Cancer letters最新文献

{"title":"Characterizing chromosome instability reveals its association with lipid-associated macrophages and clonal evolution of lymph node metastasis in esophageal squamous cell carcinoma","authors":"Wei Dai ,&nbsp;Josephine Mun-Yee Ko ,&nbsp;Valen Zhuoyou Yu ,&nbsp;Zhaozheng Hou ,&nbsp;Larry Ka-Yue Chow ,&nbsp;Michael King Yung Chung ,&nbsp;Kazi Anisha Islam ,&nbsp;Bianca Hoi-yan Ng ,&nbsp;Carissa Wing-Yan Wong ,&nbsp;Ka-Kiu Leung ,&nbsp;Cancan Chen ,&nbsp;Ian Yu Hong Wong ,&nbsp;Simon Ying-Kit Law ,&nbsp;Anthony Wing-Ip Lo ,&nbsp;Alfred King-Yin Lam ,&nbsp;Maria Li Lung","doi":"10.1016/j.canlet.2025.217874","DOIUrl":"10.1016/j.canlet.2025.217874","url":null,"abstract":"<div><div>Esophageal cancer is an aggressive cancer, and metastasis is one of the major factors contributing to treatment failure, leading to poor clinical outcomes. Chromosome instability (CIN) is frequently observed in esophageal squamous cell carcinoma (ESCC). However, the functional impact of CIN is not well studied in ESCC metastasis. We aim to study the role and underlying mechanisms of CIN in lymph node (LN) metastasis. Integrated analysis was performed using single-cell RNA sequencing data with matched whole-exome sequencing in primary ESCC, genomic sequencing in ESCC organoids and clinical specimens, and spatial protein profiling to characterize CIN and relevant tumor immune microenvironment (TIME) associated with LN metastasis. CIN in primary ESCC <strong>i</strong>s significantly associated with LN metastasis at diagnosis, particularly in those patients with homologous recombination deficiency and use of alternative end joining (alt-EJ). Primary CIN ESCC exhibited increased epithelial-mesenchymal transition (EMT), hypoxia, angiogenesis, RNA metabolism, and heat stress, associated with a strong metastatic potential. Although CIN ESCC ha<strong>s</strong> elevated neoantigen loads, its TIME was enriched for immunosuppressive lipid-associated tumor-associated macrophages (LA-TAMs). Secreted phosphoprotein 1 (SPP1) plays a key role in mediating the communications of CIN ESCC cells and LA-TAMs. In LN metastases, structural CIN (sCIN) with retrotransposon insertion and reactivation is important for ESCC clonal evolution and cell proliferation, associated with increased LA-TAMs infiltration and poor overall patient survival. ESCC with high CIN has a strong metastatic potential. Our findings reveal a novel link between error-prone DSB repair pathways and LA-TAMs through CIN in LN metastasis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217874"},"PeriodicalIF":9.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-based radiomic features predict outcomes and the added benefit of chemoimmunotherapy over chemotherapy in extensive stage small cell lung cancer: A multi-institutional study","authors":"Mohammadhadi Khorrami ,&nbsp;Pushkar Mutha ,&nbsp;Cristian Barrera ,&nbsp;Vidya S. Viswanathan ,&nbsp;Fatemeh Ardeshir-Larijani ,&nbsp;Prantesh Jain ,&nbsp;Kristin Higgins ,&nbsp;Anant Madabhushi","doi":"10.1016/j.canlet.2025.217872","DOIUrl":"10.1016/j.canlet.2025.217872","url":null,"abstract":"<div><div>Small cell lung cancer (SCLC) is aggressive with poor survival outcomes, and most patients develop resistance to chemotherapy. No predictive biomarkers currently guide therapy. This study evaluates radiomic features to predict PFS and OS in limited-stage SCLC (LS-SCLC) and assesses PFS, OS, and the added benefit of chemoimmunotherapy (CHIO) in extensive-stage SCLC (ES-SCLC). A total of 660 SCLC patients (470 ES-SCLC, 190 LS-SCLC) from three sites were analyzed. LS-SCLC patients received chemotherapy and radiation, while ES-SCLC patients received either chemotherapy alone or CHIO. Radiomic and quantitative vasculature tortuosity features were extracted from CT scans. A LASSO-Cox regression model was used to construct the ES- Risk-Score (ESRS) and LS- Risk-Score (LSRS). ESRS was associated with PFS in training (HR = 1.54, adj. P = .0013) and two independent validation sets (HR = 1.32, adj. P = .0001; HR = 2.4, adj. P = .0073) and with OS in training (HR = 1.37, adj. P = .0054) and validation sets (HR = 1.35, adj. P &lt; .0006; HR = 1.6, adj. P &lt; .0085) in ES-SCLC patients treated with chemotherapy. High-risk patients had improved PFS (HR = 0.68, adj. P &lt; .001) and OS (HR = 0.78, adj. P = .026) with CHIO. LSRS was associated with PFS in training and two independent validation sets (HR = 1.9, adj. P = .007; HR = 1.4, adj. P = .0098; HR = 2.1, adj. P = .028) in LS-SCLC patients receiving chemoradiation. Radiomics is prognostic for PFS and OS and predicts chemoimmunotherapy benefit in high-risk ES-SCLC patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217872"},"PeriodicalIF":9.