Cancer Communications最新文献

{"title":"Cover Image, Volume 45, Issue 1","authors":"Jiali Yao,&nbsp;Linlin Ji,&nbsp;Guang Wang,&nbsp;Jin Ding","doi":"10.1002/cac2.12551","DOIUrl":"https://doi.org/10.1002/cac2.12551","url":null,"abstract":"<p>The cover image is based on the article <i>Effect of neutrophils on tumor immunity and immunotherapy resistance with underlying mechanisms</i> by Jiali Yao et al., https://doi.org/10.1002/cac2.12613.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12551","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143118821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating tumor cells share RNA modules with early embryo trophectoderm and with metastatic cancer","authors":"Stefano Volinia,&nbsp;Anna Terrazzan,&nbsp;Tomasz S. Kaminski,&nbsp;Krystian Jadzewski,&nbsp;Eva Reali,&nbsp;Nicoletta Bianchi,&nbsp;Jeff Palatini","doi":"10.1002/cac2.12664","DOIUrl":"10.1002/cac2.12664","url":null,"abstract":"&lt;p&gt;Metastasis is the primary cause of cancer-related deaths, accounting for an estimated 66% to 90% of fatalities [&lt;span&gt;1&lt;/span&gt;]. It is a multistep process involving the dissemination of circulating tumor cells (CTCs) and their colonization of distant organs [&lt;span&gt;2, 3&lt;/span&gt;]. A higher number of detected CTCs in cancer patients is associated with shorter survival [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;We analyzed 544 single-cell RNA sequencing (scRNA-seq) profiles of bona fide CTCs, identified as keratin-positive and aneuploid, from over 3,000 putative CTC profiles available in public databases, as detailed in Supplementary Table S1. Most of the CTCs originated from patients with breast cancer (&lt;i&gt;n&lt;/i&gt; = 502, 92.3%), while a smaller number were derived from patients with prostate cancer (&lt;i&gt;n&lt;/i&gt; = 42). All experimental methods are described in the Supplementary Materials and Methods.&lt;/p&gt;&lt;p&gt;All bona fide CTCs were positive for KRT18 and negative for PTPRC (CD45), as expected. Three main CTC subgroups were identified (Supplementary Figure S1). We labeled the two epithelial (EPCAM&lt;sup&gt;+&lt;/sup&gt;) subgroups as epithelial A (epiA) and epithelial B (epiB), while the third subgroup was mesenchymal (VIM&lt;sup&gt;+&lt;/sup&gt;/EPCAM&lt;sup&gt;−&lt;/sup&gt;). CAV1 and AXL showed the highest specificity for mesenchymal CTCs, whereas LY6E was the most distinctive gene for epiB CTCs (Supplementary Tables S2–S4). Further analysis revealed that mesenchymal and epiB, but not epiA CTCs, were actively engaged in the cell cycle, as inferred using the R package Tricycle (Supplementary Figure S1). The biological implications of these three CTC subgroups are highly relevant. Mesenchymal CTCs expressed significantly lower levels of KRT18 and other keratins, such as KRT19 and KRT7, compared to epithelial CTCs. Conversely, vimentin, another class of intermediate filaments, was highly expressed in mesenchymal CTCs. The shift from keratins to vimentin is a hallmark molecular event in epithelial-to-mesenchymal transition (EMT). EMT regulators ZEB1, ZEB2, and SNAI2 were upregulated in mesenchymal CTCs, indicating that EMT was responsible for their origin. These findings highlight the need to prioritize the detection and targeting of epiB and mesenchymal CTCs. PD-L1 (CD274), an important target for immunotherapy in clinical practice, was expressed in only a small fraction of mesenchymal CTCs and even less in epithelial CTCs (Supplementary Figure S2). In contrast, two other immune checkpoint genes, CD276 (B7-H3) and PVR (CD155), were highly expressed in CTCs, comparable to their expression in trophoblasts. This suggests an immuno-evasive phenotype common to most CTCs, driven by the expression of CD276 and PVR.&lt;/p&gt;&lt;p&gt;Is there a functional relationship between CTCs and trophoblast cells, as suggested by the co-expression of genes such as CD276, SP6, and LY6E (Supplementary Figure S3)? To address this question, we examined potential links between CTCs and the placenta or early embryo by integrating scRNA-seq profi","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"500-504"},"PeriodicalIF":20.