Cancer Communications最新文献

{"title":"Parkin deficiency promotes colorectal tumorigenesis and progression through RIPK3-dependent necroptotic inflammation","authors":"Zheming Wu, Huaping Xiao, Jake A Kloeber, Yaobin Ouyang, Ping Yin, Jinzhou Huang, Bin Chen, Shouhai Zhu, Jing Lu, Yiqun Han, Xinyi Tu, Sonja Dragojevic, Kuntian Luo, Adrian T Ting, Meng Welliver, Zhenkun Lou","doi":"10.1002/cac2.12648","DOIUrl":"10.1002/cac2.12648","url":null,"abstract":"<p>Colorectal cancer (CRC), recognized as one of the most commonly diagnosed cancers globally, is a complex disease influenced by various factors, including lifestyle, genetics, and the environment [<span>1</span>]. Chronic bowel inflammation is one of the primary contributors to colorectal carcinogenesis [<span>2</span>]. The persistent systemic inflammatory response associated with tumors contributes to cachexia and malnutrition in patient, leading to increased morbidity and mortality. Previous studies have demonstrated that Parkin acts as a negative regulator of necroptosis by binding to and polyubiquitinating RIPK3 (Receptor-Interacting Protein Kinase 3), a pivotal regulator of necroptosis [<span>3</span>]. Loss of Parkin promotes hyperactivation of RIPK3, necroptosis, and inflammation-driven colorectal tumorigenesis. In colitis-associated models, inhibiting RIPK3 significantly reduces pro-inflammatory cytokine expression and cancerous polyp formation. However, the role of RIPK3 in tumorigenesis is complex [<span>4, 5</span>], and the physiological relationship between Parkin and RIPK3 in vivo remains incompletely understood.</p><p>To further investigate the tumor-suppressive effect of Parkin through the inhibition of RIPK3 in vivo, we crossed <i>Prkn</i> <sup>−/−</sup> mice and <i>Ripk3</i> <sup>−/−</sup> mice to generate <i>Prkn</i>/<i>Ripk3</i> double-knockout (DKO) mice from heterozygous <i>Prkn</i> <sup>+/−</sup> <i>Ripk3</i> <sup>+/−</sup> breeding pairs [<span>6, 7</span>]. The DKO mice were born at the expected Mendelian frequencies and were viable, healthy, and fertile (Figure 1A). Genotyping, genome sequence and Western blot analysis of mice from each group confirmed the successful generation of <i>Prkn</i> <sup>−/−</sup>, <i>Ripk3</i> <sup>−/−</sup> and DKO (Supplementary Figure S1, Supplementary Table S1). Long-term observations revealed that <i>Prkn</i> <sup>−/−</sup> mice had shorter lifespans and began to die around 8 months of age (Figure 1B). In contrast, <i>Ripk3</i> single-knockout mice and DKO mice exhibited survival curves similar to those of wide-type (WT) mice. These results indicate that Parkin deficiency may induce abnormalities that contribute to reduced survival, and this phenotype is regulated by Ripk3.</p><p>As reported previously [<span>3</span>], we found an increased frequency of rectal prolapse in <i>Prkn <sup>−/−</sup></i> mice (Figure 1C, Supplementary Figure S2A). However, in DKO mice, the number of mice with rectal prolapse significantly decreased. Meanwhile, the weight of <i>Prkn <sup>−/−</sup></i> mice was significantly less than that of WT mice (Supplementary Figure S2B). However, further knockout of <i>Ripk3</i> in <i>Prkn <sup>−/−</sup></i> mice did not rescue this low-weight phenotype. To explore this further, we dissected mice of all genotypes with similar ages and genders and found that the <i>Prkn <sup>−/−</sup></i> mice had more polyps and obvious lesion in their small intestine, while knocking o","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"406-410"},"PeriodicalIF":20.1,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12648","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926529","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 multi-omics reveals tumor microenvironment factors underlying poor immunotherapy responses in ALK-positive lung cancer","authors":"Seungbyn Baek, Euijeong Sung, Gamin Kim, Min Hee Hong, Chang Young Lee, Hyo Sup Shim, Seong Yong Park, Hye Ryun Kim, Insuk Lee","doi":"10.1002/cac2.12658","DOIUrl":"10.1002/cac2.12658","url":null,"abstract":"<p>Lung cancer remains the leading cause of cancer death in 2024, with ∼80% being non-small cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) rearrangements occur in ∼5% of NSCLC cases, typically treated with ALK inhibitors, though resistance often develops [<span>1</span>]. Immunotherapy has been explored for advanced or resistant ALK-positive NSCLC, but immune checkpoint blockade (ICB) treatments have shown limited clinical benefits [<span>1</span>].