cell growth inhibition induced by USP7 inhibition. Analyses of clinical samples revealed that USP7 overexpression was associated with poor prognosis in patients with HER2+ breast cancer. Thus, this study revealed that USP7, as a DUB of HER2, may be a potential therapeutic target for patient with HER2+ breast cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101192"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[18F]-FLT-PET to evaluate how the sequencing of chemotherapies impacts the efficacy of combination treatment in mouse models of triple-negative breast cancer","authors":"Yun Lu ,&nbsp;Jonathan Moye ,&nbsp;Adriana V.F. Massicano ,&nbsp;Carlos A. Gallegos ,&nbsp;Shannon E Lynch ,&nbsp;Patrick N. Song ,&nbsp;Sharon Samuel ,&nbsp;Anna G. Sorace","doi":"10.1016/j.neo.2025.101184","DOIUrl":"10.1016/j.neo.2025.101184","url":null,"abstract":"<div><h3>Introduction</h3><div>Triple-negative breast cancer (TNBC) lacks targeted therapies due to an absence of biomarkers, making chemotherapy the primary treatment option for early-stage cancer. This study evaluates whether the order and sequence of combination chemotherapy—doxorubicin (DRB) and paclitaxel (PTX)—affects treatment efficacy in TNBC.</div></div><div><h3>Methods</h3><div>I<em>n vitro</em> and <em>in vivo</em> models (MDA-MB-231 human and 4T1 syngeneic mouse TNBC) were used to assess treatment efficacy across three groups: saline control, DRB→PTX, and PTX→DRB. [¹⁸F]fluorothymidine (FLT) Positron emission tomography (PET) imaging was performed at baseline, day 3, and day 6 to monitor changes in tumor proliferation, and flow cytometry on day 6 examined immune profile differences in endpoint cohorts. Statistical significance was evaluated using the ANOVA and Kolmogorov-Smirnov test.</div></div><div><h3>Results</h3><div>In <em>vitro</em> experiments showed PTX→DRB treatment significantly reduced S/G2/M cell cycles and cancer cell viability. The MDA-MB-231 tumor model showed that PTX→DRB treatment significantly decreased cell proliferation and tumor heterogeneity comparing day 6 to baseline. In 4T1 models, DRB→PTX suppressed tumor growth and enhanced B cell and macrophage recruitment in immunocompetent but not immunocompromised mice. In both models, [¹⁸F]-FLT-PET plays a crucial role in directing the sequencing of chemotherapy in TNBC.</div></div><div><h3>Conclusions</h3><div>Our study highlights the immune system's critical role in enhancing chemotherapy's efficacy. It provides compelling evidence that imaging can guide the sequencing of therapies by tracking changes in cellular proliferation and the heterogeneity of tumor response. This approach underscores the potential to refine treatment strategies for improved therapeutic outcomes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101184"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Escitalopram facilitates tumor growth and metastasis in rodents: Is it safe?","authors":"Yosi Azan ,&nbsp;Adam Margalit ,&nbsp;Gal Wiener ,&nbsp;Elad Sandbank ,&nbsp;Ravid Doron ,&nbsp;Liat Sorski ,&nbsp;Ella Rosenne ,&nbsp;Avital Luba Plosky ,&nbsp;Avital Gilam ,&nbsp;Anabel Eckerling ,&nbsp;Noam Shomron ,&nbsp;Shamgar Ben-Eliyahu","doi":"10.1016/j.neo.2025.101182","DOIUrl":"10.1016/j.neo.2025.101182","url":null,"abstract":"<div><div>Cancer patients are often treated perioperatively with serotonin reuptake inhibitors (SSRIs) to counteract anxiety and depression. Recent studies suggest that long-term cancer outcomes may also be affected by SSRI use in an agent-dependent manner. Importantly, the perioperative use of SSRIs is prevalent clinically, but has rarely been studied empirically. Herein, we studied escitalopram, a commonly prescribed SSRI in cancer patients, in vitro, and in vivo in the context of surgery and/or cancer progression in immune-competent rodents, employing the Panc02 (pancreatic), MADB106, 4T1, EO771 (mammary), and CT26 (colon) syngeneic tumor models, assessing primary tumor growth and metastasis. Escitalopram (10-15mg/kg/day, 14-30 days) was administered