Neoplasia最新文献

{"title":"EGFRvIII-driven microenvironmental fibroblast activation and transformation accelerate oral cancer progression via lipocalin-2/STAT3 axis","authors":"Hsuan-Yu Peng ,&nbsp;Kwang-Yu Chang ,&nbsp;Wei-Min Chang ,&nbsp;Chia-Yu Wu ,&nbsp;Hsin-Lun Lee ,&nbsp;Yung-Chieh Chang ,&nbsp;Ko-Jiunn Liu ,&nbsp;Shine-Gwo Shiah ,&nbsp;Ching-Chuan Kuo ,&nbsp;Jang-Yang Chang","doi":"10.1016/j.neo.2025.101193","DOIUrl":"10.1016/j.neo.2025.101193","url":null,"abstract":"<div><div>Oral squamous cell carcinoma (OSCC) is an aggressive malignancy frequently characterized by dysregulated epidermal growth factor receptor (EGFR) signaling. Among EGFR mutation, EGFRvIII, an extracellular domain truncated form without exons 2–7, exhibits ligand-independent and constitutive EGFR activation. Although EGFRvIII functions as an oncogene in glioblastoma, its role in OSCC remains unclear. Here, we demonstrate that EGFRvIII is highly prevalent in OSCC, with approximately 70 % of OSCC tumor samples revealing high EGFRvIII expression. EGFRvIII enhances metastatic and proliferative potential, while its knockdown significantly reduces these malignant phenotypes. Beyond its direct oncogenic effects, EGFRvIII actively remodels the tumor microenvironment (TME) by recruiting and activating fibroblasts. In both xenograft models and co-culture systems, OSCC cells expressing EGFRvIII stimulated the expression of fibroblast activation markers—including α-smooth muscle actin (α-SMA), platelet-derived growth factor receptors (PDGFRA/PDGFRB), and collagen—thereby promoting a tumor-supportive stroma. Moreover, RNA sequencing and cytokine array analyses revealed that EGFRvIII induces lipocalin-2 (LCN2) expression and secretion. Elevated LCN2 in the conditioned medium from OSCC-EGFRvIII cells further stimulates fibroblast activation via the STAT3 signaling pathway, as pharmacological inhibition of STAT3 attenuates LCN2-driven fibroblast activation. Furthermore, exposure to environmental carcinogens such as nicotine-derived nitrosamine ketone (NNK) and arecoline enhances EGFRvIII expression and downstream signaling, exacerbating tumor aggressiveness. These findings reveal a positive feedback loop in which EGFRvIII fosters OSCC progression by stimulating LCN2-STAT3-mediated fibroblast activation. Targeting EGFRvIII and its downstream effectors may therefore represent a promising strategy to mitigate OSCC progression and improve therapeutic outcomes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101193"},"PeriodicalIF":4.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213153","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":"Alteration in expression and subcellular localization of the androgen receptor- regulated FAM111A protease is associated with emergence of castration resistant prostate cancer","authors":"Maria Malvina Tsamouri ,&nbsp;Stephen J. Libertini ,&nbsp;Salma Siddiqui ,&nbsp;Maitreyee K. Jathal ,&nbsp;Blythe P. Durbin-Johnson ,&nbsp;Clifford G. Tepper ,&nbsp;Eva Corey ,&nbsp;Jun Luo ,&nbsp;Kenneth A. Iczkowski ,&nbsp;Paramita M. Ghosh ,&nbsp;Maria Mudryj","doi":"10.1016/j.neo.2025.101181","DOIUrl":"10.1016/j.neo.2025.101181","url":null,"abstract":"<div><div>The androgen receptor (AR) is a pivotal regulator of growth and survival of prostate cancer (PCa) and the majority of lethal castration-resistant prostate cancers (CRPC) remain reliant on AR signaling. PCa exhibits variability in progression and responses to treatment suggesting genetic heterogeneity. Two independent studies identified PCa predisposing single nucleotide polymorphisms (SNPs) within the FAM111A protease gene, but the mechanistic basis of this association remained elusive. Our <em>in vitro</em> and <em>in vivo</em> studies uncovered that AR represses FAM111A in castration sensitive and resistant cells via an AR binding site within the <em>FAM111A</em> gene. FAM111A levels are significantly lower in matched castration-resistant than in castration-sensitive cells and xenografts, and lower in metastatic lesions than in primary tumors. We discovered that FAM111A is AR-repressed in castration sensitive PCa xenograft and multiple PCa cells. Additionally, FAM111A subcellular localization changes dramatically with acquisition of castration