</p><p>A comprehensive study of ALK-positive NSCLC tumor microenvironment (TME) is needed to understand immunotherapy limitations and improve treatment strategies. We generated and collected single-cell RNA sequencing (scRNA-seq) and single-cell Assay for Transposase Accessible Chromatin with high-throughput sequencing (scATAC-seq) datasets from lung adenocarcinoma (LUAD) patients with ALK rearrangements and wild type without major oncogenic drivers (WT) (Supplementary Table S1). By comparing TME, we aimed to identify features explaining poor immunotherapy responses (Figure 1A).</p><p>After batch corrections for each of the RNA and ATAC profiles, we identified epithelial, stromal, and immune cells (Supplementary Figure S1A, Supplementary Table S2). From the immune compartment, we identified major cell types such as myeloid cells, T cells, natural killer (NK) cells, and B cells (Figure 1B, Supplementary Figure S1B, Supplementary Table S3). Integration of the RNA and ATAC profiles confirmed consistency between these two omics profiles (Supplementary Figure S1C-D). Compositional analysis revealed that ALK-positive samples showed an enrichment of innate immune cells (myeloid and NK cells) and depletion of adaptive immune cells (T and B cells) (Figure 1C, Supplementary Figure S1E-F), suggesting weak adaptive anti-tumoral responses in ALK-positive TME.</p><p>Oncogenic mutations primarily impact epithelial cells, so we classified epithelial cell malignancy with the cell-classifier and copy number variations (Supplementary Figure S1G-H) and measured <i>ALK</i> and <i>PD-L1</i> expression. Malignant cells expressing <i>ALK</i> or <i>PD-L1</i> were predominantly from ALK-positive malignant cells (Supplementary Figure S1I). We observed that ALK-positive tumors had a higher malignant-to-normal epithelial cell ratio than WT tumors (Figure 1D). Additionally, malignant cells in ALK-positive tumors exhibited increased stemness, indicating greater developmental potential (Figure 1E). Top 100 upregulated genes in ALK-positive tumors were linked to aggressive cancer pathways like epithelial-mesenchymal transition (EMT) and hypoxia [<span>2</span>] (Figure 1F).</p><p>To identify malignant subsets with higher progression potential, we constructed developmental trajectories (Supplementary Figure S1J). State 4, enriched with ALK-positive malignant cells, showed higher stemness and elevated stress, hypoxia, and EMT gene signatures (Supplementary Figure S1J-L, Supplementary Table S4). Survival analysis with LUAD pa","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"422-427"},"PeriodicalIF":20.1,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12658","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926603","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":"Incidence of and survival with bone and soft tissue sarcoma: A nation-wide study over four decades","authors":"Maria Anna Smolle, Florian Alexander Wenzl, Joanna Szkandera, Susanne Scheipl, Bernadette Liegl-Atzwanger, Jasminka Igrec, Andreas Leithner","doi":"10.1002/cac2.12653","DOIUrl":"10.1002/cac2.12653","url":null,"abstract":"<p>Demographic and environmental factors determine the incidence of and survival with malignancies, including sarcoma [<span>1</span>]. Accordingly, the annual incidence of soft tissue sarcomas (STS) has markedly increased since the early 2000s [<span>2, 3</span>]. Likewise, there appears to be an overall increase in the incidence of bone sarcomas (BS) since 1975 [<span>4, 5</span>]. In parallel, one study reports moderate improvement in the survival of adult patients with BS and STS up to 2007 [<span>6</span>]. Previous studies were often based on cancer registries with low coverage rates [<span>3, 7, 8</span>], focused on limited time periods [<span>3, 9, 10</span>], or did not include data from recent years [<span>3, 6</span>]. Thus, current data from high-income European countries with an advanced health care system on incidence and prognosis of sarcoma patients are scarce. Consequently, the purpose of this study was to analyse the incidence of and survival with BS and STS in the general population of Austria from 1983 to 2020. A detailed description of materials and methods is outlined in the Supplementary Materials (Supplementary Materials and Methods).