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12664","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in epithelioid sarcoma","authors":"Jia Xiang Jin,&nbsp;Fabia Fuchslocher,&nbsp;Martha Carreno-Gonzalez,&nbsp;Felina Zahnow,&nbsp;A. Katharina Ceranski,&nbsp;Rainer Will,&nbsp;Dominic Helm,&nbsp;Felix Bestvater,&nbsp;Ana Banito,&nbsp;Roland Imle,&nbsp;Shunya Ohmura,&nbsp;Florencia Cidre-Aranaz,&nbsp;Thomas G. P. Grünewald","doi":"10.1002/cac2.12665","DOIUrl":"10.1002/cac2.12665","url":null,"abstract":"&lt;p&gt;Epithelioid sarcoma (EpS) is a high-grade malignancy of unknown histogenesis first described in 1970 [&lt;span&gt;1&lt;/span&gt;], characterized by high rates of relapse and metastasis, with 5-year survival rates of 60%-75% [&lt;span&gt;2&lt;/span&gt;]. The only Food and Drug Administration (FDA)-approved targeted therapy, the enhancer of zeste homology 2 (EZH2) inhibitor tazemetostat, achieved transient responses in only 15% of patients [&lt;span&gt;2&lt;/span&gt;]. To establish a solid mechanistic basis, we investigated the role of SWI/SNF related BAF chromatin remodeling complex subunit B1 (&lt;i&gt;SMARCB1&lt;/i&gt;) via multi-omics analyses. We engineered isogenic cell line models single-cell-cloned to minimize genetic variability, featuring doxycycline-(DOX)-inducible &lt;i&gt;SMARCB1&lt;/i&gt; expression systems alongside respective empty vector controls. The cell lines (FU-EPS-1; HS-ES-1, -2M, -2R; NEPS; VA-ES-BJ) exhibited homozygous &lt;i&gt;SMARCB1&lt;/i&gt; deletion and represented proximal and distal subtypes, with prominent &lt;i&gt;SMARCB1&lt;/i&gt; re-expression upon DOX-treatment (Figure 1A). DOX concentrations were adjusted to achieve SYBR/TaqMan-qPCR-controlled &lt;i&gt;SMARCB1&lt;/i&gt; levels comparable to &lt;i&gt;SMARCB1&lt;/i&gt;-proficient Ewing sarcoma (EwS) cell lines, minimizing experimental artefacts associated with supraphysiological expression (Supplementary Figure S1A-B). Western blots demonstrated that SMARCB1 underwent nuclear translocation and re-incorporation into the SWI/SNF complex (Figure 1B). Transcriptome profiling using Affymetrix Clariom D microarrays (GEO: GSE276634) and Weighted Gene Correlation Network Analysis (WGCNA) based on Gene Set Enrichment Analysis (GSEA) revealed downregulated signatures related to DNA-repair and epigenetic regulation, alongside upregulated developmental pathways upon &lt;i&gt;SMARCB1&lt;/i&gt; re-expression (Figure 1C). These findings were accompanied by dose-dependent reductions in clonogenicity (Figure 1D, Supplementary Figure S1C), while propidium-iodide-(PI)-based flow-cytometric cell-cycle-analysis showed delayed G1-to-S-phase transition (Supplementary Figure S1D). Orthotopic subcutaneous (s.c.) xenotransplantation experiments using VA-ES-BJ in immunocompromised &lt;i&gt;Nod/Scid/gamma&lt;/i&gt; (NSG) mice recapitulated the typical EpS morphology (Supplementary Figure S1E). After tumors became palpable, &lt;i&gt;SMARCB1&lt;/i&gt; re-expression via DOX supplementation in drinking water resulted in significantly reduced tumor growth (Figure 1E).&lt;/p&gt;&lt;p&gt;Since these findings underscored significant &lt;i&gt;SMARCB1&lt;/i&gt;-associated epigenetic regulation (Figure 1C) [&lt;span&gt;3&lt;/span&gt;], we next investigated SWI/SNF chromatin-remodeling functionality via Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq; GEO: GSE281434) in FU-EPS-1, HS-ES-2M, NEPS and VA-ES-BJ to compare the effects of &lt;i&gt;SMARCB1&lt;/i&gt;-deficient and physiological SWI/SNF assemblies. &lt;i&gt;SMARCB1&lt;/i&gt; re-expression increased chromatin accessibility at putative enhancer sites (box 1) and gene bodies (box 2) (Figure 1F). Conversely, SWI/SNF-inhibi","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"494-499"},"PeriodicalIF":20.