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RCMIX model based on pre-treatment MRI imaging predicts T-downstage in MRI-cT4 stage rectal cancer","authors":"Feiyu Bai ,&nbsp;Leen Liao ,&nbsp;Yuanling Tang ,&nbsp;Yihang Wu ,&nbsp;Zhangjie Wang ,&nbsp;Hengyu Zhao ,&nbsp;Jingming Huang ,&nbsp;Xin Wang ,&nbsp;Peirong Ding ,&nbsp;Xiaojian Wu ,&nbsp;Zerong Cai","doi":"10.1016/j.canlet.2025.217871","DOIUrl":"10.1016/j.canlet.2025.217871","url":null,"abstract":"<div><div>Neoadjuvant therapy (NAT) is the standard treatment strategy for MRI-defined cT4 rectal cancer. Predicting tumor regression can guide the resection plane to some extent. Here, we covered pre-treatment MRI imaging of 363 cT4 rectal cancer patients receiving NAT and radical surgery from three hospitals: Center 1 (n = 205), Center 2 (n = 109) and Center 3 (n = 52). We propose a machine learning model named RCMIX, which incorporates a multilayer perceptron algorithm based on 19 pre-treatment MRI radiomic features and 2 clinical features in cT4 rectal cancer patients receiving NAT. The model was trained on 205 cases of cT4 rectal cancer patients, achieving an AUC of 0.903 (95 % confidence interval, 0.861–0.944) in predicting T-downstage. It also achieved AUC of 0.787 (0.699–0.874) and 0.773 (0.646–0.901) in two independent test cohorts, respectively. cT4 rectal cancer patients who were predicted as Well T-downstage by the RCMIX model had significantly better disease-free survival than those predicted as Poor T-downstage. Our study suggests that the RCMIX model demonstrates satisfactory performance in predicting T-downstage by NAT for cT4 rectal cancer patients, which may provide critical insights to improve surgical strategies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217871"},"PeriodicalIF":9.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of an Individualized Immune-Related miRNA Pair Signature for Survival Prediction of Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Cancer.","authors":"Peng Wu, Dexin Shang, Li Liu, Le Wang, Guochao Zhang, Liyan Xue, Feng Li, Xiaoli Zheng, Yonglei Zhang, Haijun Yang, Yufen Yuan, Ruixue Lei, Dongyu Li, Xuanyu Gu, Ruijie Ma, Jingjing Liu, Jilin Peng, Bohui Zhao, Junhan Zhou, Chuqi Lin, Nan Sun, Chaoqi Zhang, Jie He","doi":"10.1016/j.canlet.2025.217866","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217866","url":null,"abstract":"<p><strong>Background: </strong>Immune-related microRNAs (ImiRNAs) have emerged as potential biomarkers owing to their universality and tissue-specificity. Although neoadjuvant chemoradiotherapy (NCRT) has been incorporated into standardized guidelines for esophageal squamous cell carcinoma (ESCC), its efficacy is hindered by tumor and individual heterogeneity. This study aimed to develop a specific ImiRNA pair signature to predict the long-term survival benefits of NCRT for ESCCs.</p><p><strong>Methods: </strong>Endoscopic biopsies of 215 ESCCs were collected from three centers. ImiRNAs were identified via miRNA sequencing and immune gene annotations. A pairwise-comparison method and LASSO-Cox regression constructed prognostic models, validated in two cohorts (n=113). Immunohistochemistry was employed to gain insights into the real tumor immune microenvironment after treatment.</p><p><strong>Results: </strong>The ESCC NCRT immune-related miRNA pair signature (EN-ImiRPS), incorporating six ImiRNA pairs, demonstrated robust prognostic accuracy for both overall survival (HR: 9.76, 95% CI: 4.30-22.16; P < 0.001) and recurrence-free survival (HR: 5.31, 95% CI: 2.63-10.70; P < 0.001). Time-dependent AUCs (1/3/5-year: 0.87/0.91/0.87) outperformed pathological complete response (AUC: 0.63-0.67). An absolute-expression model showed inferior performance. Low-risk patients exhibited significantly higher CD8+ T cell infiltration (P < 0.05), suggesting enhanced anti-tumor immunity.