</p><p>Across the 38-year observation period, 2,491 patients in Austria were diagnosed with BS (Supplementary Tables S1-S2, Supplementary Figure S1). Male-to-female ratio was 1.27, favouring males (range over the years: 0.56-1.23), which remained constant over time <i>(P =</i> 0.529; Supplementary Table S3).</p><p>Throughout the observation period, mean age-adjusted BS incidence was 0.80 per 100,000 (95% confidence interval [CI]: 0.61-0.98; Figure 1A). We observed a significant increase in incidence from 1983 to 2020, with an average annual percentage change (AAPC) of 7.2% (95%CI: 6.2%-8.5%; <i>P</i> < 0.001; Supplementary Table S4). Similar results were obtained in a sensitivity analysis excluding the initial 7 years of the observation period (<i>ie</i>, 1983-1989; AAPC: 1.5% [95%CI: 1.0%-2.1%]; <i>P</i> < 0.001) and chondrosarcoma diagnoses (AAPC: 5.8% [95%CI: 4.9%-7.2%]; <i>P</i> < 0.001; Supplementary Figure S2A; Supplementary Table S4).</p><p>Age at diagnosis of BS followed a bimodal distribution, with peaks in incidence around the age of 15 years and 70 years (Figure 1B), both in males and females (Supplementary Figure S3A). Notably, a shift towards increased BS incidence in older age groups was present in recent years (Supplementary Figure S4A, Supplementary Figure S5A). In a sensitivity analysis excluding all chondrosarcoma diagnoses, a similar pattern was observed (Supplementary Figure S2B).</p><p>Five-year relative survival was 65.9% (95%CI: 63.9%-67.9%). No change in 5-year relative survival was found from the first time period (1987-1990; 5-year relative survival: 65.3% [95%CI: 50.7%-76.7%]) to the last time period (2015-2020; 5-year relative survival: 66.7% [95%CI: 62.5%70.7%]; <i>P</i> = 0.735; Figure 1C). Of note, the youngest age group (0-20 years) had better 5-year r","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"397-400"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12653","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920859","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":"Cytotoxic and regulatory T cell interactions calculated from image mass cytometry predict immunochemotherapy response in triple-negative breast cancer","authors":"Xiang Wang, Jing Dong, Jian-Rong Li, Yupei Lin, Bikram Sahoo, Yong Li, Yanhong Liu, Robert Taylor Ripley, Jia Wu, Jianjun Zhang, Christopher I Amos, Chao Cheng","doi":"10.1002/cac2.12652","DOIUrl":"10.1002/cac2.12652","url":null,"abstract":"<p>In the tumor microenvironment (TME), various types of immune cells interact with each other and with cancer cells, playing critical roles in cancer progression and treatment [<span>1</span>]. Numerous studies have reported that the infiltration levels of specific immune cells are associated with patient prognosis and response to immunotherapies [<span>2, 3</span>]. For instance, the density of pre-existing tumor infiltrating lymphocytes in the TME has been found to positively correlate with patient responses to anti-PD-1 treatment in triple-negative breast cancer (TNBC) [<span>3</span>]. However, the relationship between immune cell-cell interactions (CCIs) in the TME and patient clinical outcomes remains unclear due to the limited availability of large-scale datasets for systematic CCI investigation. Recently, imaging mass cytometry (IMC) has been utilized to characterize the immune landscape within the TME of tumor samples [<span>4</span>]. IMC can detect 30 to 40 protein markers on a single tissue slide, enabling the visualization of spatial distributions of various cell types at single-cell resolution. Analyzing IMC data enables the quantification of interactions between all TME cell types by examining their spatial distributions.</p><p>In this study, we conducted a systematic analysis to investigate the association between CCIs and treatment responses of cancer patients using a large IMC dataset. The dataset comprises the immune landscape of 660 tumor samples from 279 TNBC patients enrolled in a randomized clinical trial [<span>4</span>]. These patients were treated with either neoadjuvant chemotherapy (<i>n</i> = 141) or immunochemotherapy therapy (chemotherapy combined with anti-PD-L1 immunotherapy, (<i>n</i> = 138), with tumor samples collected at three time points for IMC analysis: baseline, early on-treatment, and post-treatment. We applied a modified method introduced by Windhager <i>et al.