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12665","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of mTOR attenuates the initiation and progression of BRCA1-associated mammary tumors","authors":"Hye Jung Baek,&nbsp;Geun Hee Han,&nbsp;Eun Joo Cho,&nbsp;Jihao Xu,&nbsp;Min Kyung Ki,&nbsp;Eun Jung Park,&nbsp;Tae Hyun Kim,&nbsp;Dong Hoon Shin,&nbsp;Heesun Cheong,&nbsp;Chu-Xia Deng,&nbsp;Sung Chul Lim,&nbsp;Chang-il Hwang,&nbsp;Daehee Hwang,&nbsp;Sang Soo Kim","doi":"10.1002/cac2.12663","DOIUrl":"10.1002/cac2.12663","url":null,"abstract":"&lt;p&gt;Inherited mutation in breast cancer susceptibility gene 1 (&lt;i&gt;BRCA1&lt;/i&gt;) is strongly associated with mammary tumors that exhibit triple-negative characteristics, are insensitive to endocrine-targeted therapies, and show basal-like properties, including aggressive phenotypes [&lt;span&gt;1, 2&lt;/span&gt;]. It has been reported that the average cumulative risk of breast cancer for &lt;i&gt;BRCA1&lt;/i&gt; mutation carriers by age 70 years is 57% (95% confidence interval [CI]: 47%-66%) [&lt;span&gt;3&lt;/span&gt;]. Despite the high incidence and aggressive characteristics of &lt;i&gt;BRCA1&lt;/i&gt;-associated breast cancer, few substantial improvements in preventing or treating this cancer have been made, largely due to the challenges of clinic-based cohort studies. During malignant transformation, cancer progression is facilitated by metabolic reprogramming–one of the hallmark characteristics of cancer. Previously, we found that inhibition of AKT is a potential strategy for the prevention and therapeutic management of &lt;i&gt;Brca1&lt;/i&gt;-mutant mammary tumors. However, pharmacological inhibition proved less effective and less safe compared to genetic perturbation, limiting its potential for clinical application [&lt;span&gt;4&lt;/span&gt;]. Meanwhile, mTOR, a key regulator of metabolism and a downstream target of the PI3K/AKT signaling pathway, has emerged as a promising therapeutic target for several diseases, including treatment of cancer [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In addition to identifying the contribution of mTOR signaling to BRCA1-deficient cells (Supplementary Figure S1), we provide genetic and pharmacological evidence using multi-orthogonal preclinical models [&lt;span&gt;6-8&lt;/span&gt;] that mTOR is closely involved in the development and growth of &lt;i&gt;Brca1&lt;/i&gt;-mutated mammary tumors (Figure 1A). To investigate the role of mTOR in the absence of BRCA1, we assessed the development of mammary glands in post-pubertal &lt;i&gt;Brca1/Mtor&lt;/i&gt;-mutant mice by examining ductal and lobular development of the fourth mammary gland. Measurements of mammary gland density using the Branch software (ver. 1.1 [&lt;span&gt;9&lt;/span&gt;]) showed that ductal length and branching were significantly diminished in the mammary glands of &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; mice (Figure 1B,C, Supplementary Figure S2). To determine whether mTOR contributes to BRCA1-deficient mammary tumor formation, we examined tumor formation in cohorts of &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 28), &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 30), &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 24), and &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 29) mice (Top left of Figure 1A). &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; and &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; mice showed no signs of mammary abnormalities, including tumors, up to 24 months of age. In contrast, &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; mutant mice developed breast cancer, reaching a high incidence (37.5%; 9/24) by 24 months of age. During the s","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"486-490"},"PeriodicalIF":20.