</p><p><strong>Conclusions: </strong>We established a multicenter, ImiRNA pair-based signature that accurately predicts long-term survival in ESCC patients receiving NCRT. The model's stability across cohorts and its association with immune microenvironment features highlight its potential for guiding personalized therapy. This study also identifies key ImiRNAs for further mechanistic exploration of tumor-immune interactions.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217866"},"PeriodicalIF":9.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TAp73α drives cancer metastasis via PPI-mediated derepression of the neuronal HDAC2/REST-GABBR2 axis","authors":"Nico Murr ,&nbsp;Christin Richter ,&nbsp;Shailendra K. Gupta ,&nbsp;Elke Hammer ,&nbsp;Nares Trakooljul ,&nbsp;Anja Stoll ,&nbsp;Steffen Möller ,&nbsp;Lukas E. Neumann ,&nbsp;Brigitte M. Pützer ,&nbsp;Alf Spitschak","doi":"10.1016/j.canlet.2025.217867","DOIUrl":"10.1016/j.canlet.2025.217867","url":null,"abstract":"<div><div>Metastasis is the leading cause of death in patients with malignant melanoma, yet the molecular and transcriptional mechanisms remain elusive. This study reveals a crucial role of the p53 homolog, TAp73α, in promoting melanoma metastasis. Using multi-omics approaches combining transcriptomics, proteomics, cistromics and 3D modeling, we discovered a paradigm-shifting mechanism by which TAp73α binds directly to HDAC2, disassembles the HDAC2/REST repressor complex and aberrantly triggers activation of the neuronal receptor GABBR2 in cancer cells. TAp73α-induced derepression of GABBR2 expression leads to upregulation of EMT markers, promotes cancer cell invasiveness and proliferation, and correlates with poor survival outcomes. Our findings redefine the function of p73 in cancer pathogenesis and identify the TAp73α-HDAC2/REST-GABBR2 axis as a novel driver of melanoma progression. These insights could guide future strategies on melanoma treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217867"},"PeriodicalIF":9.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual blockade of PD-1 and CTLA-4 generates long-lasting immunity against irradiated glioblastoma","authors":"Mara De Martino ,&nbsp;Camille Daviaud ,&nbsp;María Cecilia Lira ,&nbsp;Kayla Hernandez-Zirofsky ,&nbsp;Claire Vanpouille-Box","doi":"10.1016/j.canlet.2025.217856","DOIUrl":"10.1016/j.canlet.2025.217856","url":null,"abstract":"<div><div>Radiation therapy (RT) can release pro-inflammatory signals to jumpstart an anti-tumor immune response. However, glioblastoma (GBM) often recurs, suggesting that RT might not act as an immune adjuvant in this disease. A possible explanation for the lack of immune stimulation is the use of irradiation regimens that do not effectively stimulate anti-tumor immunity against GBM. Here, we tested the ability of various RT schedules to elicit type I interferon (IFN-I) response and explored its synergy with immunotherapy (IT) to trigger anti-tumor immunity against GBM. Using three murine GBM models, we show <em>in vitro</em> that single dose radiation ranging from 0Gy to 20Gy and fractionated radiation schedules (i.e. 3 daily fractions of 8Gy; 3 × 8Gy and 5 daily fractions of 6Gy; 5 × 6Gy) accumulates double stranded DNA and release IFN-I related cytokines in a dose-dependent fashion; with fractionated schedules being superior in triggering cancer-cell intrinsic IFN-I responses. Side-by-side comparison of various radiation regimen <em>in vivo</em> revealed that 5 × 6Gy better control GBM across the three GBM models tested. However, the addition of anti-PD1 or anti-CTLA4 to an immunogenic radiation schedule (i.e. 5 × 6Gy) did not prolong survival of irradiated mice. Surprisingly, only the dual blockade of PD-1 and CTLA4 promoted the expansion of proliferative T cells and conveyed immunological memory against irradiated GBM. Overall, this study demonstrates that an immunogenic radiation regimen is not sufficient to mount an anti-tumor immune response when combine with IT as monotherapy and highlights the need to combine an immunogenic irradiation with multiple IT to overcome immunosuppression of GBM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217856"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipocytes promote cancer stemness properties in oral squamous cell carcinoma through C3/C3AR axis and sphingolipid metabolism","authors":"Tian Xu Qin ,&nbsp;Ying Ying Zhu ,&nbsp;Wai Hoe Ng ,&nbsp;Siew Kit Ng ,&nbsp;Min Fey Chek ,&nbsp;Kai Dun Tang","doi":"10.1016/j.canlet.2025.217848","DOIUrl":"10.1016/j.canlet.2025.217848","url":null,"abstract":"<div><div>There is convincing evidence that being overweight or having obesity is associated with an increased risk of developing oral squamous cell carcinoma (OSCC). Despite OSCC frequently spread to the cervical lymph nodes, where adipose tissue is the predominant tissue within the microenvironment, it is still largely unknown whether adipocytes could contribute to the formation of oral cancer stem cells (CSCs) niche during the oral carcinogenesis. Here, we report that adipocytes promote the CSCs phenotype of OSCC cells through the activation of complement C3 (C3). Subsequent clinical data analysis revealed that the elevated levels of C3 and its receptor C3AR are associated with aggressive features and shorter survival in human OSCC patients. Furthermore, C3 exists as an autocrine factor and through C3AR interaction regulates OSCC stemness and properties such as cell proliferation, migration and invasion. On the other hand, C3 and C3AR were found to be highly abundant in adipocytes upon co-cultured with OSCC cells, demonstrating its paracrine effect on adipocyte-CSCs interaction, which in turn promotes CSC properties and supports oral carcinogenesis. Intriguingly, the inhibition of functional C3/C3AR axis by sphingosine, a bioactive sphingolipid metabolite, resulted in the suppression of OSCC cells growth and adipocyte-promoted oral CSC self-renewal. In conclusion, our findings provide a novel insight into the mechanisms underlying the role of C3/C3AR axis in mediating the reciprocal interactions between adipocytes and OSCC cells, acting in an autocrine and paracrine manner, and specific inhibition of this interaction by sphingosine offers a potential targeted therapeutic approach for OSCC treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217848"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs","authors":"Liangjie Sun ,&nbsp;Xiaolei Gao ,&nbsp;Meng Wang ,&nbsp;Yixin Zhang ,&nbsp;Ruiqing Sun ,&nbsp;Yang Chen ,&nbsp;Yan Bai ,&nbsp;Yi Li ,&nbsp;Lan Luo ,&nbsp;Chong Ding ,&nbsp;Yixiang Wang","doi":"10.1016/j.canlet.2025.217854","DOIUrl":"10.1016/j.canlet.2025.217854","url":null,"abstract":"<div><div>The role of p53 deficiency or mutation in regulating nonhistone protein crotonylation and its impact on cancer development remain unclear. The present study identified crotonylation as a therapeutic target in patients with p53 deficiency or mutation in colorectal cancer. Crotonylome analysis revealed that p53 deficiency upregulated heterogeneous nuclear ribonucleoprotein C (HNRNPC) and HNRNPC^K189Cr, promoting colorectal cancer cell proliferation by stabilizing CCND1 and MCM3 mRNAs through the MDM2/HDAC3 axis. Functional studies using HNRNPC^K189Q (activating mutation) and HNRNPC^K189R (inactivating mutation) confirmed the role of HNRNPC^K189Cr in tumor growth. HDAC3 was identified as a specific decrotonylase of HNRNPC^K189Cr. Sodium phytate, an HDAC3 agonist, effectively decrotonylated HNRNPC^K189Cr and, in combination with HNRNPC siRNA, significantly inhibited the <em>in vitro</em> and <em>in vivo</em> growth of HCT116 p53^−/− cells. An AOM/DSS-induced colorectal cancer model in K14-cre; p53 ^fl/fl mice validated the role of the p53/MDM2/HDAC3/HNRNPC^K189Cr axis in tumor progression. Additionally, the findings in the oral cancer cells WSU-HN6 and non-small lung cancer cells H1299 were in line with those in the HCT116 cells, suggesting that the p53/MDM2/HDAC3/HNRNPC^K189Cr regulatory mechanism plays a key role in a conserved manner. These findings revealed a novel mechanism by which p53 deficiency or mutation drives tumor progression via HNRNPC^K189Cr through MDM2/HDAC3 axis-mediated CCND1 and MCM3 mRNA stability. Targeting HNRNPC and its crotonylation with sodium phytate and HNRNPC <em>siRNA</em> offers a promising therapeutic strategy, potentially converting p53 from an “undruggable” target to a “druggable” target.