</i> [<span>5</span>] to quantify interactions for all pairs of cell types captured by IMC and examined their associations with patient outcomes (Supplementary Material and Methods). Our results indicated that compared to the infiltration levels of immune cells, CCIs between specific immune cell types were more strongly correlated with patient responses. Notably, we found that the interaction between regulatory T cells (Treg) and GZMB<sup>+</sup> cytotoxic CD8<sup>+</sup> T (Tc) cells in pre-treatment samples was predictive of patient response to immunochemotherapy but not to chemotherapy alone in TNBC.</p><p>The processed IMC data provides the coordinates of all single cells along with their cell type annotations. To quantify the interaction from cell type X to Y (X→Y), we calculated the average number of X cells among the 10 nearest neighbors of each Y cell and standardized this as a Z-score by comparing it with a null distribution generated through permutations. In each permutation, we shuffled the labels of all cell types except epithelial cel","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"392-396"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12652","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920857","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":"Efficient 5-ALA-photodynamic therapy in nasopharyngeal carcinoma induces an immunoactivation mediated by tumoral extracellular vesicles and associated with immunogenic cell death","authors":"Camille Trioën, Thomas Soulier, Jacquie Massoud, Clément Bouchez, Nicolas Stoup, Anthony Lefebvre, Anne-Sophie Dewalle, Guillaume Paul Grolez, Nadira Delhem, Olivier Moralès","doi":"10.1002/cac2.12656","DOIUrl":"10.1002/cac2.12656","url":null,"abstract":"<p>Nasopharyngeal carcinoma (NPC) is a rare cancer, with 120,334 cases worldwide in 2022, but it remains endemic in Southeast Asia and North Africa. Early-stage NPC is typically treated with radiotherapy, often combined with chemotherapy for advanced stages [<span>1</span>]. Despite a 5-year survival rate of 70% to 90% for locoregional disease, late-stage diagnosis and locoregional or distant recurrence and metastasis (R/M) result in a poor prognosis for many patients, underscoring the urgent need for novel therapeutic strategies [<span>2-4</span>]. The tumor microenvironment, enriched with immunosuppressive elements such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), plays a central role in promoting immune evasion and resistance to therapy. In NPC, effective therapeutic strategies should not only induce tumor cell death but also reprogram this immunosuppressive microenvironment to restore robust anti-tumor immunity. To address these challenges, we propose evaluating the efficacy of photodynamic therapy (PDT) and its immunoactivating properties in NPC. PDT is a non-invasive treatment that induces cell death via reactive oxygen species (ROS) and activates an anti-tumor immune response by releasing tumor antigens and damage-associated molecular patterns (DAMPs) [<span>5, 6</span>]. After examining the direct cell death induced by 5-aminolevulinic acid (5-ALA)-PDT, we investigated its ability to trigger immune activation and its effects on immune cell populations and their secretome. Lastly, we conducted an in-depth analysis of molecular and vesicular (extracellular vesicle) components to understand the mechanisms underlying immune response activation. Detailed study designs and methods are available in the Supplementary Materials.</p><p>The prodrug 5-ALA is preferentially absorbed by tumor cells and metabolized into protoporphyrin IX (PpIX), the photosensitizer, via the heme synthesis pathway (Supplementary Figure S1A). To evaluate 5-ALA-PDT in NPC cell lines, we assessed their capacity to convert 5-ALA into PpIX. We observed that NPC cell lines expressed key enzymes and transporters involved in the heme pathway, with no significant differences, confirming their ability to metabolize 5-ALA into PpIX (Supplementary Figure S1B). We then incubated NPC cells with varying concentrations of 5-ALA, showing successful conversion of 5-ALA into intracellular PpIX after 2 hours, followed by extracellular release of PpIX between 6 to 8 hours (Figure 1A, Supplementary Figure S1C). Based on these findings and considering clinical data, we selected a 4-hour incubation period for subsequent experiments.