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of KN026 and docetaxel for HER2-positive breast cancer: a phase II clinical trial","authors":"Jianli Ma,&nbsp;Jingxuan Wang,&nbsp;Ting Xu,&nbsp;Quchang Ouyang,&nbsp;Xiaojia Wang,&nbsp;Jingfen Wang,&nbsp;Lu Gan,&nbsp;Zhong Ouyang,&nbsp;Daren Lin,&nbsp;Tao Sun,&nbsp;Changping Shan,&nbsp;Herui Yao,&nbsp;Baochun Zhang,&nbsp;Zhengguang Li,&nbsp;Zhixiang Zhuang,&nbsp;Ying Lu,&nbsp;Hongwei Yang,&nbsp;Jian Huang,&nbsp;Xingwang Yang,&nbsp;Hongmei Sun,&nbsp;Qingyuan Zhang","doi":"10.1002/cac2.12662","DOIUrl":"10.1002/cac2.12662","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive recurrent/metastatic breast cancer currently includes pertuzumab plus trastuzumab and docetaxel. This study aimed to evaluate the effectiveness of KN026, an anti-HER2 bispecific antibody, plus docetaxel in first-line treatment of HER2-positive recurrent/metastatic breast cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This open-label, single-arm, phase II study enrolled patients with HER2-positive recurrent/metastatic breast cancer in 19 centers across China from December 30, 2019 to May 27, 2021. Patients were administered KN026 (30 mg/kg) plus docetaxel (75 mg/m²) in 21-day cycles. Primary endpoints included the objective response rate (ORR) and duration of response (DOR). In addition, overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety profile were examined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 57 patients were included. In the efficacy analysis set of 55 patients, the ORR was 76.4% (95% confidence interval [CI], 63.0%-86.8%), and the CBR was 85.5% (95% CI, 73.3%-93.5%). The median DOR was not reached (95% CI, 20.7 months-not reached). In the safety set of 57 patients, the median PFS was 27.7 months (95% CI, 18.0 months-not reached). The median OS was not reached, with OS rates at 12, 24 and 30 months of 93.0%, 84.1% and 78.5%, respectively. Grade ≥3 treatment-emergent adverse events (AEs) were detected in 36 (63.2%) patients. No deaths were attributed to KN026 or docetaxel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>KN026 plus docetaxel showed promising efficacy and a manageable safety profile in first-line treatment of HER2-positive recurrent/metastatic breast cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"476-485"},"PeriodicalIF":20.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioequivalence of alternative pembrolizumab dosing regimens: current practice and future perspectives","authors":"Ruben Malmberg,&nbsp;Bram C. Agema,&nbsp;Maaike M. Hofman,&nbsp;Stefani Oosterveld,&nbsp;Sander Bins,&nbsp;Daphne W. Dumoulin,&nbsp;Arjen Joosse,&nbsp;Joachim G. J. V. Aerts,&nbsp;Reno Debets,&nbsp;Birgit C. P. Koch,&nbsp;Astrid A. M. van der Veldt,&nbsp;Roelof W. F. van Leeuwen,&nbsp;Ron H. J. Mathijssen","doi":"10.1002/cac2.12661","DOIUrl":"10.1002/cac2.12661","url":null,"abstract":"&lt;p&gt;Immune checkpoint inhibitors (ICIs), including humanized anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) monoclonal antibodies (mAbs), such as pembrolizumab, have transformed cancer treatment. Pembrolizumab was initially approved as a three-weekly (Q3W) 2 mg/kg weight-based dose by the Food and Drug Administration (FDA), which was later replaced by a 200 mg Q3W fixed-dose, mainly based on in silico simulations. Later, a fixed 400 mg six-weekly (Q6W) regimen was approved based on pharmacokinetic simulations [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Due to increasing ICI use and high costs per treatment, increasingly large portions of healthcare budgets are shifted to ICI treatment. Therefore, it is important to handle ICIs as efficiently and cost-effectively as possible. Hence, the Q6W regimen was introduced, lowering the total amount of ICI administrations per patient and the strain on healthcare capacity, and improving patient convenience. The cost-effectiveness of ICI treatment could be optimized further by using alternative dosing strategies (ADS) [&lt;span&gt;1&lt;/span&gt;]. Some of these ADS have already been tested for pembrolizumab in some countries [&lt;span&gt;2, 3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Recently, the FDA provided bioequivalence guidelines for ADS, specifically for anti-PD-1/PD-L1 mAbs [&lt;span&gt;4&lt;/span&gt;]. These guidelines support the use of pharmacokinetic-modeling to simulate steady-state trough concentrations (C&lt;sub&gt;trough,ss&lt;/sub&gt;) and area under the curve (AUC; exposure) to establish bioequivalence for anti-PD-1/PD-L1 mAbs. In these guidelines, ADS are considered bioequivalent when both C&lt;sub&gt;trough,ss&lt;/sub&gt; and exposure are at most 20% lower compared