resistance, where in castration sensitive cells FAM111A is predominantly in the nucleoli, but with castration resistance it becomes more dispersed in the nucleus and in the cytoplasm. FAM111A depletion in castration sensitive and resistant cells enhances the efficacy of PARP1 inhibitors olaparib and niraparib, consistent with its role in DNA repair. Moreover, FAM111A depletion reduces AR target gene prostate specific antigen (<em>PSA)</em> and transmembrane serine protease 2 (<em>TMPRSS2)</em> transcription, indicating that FAM111A modulates AR-dependent gene expression forming a FAM111A-AR co-regulatory loop in PCa. Our studies argue that AR-dependent FAM111A regulation modulates PCa gene expression, acquisition of castration resistance, and sensitivity to agents that target DNA damage repair.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101181"},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168492","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 “Ovulation sources ROS to confer mutagenic activities on the TP53 gene in the fallopian tube epithelium” [Neoplasia 59 (2025 Dec 4) 101085]","authors":"Kanchana Subramani ,&nbsp;Hsuan-Shun Huang ,&nbsp;Pao-Chu Chen ,&nbsp;Dah-Ching Ding ,&nbsp;Tang-Yuan Chu","doi":"10.1016/j.neo.2025.101183","DOIUrl":"10.1016/j.neo.2025.101183","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101183"},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168491","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":"CD56 on intratumoral NK cells: orchestrating NK cell-mediated anti-tumor effects in bladder cancer","authors":"Zaineb Hassouneh ,&nbsp;Onika D.V. Noel ,&nbsp;Niannian Ji ,&nbsp;Michelle E. Kim ,&nbsp;Natalia Bowman ,&nbsp;Robert S. Svatek ,&nbsp;Emily Mace ,&nbsp;Neelam Mukherjee","doi":"10.1016/j.neo.2025.101187","DOIUrl":"10.1016/j.neo.2025.101187","url":null,"abstract":"<div><div>Bladder cancer (BCa) exhibits favorable responses to immunotherapy, but a significant percentage of patients fail to show a response owing to an inadequate tumor-immune landscape. We previously showed that NK cells are one of the predominant tumor-infiltrating lymphocytes in BCa and correlate with improved patient survival. However, that link was observed only with CD56^bright NK cells while the CD56^dim subset exhibited reduced cytotoxicity and higher accumulation in advanced BCa stages. The role of CD56 in NK cell functionality in BCa, however, remains unclear. Using flow cytometry and cytotoxicity assays, we demonstrated a significant decrease in cytotoxicity and activation of NK92 cells against BCa upon CD56 deletion. Further, migration assays and atomic force microscopy showed CD56 deletion impaired NK92 cell migration and adhesion to bladder tumor cells, reducing NK92 cell-mediated apoptosis of BCa cells. Prolonged exposure to bladder tumors led to CD56 loss in NK92 cells, suggesting tumor-induced NK92 cell dysfunction via CD56 reduction, consistent with our previous findings. Confocal microscopy revealed an overlap of CD56 and phosphorylated Pyk2, a critical kinase at the tumor-immune synapse, potentially mediating the downstream cytotoxicity effects. Blocking Pyk2 phosphorylation decreased CD56-mediated NK92 cell activation and reduced NK92 cell-mediated cytotoxicity against BCa. Finally, we showed that CD56 is also expressed by BCa cells and may be a predictive biomarker for NK cell-based immunotherapy, with its shedding indicating a mechanism for NK cell evasion. Our study identifies a novel innate-immune axis in BCa, leading to a better understanding of intratumoral NK cell biology and advancing NK cell-targeted treatments.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101187"},"PeriodicalIF":4.