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217854"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear localization of YAP in pancreatic cancer: More players besides Hippo pathway.","authors":"Yiping Xie, Cheng Qin, Xiangyu Zhang, Zeru Li, Bangbo Zhao, Tianyu Li, Yutong Zhao, Yutong Yan, Haoyu Shi, Lirui Huang, Weibin Wang","doi":"10.1016/j.canlet.2025.217864","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217864","url":null,"abstract":"<p><p>The Yes-associated protein (YAP) is a critical regulator of organ size and a key player in tumorigenesis, with its activity primarily governed by the Hippo signaling pathway. YAP mainly functions as a transcriptional co-activator, therefore its activity is closely related to its nuclear localization. Recent studies have shed light on mechanisms that regulate YAP's nuclear localization and activation, independent of the Hippo pathway. Beyond its role in development and tissue homeostasis, YAP's dysregulation is implicated in various cancers, including pancreatic cancer, one of the most lethal cancers. Activated YAP translocates to the nuclear of cancer cell, subsequently promotes expression of downstream genes involved in tumor growth, metastasis, and resistance to chemotherapy, etc. Moreover, YAP can also function as a transcription suppressor, indicating its context-dependent role in cancer. A thorough understanding of YAP regulation in pancreatic cancer could offer new insights for targeted therapy approaches. Here this review concludes recent findings on Hippo-independent regulation of YAP nuclear localization and the role of YAP in pancreatic cancer progression.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217864"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic evolution of venetoclax resistance in acute myeloid leukemia unveiled by longitudinal single-cell RNA-seq","authors":"Huan Lu ,&nbsp;Huafeng Wang ,&nbsp;Qiwei Wang ,&nbsp;Deyu Huang ,&nbsp;Yingli Han ,&nbsp;Hui Wang ,&nbsp;Penglei Jiang ,&nbsp;Xinyue Qian ,&nbsp;Liping Mao ,&nbsp;Min Yang ,&nbsp;Hongyan Tong ,&nbsp;Jie Jin ,&nbsp;Pengxu Qian ,&nbsp;Hong-Hu Zhu","doi":"10.1016/j.canlet.2025.217853","DOIUrl":"10.1016/j.canlet.2025.217853","url":null,"abstract":"<div><div>Despite extensive investigation into venetoclax resistance mechanisms in acute myeloid leukemia (AML), the dynamics of bone marrow (BM) microenvironment remodeling during venetoclax-based therapies remain poorly characterized at single-cell resolution. Using paired single-cell RNA sequencing of BM specimens from AML patients undergoing DAV therapy (venetoclax/decitabine/cytarabine; pre- vs post-treatment), we systematically mapped therapy-induced transcriptional reprogramming, regulatory network alterations, and niche crosstalk across clinical response subgroups. Our analysis revealed two pivotal mechanisms governing therapeutic outcomes: First, pre-existing immune-activating niches marked by elevated HLA class I presentation synergized with therapy-enhanced CD8⁺ T cell cytotoxicity and reduced tumor-promoting stroma-leukemia interactions to facilitate favorable responses. Second, responder leukemic cells exhibited transposable element (TE)-associated type I interferon signaling upregulation. Primitive leukemic clones displayed <em>IMPDH2</em>-high states linked to <em>BCL2</em> inhibitor sensitivity, while resistant monocytic populations upregulated glycolysis and <em>MCL1</em> to bypass <em>BCL2</em> dependence. Leveraging these insights, we established a prognostic signature predicting patient responses to venetoclax-based therapies, validated in independent cohorts (Tumor Profiler, BeatAML2). High-risk patients identified by this signature demonstrated heightened sensitivity to <em>IGF-1R</em> inhibition. Functional validation in an established resistant cell line model confirmed that <em>IGF-1R</em> inhibition synergized with DAV by suppressing glucose uptake and differentiation. This study provides a comprehensive single-cell atlas of BM microenvironment evolution during venetoclax-based therapy, proposes a prognostic biomarker, and identifies a clinically actionable strategy to overcome therapeutic resistance in AML.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217853"},"PeriodicalIF":9.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}