to the dosing regimen used while establishing efficacy in clinical trials (i.e. the reference dosing regimen). A maximum of 25% increase in the maximum concentration (C&lt;sub&gt;max&lt;/sub&gt;) is used as the upper boundary, unless adequate clinical evidence shows that increasing the C&lt;sub&gt;max&lt;/sub&gt; does not increase toxicity. For pembrolizumab, incidences of toxicities were generally consistent across a 2-10 mg/kg dose range in multiple trials [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To verify whether various ADS (Figure 1, Supplementary Table S1) are bioequivalent following the current FDA guidelines, we assessed bioequivalence using pharmacokinetic modelling. Using pharmacokinetic data from a real-world cohort, the best performing model was selected with which bioequivalence was assessed in extrapolations from this cohort (“extrapolation”) and also from a virtual (“simulation”) cohort. Details on both cohorts, as well as modelling procedures, are depicted in the Supplementary Material and Methods. As a reference, the Q3W 2 mg/kg dosing regimen was used, as this regimen was used in the original approval. Results of these analyses are shown in Figure 1. The simulated ADS for pembrolizumab given every 3 or 4 weeks (Q3/4W) were bioequivalent according to the FDA guidelines. Interestingly, despite meeting the criteria for e","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"471-475"},"PeriodicalIF":20.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomics and epigenomics point to CD58-CD2 interaction in controlling primary melanoma growth and immunity","authors":"Antonia Stubenvoll,&nbsp;Maria Schmidt,&nbsp;Johanna Moeller,&nbsp;Max Alexander Lingner Chango,&nbsp;Carolyn Schultz,&nbsp;Olga Antoniadou,&nbsp;Henry Loeffler-Wirth,&nbsp;Stephan Bernhart,&nbsp;Florian Große,&nbsp;Beatrice Thier,&nbsp;Annette Paschen,&nbsp;Ulf Anderegg,&nbsp;Jan C. Simon,&nbsp;Mirjana Ziemer,&nbsp;Clara T. Schoeder,&nbsp;Hans Binder,&nbsp;Manfred Kunz","doi":"10.1002/cac2.12651","DOIUrl":"10.1002/cac2.12651","url":null,"abstract":"&lt;p&gt;Immunotherapy is currently one of the most promising treatment options for malignant melanoma [&lt;span&gt;1&lt;/span&gt;]. To uncover new immunological targets for future treatment approaches, single-cell transcriptomic and epigenomic analyses were performed on human primary melanoma (MM) and melanocytic nevus (Nev) samples (Figure 1A). The detailed methods of this study are described in the Supplementary Material.&lt;/p&gt;&lt;p&gt;MM and Nev biopsies (Supplementary Figure S1; Supplementary Table S1) were analyzed by single-cell RNA sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) (Supplementary Figure S2; Supplementary Tables S2 and S3). Using Uniform Manifold Approximation and Projection (UMAP), 28 distinct cellular clusters were identified and annotated based on scRNA-seq data from a previous report and manual curation (Figure 1B; Supplementary Figure S3A) [&lt;span&gt;2&lt;/span&gt;]. Examples of gene expression patterns for individual cell types are provided in Supplementary Table S4. Lesional T lymphocytes were quantified using scRNA-seq data and anti-CD3 immunofluorescence staining, which revealed three distinct immune states: hot (&gt;25 % T cells), intermediate (&gt;6-25 % T cells), and cold (0-6 % T cells) (Supplementary Table S5).&lt;/p&gt;&lt;p&gt;Based on a previous study examining melanoma cell differentiation statuses, the melanoma cell cluster was divided into 8 distinct subclusters (Supplementary Figure S3B, C) [&lt;span&gt;3&lt;/span&gt;]. Unsupervised clustering further refined these findings, predicting 11 cellular subclusters of melanoma cells (Figure 1C, Supplementary Table S6) [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To investigate the molecular mechanisms underlying melanoma cell dedifferentiation, RNA velocity and latent time (LT) analyses were performed (Supplementary Material and Methods). These analyses measure developmental processes based on the gene expression patterns of spliced and unspliced genes [&lt;span&gt;4&lt;/span&gt;], with LT more directly