</p><p>To determine the direct impact and efficacy of 5-ALA-PDT on NPC cell lines, we subjected the cells to 5-ALA-PDT. A dose-dependent reduction in cell viability was observed, with CNE2 cells (EC50: 104.9 µmol/L) exhibiting greater sensitivity to treatment compared to CNE1 cells (EC50: 209.7 µmol/L) (Figure 1B, Suppl","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"401-405"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12656","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920858","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":"Multiscale 3D spatial analysis of the tumor microenvironment using whole-tissue digital histopathology","authors":"Daniel Shafiee Kermany, Ju Young Ahn, Matthew Vasquez, Weijie Zhang, Lin Wang, Kai Liu, Zhan Xu, Min Soon Cho, Wendolyn Carlos-Alcalde, Hani Lee, Raksha Raghunathan, Jianting Sheng, Xiaoxin Hao, Hong Zhao, Vahid Afshar-Kharghan, Xiang Hong-Fei Zhang, Stephen Tin Chi Wong","doi":"10.1002/cac2.12655","DOIUrl":"10.1002/cac2.12655","url":null,"abstract":"<p>Spatial statistics are crucial for analyzing clustering patterns in various spaces, such as the distribution of trees in a forest or stars in the sky. Advances in spatial biology, such as single-cell spatial transcriptomics, enable researchers to map gene expression patterns within tissues, offering unprecedented insights into cellular functions and disease pathology. Common methods for deriving spatial relationships include density-based methods (quadrat analysis, kernel density estimators) and distance-based methods (nearest-neighbor distance [NND], Ripley's K function). While density-based methods are effective for visualization, they struggle with quantification due to sensitivity to parameters and complex significance tests. In contrast, distance-based methods offer robust frameworks for hypothesis testing, quantifying spatial clustering or dispersion, and facilitating comparisons with models such as uniform random distributions or Poisson processes [<span>1, 2</span>].</p><p>Ripley's K function provides a detailed measure of spatial clustering or dispersion across multiple scales by considering all pairs of points within specified distances. This is in contrast to NND, which may overlook structures that vary across scales. Ripley's K function can detect complex spatial patterns over a range of distances, making it suitable for datasets with non-uniform arrangements that exhibit different behaviors at different scales. However, its broader adoption has been hindered by computational complexity and challenges in interpretation, especially for three-dimensional data, which are common in spatial biomedical research [<span>3-6</span>].</p><p>To address these limitations, we introduce MDSpacer (Multi-Dimensional Spatial Pattern Analysis with Comparable and Extendable Ripley's K), a modeling tool that implements Ripley's K function for both 2D and 3D data, facilitating detailed analyses within and between groups (Figure 1A, B, Supplementary Figure S1). MDSpacer uses a novel normalization scheme (described in Supplementary Materials and Methods) that dramatically reduces computational overhead while delivering results in an easily interpretable and comparable format (Figure 1C–F). We validated this tool in two cancer research studies: one on metastatic bone cancer and another on ovarian cancer. In the metastatic bone cancer study, we used the Vessel3D analysis toolkit to extract spatial point information from 3D confocal images of murine femurs with early-stage spontaneous metastasis (Figure 1G–K, Supplementary Figures S2, S3, Supplementary Videos S1, S2). MDSpacer identified both expected clustering at short distances and unexpected dispersion patterns at larger scales between early-stage disseminated tumor cells (DTCs) and neural/glial antigen 2-positive (NG2<sup>+</sup>) mesenchymal cells in relation to other microenvironmental factors [<span>7-9</span>]. Interestingly, no spatial relationships were observed between DTCs and vessel bifurcatio","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":"386-390"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12655","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920860","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":"A strong internal promoter drives massive expression of YEATS-domain devoid MLLT3 transcripts in HSC and most lethal AML","authors":"Chloé Bessière, Ahmed Zamani, Romain Pfeifer, Sandra Dailhau, Camille Marchet, Benoit Guibert, Anthony Boureux, Raïssa Silva Da Silva, Nicolas Gilbert, Thérèse Commes, Fabienne Meggetto, Christian Touriol, Christian Récher, Marina Bousquet, Stéphane