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154678","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":"2025-05-27","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":"CYP1B1 promotes angiogenesis and sunitinib resistance in clear cell renal cell carcinoma via USP5-mediated HIF2α deubiquitination","authors":"Ke Ma ,&nbsp;Qinyu Li ,&nbsp;Yi Zhang ,&nbsp;Jiuyi Wang ,&nbsp;Wei Jia ,&nbsp;Jihong Liu ,&nbsp;Bo Liu ,&nbsp;Qiang Li ,&nbsp;Qinzhang Wang ,&nbsp;Kai Zeng","doi":"10.1016/j.neo.2025.101186","DOIUrl":"10.1016/j.neo.2025.101186","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC) is strongly aetiologically associated with von Hippel‒Lindau (VHL) tumour suppressor gene mutations, which result in constitutive activation of hypoxia-inducible factors and pathological angiogenesis. Although accumulating evidence indicates that antiangiogenic therapies targeting VEGF signalling can prolong the survival of ccRCC patients, the frequent development of therapeutic resistance to tyrosine kinase inhibitors such as sunitinib remains a critical clinical limitation. Through integrated multiomics analyses of sunitinib-resistant cell models, patient-derived xenografts, and clinical specimens, we systematically identified CYP1B1 as a central mediator of treatment resistance. Transcriptomic and genomic profiling revealed that CYP1B1 overexpression in resistant tumours functionally contributes to enhanced angiogenic potential and maintenance of the resistant phenotype. Mechanistic investigations demonstrated that CYP1B1 stabilizes hypoxia-inducible factor 2α (HIF2α) by facilitating USP5-mediated deubiquitination, thereby preventing proteasomal degradation. Notably, we identified VHL as a novel E3 ubiquitin ligase that regulates CYP1B1 turnover; notably, VHL deficiency in ccRCC promotes CYP1B1 protein accumulation by suppressing ubiquitination. These findings establish a feed-forward regulatory axis in which VHL loss-induced CYP1B1 stabilization promotes HIF2α signalling persistence, ultimately driving sunitinib resistance. Our study delineated the CYP1B1-USP5-HIF2α signalling cascade as a critical resistance mechanism and thus reveals a targetable vulnerability in treatment-refractory ccRCC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101186"},"PeriodicalIF":4.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137810","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":"2025-05-23","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":"PRMT1 inhibitor MS023 suppresses RNA splicing to sensitize small cell lung cancer to DNA damaging agents","authors":"Mansi K. Aparnathi ,&nbsp;Sami Ul Haq ,&nbsp;Jonathan St-Germain ,&nbsp;Kevin C.J. Nixon ,&nbsp;Joseph Walton ,&nbsp;Lifang Song ,&nbsp;Safa Majeed ,&nbsp;Parasvi S. Patel ,&nbsp;Ratheesh Subramaniam ,&nbsp;Vivek Philip ,&nbsp;Richard Marcellus ,&nbsp;Dalia Barsyte-Lovejoy ,&nbsp;Rima Al-Awar ,&nbsp;Razqallah Hakem ,&nbsp;Cheryl H. Arrowsmith ,&nbsp;Laurie Ailles ,&nbsp;Brian Raught ,&nbsp;Benjamin H. Lok","doi":"10.1016/j.neo.2025.101176","DOIUrl":"10.1016/j.neo.2025.101176","url":null,"abstract":"<div><div>Small cell lung cancer (SCLC) is a highly aggressive form of cancer, commonly treated with DNA-damaging therapies such as chemotherapy and radiotherapy. Unfortunately, relapse occurs early and frequently, suggesting that epigenetic mechanisms may play a role in this aggressive behavior. Targeting these mechanisms during initial treatment could potentially enhance anti-cancer effects. This study investigated the combination of DNA-damaging treatments with a panel of Epigenetic Chemical Probes (EpiProbes). Among these, MS023, a PRMT inhibitor, showed the greatest synergy with cisplatin and etoposide across various SCLC cell lines. The cytotoxicity of MS023 was correlated with PRMT1 gene expression and protein levels. BioID analysis revealed that many PRMT1 interactors are involved in mRNA splicing. Mechanistic validation demonstrated that MS023 impaired RNA splicing, increased DNA:RNA hybrids, and caused DNA double-strand breaks (DSBs). When combined with ionizing radiation (IR), MS023 significantly increased DSBs, as indicated by γH2AX foci. Additionally, MS023 enhanced the effects of IR and the PARP inhibitor talazoparib, both in vitro and in vivo. Therefore, targeting PRMT1 in combination with DNA-damaging therapies presents a promising strategy to improve treatment outcomes for SCLC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"66 ","pages":"Article 101176"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123809","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":"2025-05-22","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":"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":"2025-05-21","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}