reflecting transcriptional dynamics. As shown in Figure 1C, RNA velocity arrows indicate a trajectory from the melanoma subcluster of undifferentiated, neural crest (nc)-like cells on the left toward the more differentiated Mel_trans-melan_c7 and Mel_trans-melan_c8 subclusters at the right edge. LT analysis (Figure 1C) and the latent time heatmap (Figure 1D) revealed an opposing trajectory toward a more dedifferentiated state, exemplified by the Mel_trans subcluster. Here, melanoma cell dedifferentiation was linked to gene sets enriched in antigen presentation and the induction of T cell receptor signaling (Figure 1D). This aligns with the known association between high immune cell infiltrates and dedifferentiated tumors. Notably, Serpin Family E Member 2 &lt;i&gt;(SERPINE2)&lt;/i&gt; has been identified as a mediator of melanoma metastasis and tumor progression [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Next, we performed regulon analysis (https://github.com/aertslab/pySCENIC) of the melanoma cell clusters, which refers to a ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"465-470"},"PeriodicalIF":20.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12651","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting ferroptosis resistance resensitizes metastatic HR+HER2− breast cancer cells to palbociclib-hormone therapy","authors":"Charles Pottier,&nbsp;Laetitia Montero-Ruiz,&nbsp;Robin Jehay,&nbsp;Coline Wery,&nbsp;Dominique Baiwir,&nbsp;Gabriel Mazzucchelli,&nbsp;Sophie Bekisz,&nbsp;Romain Thissen,&nbsp;Claire Josse,&nbsp;Andrée Rorive,&nbsp;Stéphanie Gofflot,&nbsp;Ahmed Dahmani,&nbsp;Ludivine Morisset,&nbsp;Joëlle Collignon,&nbsp;Philipe Delvenne,&nbsp;Elisabetta Marangoni,&nbsp;Agnès Noël,&nbsp;Guy Jerusalem,&nbsp;Nor Eddine Sounni","doi":"10.1002/cac2.12646","DOIUrl":"10.1002/cac2.12646","url":null,"abstract":"&lt;p&gt;Metastatic hormone receptor-positive (HR&lt;sup&gt;+&lt;/sup&gt;), human epidermal growth factor receptor 2-negative (HER2&lt;sup&gt;−&lt;/sup&gt;) breast cancer often develops resistance to first-line treatment, typically combining cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with hormone therapy (HT) [&lt;span&gt;1, 2&lt;/span&gt;]. After an initial response, most patients become resistant, and compensatory mechanisms are not fully uncovered [&lt;span&gt;3&lt;/span&gt;]. To address this, we analyzed HR&lt;sup&gt;+&lt;/sup&gt; resistant CAMA1 and 747D cells using whole-exome and RNA sequencing, supplemented by proteomics and target validation with human samples. Additionally, we conducted combination therapy trials using xenografts and patient-derived xenografts (PDXs). Detailed study designs and methods are provided in the Supplementary file.&lt;/p&gt;&lt;p&gt;In a cohort of 27 patients with metastatic breast cancer, we observed reduced progression-free survival in second- and third-line therapies following progression post palbociclib-HT treatment (Supplementary Figure S1A and Supplementary Table S1). Resistant tumors showed reduced estrogen receptor alpha (ERα) and progesterone receptor (PR) and increased proliferation rates (Supplementary Figure S1B-D). CAMA1 and T47D cells, treated with palbociclib and fulvestrant (PF) for 2 years, developed resistance (CAMA1-PFR and T47D-PFR) confirmed by proliferation assays and elevated half-maximal inhibitory concentrations. Resistant cells exhibited reduced levels of ERα and retinoblastoma protein (Supplementary Figure S2). Exome analysis revealed no drug resistance-related mutations (Supplementary Tables S2-S3), suggesting non-genetic factors.