Pyronnet","doi":"10.1002/cac2.12650","DOIUrl":"10.1002/cac2.12650","url":null,"abstract":"<p>The AF9 (protein AF9) transcription factor, encoded by <i>MLLT3</i> (<i>mixed-lineage leukemia translocated to 3</i>) on chromosome 9, functions as a chromatin reader. Through its N-terminal YEATS (Yaf9, ENL, AF9, Taf14, and Sas5) protein domain, it interacts with acetylated [<span>1</span>] or crotonylated [<span>2</span>] histone H3, as well as with the PAF1 (RNA polymerase II-associated factor 1 homolog) and P-TEFb (positive transcription elongation factor b) components of the super elongation complex (SEC). AF9 also interacts through its poly-serine domain (Poly-Ser) with the TFIID (Transcription factor II D) subunit of the RNA polymerase II (RNApol II) complex. In addition, its C-terminal transactivation domain, AHD (nuclear anchorage protein1 homology domain), binds other SEC components, such as AFF1 and AFF4 (ALF transcription elongation factor 1 or 4), as well as transcription regulators CBX8 (chromobox 8), DOT1L (disruptor of telomeric silencing 1 like), and BCOR (B cell lymphoma 6 corepressor), as reviewed by Kabra & Bushweller [<span>3</span>] (Figure 1A). Thus, MLLT3 is an integral part of the SEC, which is essential for optimizing the catalytic activity of RNApol II transcription at specific genome loci.</p><p>Several studies have indicated that <i>MLLT3</i> is highly and specifically expressed in hematopoietic stem cells (HSCs), but it is rapidly and significantly downregulated during normal differentiation or immediately after HSCs are placed in <i>ex vivo</i> culture. In both scenarios, this shutdown parallels the rapid loss of stemness. Consistently, ectopic expression of <i>MLLT3</i> significantly prolongs self-renewal capacity of HSCs, suggesting that <i>MLLT3</i> is a crucial factor for HSC maintenance [<span>4</span>].</p><p>Based on standard quantification of RNA-sequencing reads mapping to the <i>MLLT3</i> locus, we first confirmed that, compared to the <i>MLLT1</i> paralogue used as an internal control, <i>MLLT3</i> expression was significantly higher in CD34<sup>+</sup> cells than in mature lymphocytes, granulocytes, or monocytes from healthy samples of the Leucegene dataset (Leucegene-NH, detailed in Supplementary Information) (Figure 1B, left panel). To refine this observation, made in CD34<sup>+</sup> cells containing a mixture of progenitors but only a few HSCs, we repeated the analysis in HSCs and various stages of progenitor cells sorted form healthy donors (IUCT-NH, detailed in Supplementary Information). The data clearly confirmed that <i>MLLT3</i> is highly expressed in HSCs but rapidly declines as differentiation proceeds (Figure 1B, right panel).</p><p>However, closer examination using a k-mer approach (described in Materials and Methods in Supplementary Information), which visualized RNA-sequencing read alignment along the 11 exons (E1-E11) of the reference <i>MLLT3</i> transcript, revealed an unexpected profile. Strikingly, the substantial <i>MLLT3</i> expression detected in HSCs was driven by a sharp ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":"380-385"},"PeriodicalIF":20.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12650","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920856","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":"The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of colorectal cancer, 2024 update","authors":"Feng Wang,&nbsp;Gong Chen,&nbsp;Zhen Zhang,&nbsp;Ying Yuan,&nbsp;Yi Wang,&nbsp;Yuan-Hong Gao,&nbsp;Weiqi Sheng,&nbsp;Zixian Wang,&nbsp;Xinxiang Li,&nbsp;Xianglin Yuan,&nbsp;Sanjun Cai,&nbsp;Li Ren,&nbsp;Yunpeng Liu,&nbsp;Jianmin Xu,&nbsp;Yanqiao Zhang,&nbsp;Houjie Liang,&nbsp;Xicheng Wang,&nbsp;Aiping Zhou,&nbsp;Jianming Ying,&nbsp;Guichao Li,&nbsp;Muyan Cai,&nbsp;Gang Ji,&nbsp;Taiyuan Li,&nbsp;Jingyu Wang,&nbsp;Hanguang Hu,&nbsp;Kejun Nan,&nbsp;Liuhong Wang,&nbsp;Suzhan Zhang,&nbsp;Jin Li,&nbsp;Rui-Hua Xu","doi":"10.1002/cac2.12639","DOIUrl":"10.1002/cac2.12639","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The 2024 updates of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for the diagnosis and treatment of colorectal cancer emphasize standardizing cancer treatment in China, highlighting the latest advancements in evidence-based medicine, healthcare resource access, and precision medicine in oncology. These updates address disparities in epidemiological trends, clinicopathological characteristics, tumor biology, treatment