along tumor and/or metastatic progression, via intraperitoneal injections, Alzet osmotic pumps, or drinking water. <em>In vitro</em>, escitalopram affected proliferation rates in a cell-line-, dose-, and exposure duration- dependent manner, mostly increasing or not affecting proliferation. In contrast, <em>in vivo</em> escitalopram consistently increased primary tumor growth, and experimental and spontaneous metastasis in all models tested. In pancreatic tumor-bearing mice, escitalopram increased tumor growth in two different studies by ∼1.5-fold, as indicated by bioluminescence imaging. In the mammary primary tumor models, escitalopram increased 4T1 and EO771 growth by 1.4 to 2.2-fold. Last, escitalopram increased experimental MADB106 lung metastasis and CT26 liver metastasis, as well as spontaneous post-excision 4T1 lung metastasis by 1.6 to 2.3-fold. Taken together, although additional research is needed to elucidate mediating in vivo mechanisms, and to assess clinical oncological risks of escitalopram, these findings raise concerns regarding the prevalent perioperative use of escitalopram in cancer patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101182"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunohistochemical and molecular evolutionary features of jejunoileal adenocarcinoma unveiled through comparative analysis with colorectal adenocarcinoma","authors":"Rei Ishikawa ,&nbsp;Hidetaka Yamada ,&nbsp;Hirotomo Saitsu ,&nbsp;Ryosuke Miyazaki ,&nbsp;Juri Takahashi ,&nbsp;Rino Takinami ,&nbsp;Satoshi Baba ,&nbsp;Mitsuko Nakashima ,&nbsp;Moriya Iwaizumi ,&nbsp;Satoshi Osawa ,&nbsp;Hideya Kawasaki ,&nbsp;Yoshifumi Arai ,&nbsp;Yoshiro Otsuki ,&nbsp;Hiroshi Ogawa ,&nbsp;Hiroki Mori ,&nbsp;Fumihiko Tanioka ,&nbsp;Shioto Suzuki ,&nbsp;Kazuyo Yasuda ,&nbsp;Makoto Suzuki ,&nbsp;Haruhiko Sugimura ,&nbsp;Kazuya Shinmura","doi":"10.1016/j.neo.2025.101180","DOIUrl":"10.1016/j.neo.2025.101180","url":null,"abstract":"<div><div>Jejunoileal adenocarcinoma (JIAC) is a rare type of malignancy, the clinicopathological, genetic, and evolutionary characteristics of which have rarely been reported. In this study, 52 patients with JIAC and 182 patients with colorectal adenocarcinoma (CRAC) were recruited. Immunohistochemical analyses using 34 primary antibodies identified a novel subtype, JIAC with enteroblastic differentiation (JIAED). High MUC1 expression and low Cyclin D1 expression were identified as independent poor prognostic markers. Additionally, compared with mismatch repair deficient (dMMR)-CRAC, MSH2/MSH6 loss was more frequently observed in dMMR-JIAC. These results suggested essential molecular differences between JIAC and CRAC. To better understand these differences, we selected three dMMR-JIACs and eight mismatch repair proficient (pMMR)-JIACs and evaluated molecular evolutionary history by multi-regional whole-exome sequencing. Phylogenetic trees constructed for both pMMR-JIAC and dMMR-JIAC were more consistent with a “long trunk–short branches” structure than were those of CRAC, and the variant allele frequency peaks obtained for JIAC were higher than those of CRAC. Moreover, <em>TP53</em> and <em>ARID2</em> were identified as common driver gene mutations in pMMR-JIAC, arising during early tumorigenesis. Our evolutionary analysis revealed that pMMR-CRAC follows the principle of shifting from Darwinian to neutral evolution, generating intratumoral heterogeneity (ITH). In contrast, our findings on pMMR-JIAC and dMMR-JIAC demonstrate that both remain under Darwinian evolution, even in advanced stages, resulting in lower ITH. In summary, we identified a distinct pathohistological subtype of JIAC and highlighted the unique molecular evolutionary dynamics presented in JIAC, potentially lead to the better management and treatment strategies for patients with JIAC in the future.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101180"},"PeriodicalIF":4.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144106681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}