&lt;/p&gt;&lt;p&gt;RNA sequencing of T47D cells treated with DMSO or PF for 20 days and T47D-PFR cells revealed 1,172 upregulated genes and 824 downregulated genes in the resistant cells (Supplementary Figure S3A). Gene set enrichment analysis indicated increased fatty acid localization (Supplementary Figure S3B), with a heatmap showing elevated fatty acid uptake and metabolism-related genes, such as fatty acid binding protein-6 (FABP6), FABP7, cluster of differentiation-36 (CD36), and proteasome proliferator-activated receptor-gamma (PPARγ) in T47D-PFR cells (Figure 1A). Lipid droplets accumulated in PF-treated parental and PF-resistant T47D and CAMA1 cells (Figure 1B and Supplementary Figure S3C). FABP6 levels were elevated in PF-treated parental and PF-resistant cells, with CD36 overexpression unique to T47D-PFR cells at both protein and mRNA levels (Figure 1C and Supplementary Figure S3D-E), suggesting that lipid uptake might be an adaptive response to oxidative stress [&lt;span&gt;4, 5&lt;/span&gt;]. This was supported by elevated reactive oxygen species (ROS) levels in PF-treated parental cells (Figure 1D). Furthermore, proteomic analysis in human biopsies revealed a functional network of 11 oxidative stress-triggered proteasomes (Supplementary Figure S4A and Supplementary Tables S4-S5) as indicators of oxidative stress [&lt;span&gt;6&lt;/span&gt;]. Im","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"460-464"},"PeriodicalIF":20.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12646","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Training the synergy between Bacillus Calmette-Guérin and immune checkpoint-blocking antibodies in bladder cancer","authors":"Renate Pichler,&nbsp;Martin Thurnher","doi":"10.1002/cac2.12647","DOIUrl":"10.1002/cac2.12647","url":null,"abstract":"&lt;p&gt;Fifty years after the introduction of Bacillus Calmette-Guérin (BCG), a live attenuated strain of &lt;i&gt;Mycobacterium bovis&lt;/i&gt; [&lt;span&gt;1&lt;/span&gt;], it is still the most effective and successful adjuvant immunotherapy of non-muscle invasive bladder cancer (NMIBC) [&lt;span&gt;2&lt;/span&gt;]. The guidelines of the European Association of Urology (EAU) suggest a 6-weekly induction phase followed by a maintenance schedule of BCG once weekly for 3 weeks and at 3, 6, 12, 18, 24, 30, and 36 months for 1 to 3 years [&lt;span&gt;2&lt;/span&gt;]. However, patients with BCG-unresponsive disease - defined as BCG-refractory tumors (T1 high-grade disease after at least 5 out of 6 doses of BCG induction, any high-grade disease during BCG maintenance, carcinoma in situ/Ta high-grade disease after induction, followed by recurrence after reinduction or one maintenance cycle) or early relapse including recurrence with any high-grade disease within 6 months or carcinoma in situ within 12 months after adequate BCG exposure - are unlikely to respond to further BCG alone (BCG reinduction), resulting in the necessity of radical cystectomy (RC) as a next therapeutic step [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Various ongoing studies with novel bladder-preserving strategies are therefore currently investigating whether RC can be prevented in BCG-unresponsive patients and whether the BCG-induced antitumor effect can be enhanced in BCG-naïve high-risk NMIBC by combining BCG with immune-enhancing agents, Supplementary Table S1.&lt;/p&gt;&lt;p&gt;A recently published clinical phase 1 trial (ADAPT-BLADDER) was able to show that the combination of the immune checkpoint inhibitor durvalumab and BCG is an effective therapy for BCG-unresponsive NMIBC [&lt;span&gt;3&lt;/span&gt;]. In detail, within the durvalumab + BCG cohort, the 3-, and 12-month complete response rate was high with 85% and 73%, respectively [&lt;span&gt;3&lt;/span&gt;]. Although this first encouraging preliminary data suggest that combinatory approaches synergistically improve antitumor response of BCG in patients with BCG-unresponsive NMIBC [&lt;span&gt;3&lt;/span&gt;], a better understanding of the immunological mechanisms underlying BCG activity and other combination agents is essential for patient selection, biomarker and future drug development.&lt;/p&gt;&lt;p&gt;BCG is a very special vaccine because of its ability to reprogram macrophages metabolically and epigenetically. As a result, repetitive administration of BCG increases macrophage responsiveness, a phenomenon referred to as “trained immunity”. BCG is an effective stimulus for inducing trained immunity. Upon detection of BCG by pattern recognition receptors [&lt;span&gt;4&lt;/span&gt;], activation of the Akt/mTOR pathway is crucial to shift cellular metabolism towards glycolysis and glutaminolysis, which - in turn - are required for the induction of trained immunity in human monocytes by BCG. Moreover, epigenetic mechanisms regulate the induction of these pathways at the level of chromatin organization. Specifically, an increase of H3K4me3, a histone mark denot","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"438-441"},"PeriodicalIF":20.