approaches, and drug selection for colorectal cancer patients across diverse regions and backgrounds. Key revisions include adjustments to evidence levels for intensive treatment strategies, updates to regimens for deficient mismatch repair (dMMR)/ microsatellite instability-high (MSI-H) patients, proficient mismatch repair (pMMR)/ microsatellite stability (MSS) patients who have failed standard therapies, and rectal cancer patients with low recurrence risk. Additionally, recommendations for digital rectal examination and DNA polymerase epsilon (<i>POLE</i>)/ DNA polymerase delta 1 (<i>POLD1</i>) gene mutation testing have been strengthened. The 2024 CSCO Guidelines are based on both Chinese and international clinical research, as well as expert consensus, ensuring their relevance and applicability in clinical practice, while maintaining a commitment to scientific rigor, impartiality, and timely updates.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":"332-379"},"PeriodicalIF":20.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909451","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":"Current status and perspectives of esophageal cancer: a comprehensive review","authors":"Wei Jiang,&nbsp;Bo Zhang,&nbsp;Jiaqi Xu,&nbsp;Liyan Xue,&nbsp;Luhua Wang","doi":"10.1002/cac2.12645","DOIUrl":"10.1002/cac2.12645","url":null,"abstract":"<p>Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":"281-331"},"PeriodicalIF":20.1,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12645","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892071","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":"Orchestrated desaturation reprogramming from stearoyl-CoA desaturase to fatty acid desaturase 2 in cancer epithelial-mesenchymal transition and metastasis","authors":"Zhicong Chen,&nbsp;Yanqing Gong,&nbsp;Fukai Chen,&nbsp;Hyeon Jeong Lee,&nbsp;Jinqin Qian,&nbsp;Jing Zhao,&nbsp;Wenpeng Zhang,&nbsp;Yamin Li,&nbsp;Yihui Zhou,&nbsp;Qiaobing Xu,&nbsp;Yu Xia,&nbsp;Liqun Zhou,&nbsp;Ji-Xin Cheng","doi":"10.1002/cac2.12644","DOIUrl":"10.1002/cac2.12644","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Adaptative desaturation in fatty acid (FA) is an emerging hallmark of cancer metabolic plasticity. Desaturases such as stearoyl-CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2) have been implicated in multiple cancers, and their dominant and compensatory effects have recently been highlighted. However, how tumors initiate and sustain their self-sufficient FA desaturation to maintain phenotypic transition remains elusive. This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts, which guided subsequent functional and mechanistic investigations. The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines. Specific desaturation activities were characterized through various isomer-resolved lipidomics methods and sensitivity assays using desaturase inhibitors. In-situ lipid profiling was conducted using multiplex stimulated Raman scattering imaging. Functional assays were performed both in vitro and in vivo, with RNA-sequencing employed for the mechanism verification.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;After integration of the RNA-protein-metabolite levels, the data revealed that a reprogramming from SCD-dependent to FADS2-dependent desaturation was linked to cancer epithelial-mesenchymal transition (EMT) and progression in both patients and cell lines. FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity. A FADS2/β-catenin self-reinforcing feedback loop facilitated the degree of lipid unsaturation, membrane fluidity, metastatic potential and EMT signaling. Moreover, SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate-activated protein kinase activation. Notably, this desaturation reprogramming increased transforming growth factor-β2, effectively sustaining aggressive phenotypes and metabolic plasticity during EMT.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings revealed a metabolic reprogramming from SCD-dependent to FADS2-dependent desaturation during cancer EMT and progression, which concurrently supports EMT plasticity. Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy.&lt;/p&gt;\u0000 ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":"245-280"},"PeriodicalIF":20.1,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12644","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892117","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}