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12647","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"To what extent is the association between obesity and colorectal cancer risk mediated by systemic inflammation?","authors":"Fatemeh Safizadeh,&nbsp;Marko Mandic,&nbsp;Michael Hoffmeister,&nbsp;Hermann Brenner","doi":"10.1002/cac2.12659","DOIUrl":"10.1002/cac2.12659","url":null,"abstract":"&lt;p&gt;Both overall and abdominal obesity are well-established risk factors for various cancer types, including colorectal cancer (CRC) [&lt;span&gt;1&lt;/span&gt;]. However, how adiposity impacts CRC development has been insufficiently investigated. Three primary hypotheses have been suggested to elucidate the biological pathways that link adiposity and CRC: alterations in insulin signaling, dysregulation of adipose tissue-derived inflammation, and sex hormone metabolism [&lt;span&gt;2, 3&lt;/span&gt;]. New mechanisms are also emerging, including altered gut microbiome and gut hormones, such as Ghrelin and nonalcoholic fatty liver disease (NAFLD). One of the key mechanisms proposed, and a common feature in most pathways, is inflammation [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Adiposity is associated with a systemic subclinical inflammation and higher levels of inflammatory biomarkers such as C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin‑1β (IL‑1β), IL‑6, and IL‑18 [&lt;span&gt;2&lt;/span&gt;]. Inflammation can contribute to cancer development through mechanisms, such as the production of free radicals, including reactive oxygen intermediates, by suppressing the immune system, causing abnormal cell signaling, which promotes proliferative and anti-apoptotic pathways, angiogenesis, and cell migration [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To quantify how much of the association between adiposity and CRC risk might be explained by inflammation, as reflected in increased serum levels of CRP —a nonspecific marker of systemic inflammation, we used body mass index (BMI) as a measure of general obesity, and waist circumference (WC) and waist-to-hip ratio (WHR) as measures of abdominal obesity, and we paid particular attention to a potential role of reverse causation due to cancer-related changes in body weight and CRP levels.&lt;/p&gt;&lt;p&gt;Data from 499,926 UK Biobank study participants aged 40-69, collected from 22 UK Biobank assessment centers, were utilized. Detailed information on the study population and design, exposure and outcome assessments, and statistical analysis is provided in the Supplementary Materials and Methods. After excluding participants with previous cancer diagnosis (except non-melanoma skin cancer), missing BMI, WHR, WC, and CRP, 429,073 participants remained and were included in the analysis (Supplementary Figure S1). Of these, 5,544 were diagnosed with CRC during a median follow-up of 11.8 years (interquartile range: 11.0-12.5). Main characteristics of the cohort are shown in Supplementary Table S1. Median age at baseline was 57 years, 53.2% of participants were female, and 94.6% were white. Median BMI, WC, and WHR for the whole cohort population were 26.7 kg/m&lt;sup&gt;2&lt;/sup&gt;, 90.0 cm, and 0.87, respectively. Furthermore, approximately 22% of the population had CRP levels greater than or equal to 3 mg/L at baseline.&lt;/p&gt;&lt;p&gt;Individuals classified as overweight or obese exhibited elevated CRP levels compared to those with a normal BMI. Additionally, participants in higher quartiles for both ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"456-459"},"PeriodicalIF":20.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12659","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}