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MET and NF2 alterations confer primary and early resistance to first-line alectinib treatment in ALK-positive non-small-cell lung cancer.
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-04-01 DOI: 10.1002/1878-0261.70029
Jie Hu, Ning Ding, Xiaobo Xu, Yedan Chen, Yong Zhang, Jingwen Liu, Jiebai Zhou, Hairong Bao, Donghui Zhang, Yijun Song, Yang Shao, Yuanlin Song

Although first-line alectinib has prolonged survival in ALK-mutated non-small-cell lung cancers (NSCLCs), the response to treatment varies among patients, and the primary/early development of alectinib resistance mechanisms is still not fully understood. Here, we analyzed molecular profiles of 108 alectinib-treated patients (first-line and second-line after crizotinib) with confirmed relapse by targeted sequencing of cancer-related genes. After first-line treatment, off-target MET and NF2 alterations were more frequent than on-target alterations within the first 6 months, causing primary or early resistance. Conversely, on-target alterations became prevalent after 1 year of first-line alectinib treatment and predominantly after second-line. The incidence of acquired resistance also depended on EML4-ALK variants. In variant 1 (v1), off-target alterations were responsible for 50% of resistance cases after first-line alectinib therapy, whereas on-target mutations had no contribution in this subgroup. In variant 3 (v3), on-target alterations resulted in 46% of resistance cases, whereas only 18% were caused by off-target mutations. After second-line treatment, the most common mutations in v1 were L1196M (42%) and G1269A (25%), while G1202R was detected in 45% of v3 tumors. These findings emphasize the importance of stratifying resistance mechanisms to guide tailored treatment for ALK-positive NSCLCs.

{"title":"MET and NF2 alterations confer primary and early resistance to first-line alectinib treatment in ALK-positive non-small-cell lung cancer.","authors":"Jie Hu, Ning Ding, Xiaobo Xu, Yedan Chen, Yong Zhang, Jingwen Liu, Jiebai Zhou, Hairong Bao, Donghui Zhang, Yijun Song, Yang Shao, Yuanlin Song","doi":"10.1002/1878-0261.70029","DOIUrl":"https://doi.org/10.1002/1878-0261.70029","url":null,"abstract":"<p><p>Although first-line alectinib has prolonged survival in ALK-mutated non-small-cell lung cancers (NSCLCs), the response to treatment varies among patients, and the primary/early development of alectinib resistance mechanisms is still not fully understood. Here, we analyzed molecular profiles of 108 alectinib-treated patients (first-line and second-line after crizotinib) with confirmed relapse by targeted sequencing of cancer-related genes. After first-line treatment, off-target MET and NF2 alterations were more frequent than on-target alterations within the first 6 months, causing primary or early resistance. Conversely, on-target alterations became prevalent after 1 year of first-line alectinib treatment and predominantly after second-line. The incidence of acquired resistance also depended on EML4-ALK variants. In variant 1 (v1), off-target alterations were responsible for 50% of resistance cases after first-line alectinib therapy, whereas on-target mutations had no contribution in this subgroup. In variant 3 (v3), on-target alterations resulted in 46% of resistance cases, whereas only 18% were caused by off-target mutations. After second-line treatment, the most common mutations in v1 were L1196M (42%) and G1269A (25%), while G1202R was detected in 45% of v3 tumors. These findings emphasize the importance of stratifying resistance mechanisms to guide tailored treatment for ALK-positive NSCLCs.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ShcD adaptor protein drives invasion of triple negative breast cancer cells by aberrant activation of EGFR signaling. ShcD 适应蛋白通过表皮生长因子受体信号的异常激活驱动三阴性乳腺癌细胞的侵袭。
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-28 DOI: 10.1002/1878-0261.70022
Hayley R Lau, Hayley S Smith, Begüm Alural, Claire E Martin, Laura A New, Manali Tilak, Sara L Banerjee, Hannah N Robeson, Nicolas Bisson, Anne-Claude Gingras, Jasmin Lalonde, Nina Jones

Triple-negative breast cancer (TNBC) is highly metastatic and presents clinical challenges given the lack of targeted therapies. Here, we report that the ShcD phosphotyrosine adaptor protein is upregulated in TNBC, and its expression correlates with overall reduced patient survival and decreased response to chemotherapy. In human breast cancer cells, we demonstrate that ShcD expression promotes cell invasion and reduces adhesion, and that these effects are abrogated by mutating the ShcD phosphotyrosine binding (PTB) domain. Similarly, in a three-dimensional assembloid model, ShcD-expressing spheroids derived from brain metastatic TNBC cells show enhanced infiltration into cerebral organoids. Using a proteomic screen for ShcD binding partners, we identify multiple components of epidermal growth factor receptor (EGFR) signaling and confirm these interactions with ShcD but not the PTB mutant. Interestingly, the ShcD interactome correlates with EGFR tyrosine kinase inhibitor resistance, in line with our findings that ShcD overexpression results in hyperphosphorylation of EGFR while ShcD knockout or PTB mutation reverts this response. Lastly, pharmacological inhibition of the ShcD PTB domain using indomethacin in TNBC cells decreases EGFR binding and hyperphosphorylation and reduces cell invasion. Altogether, our results identify ShcD as a potential contributor to metastasis in TNBC, and they provide a molecular basis for clinical targeting of adaptor proteins.

{"title":"ShcD adaptor protein drives invasion of triple negative breast cancer cells by aberrant activation of EGFR signaling.","authors":"Hayley R Lau, Hayley S Smith, Begüm Alural, Claire E Martin, Laura A New, Manali Tilak, Sara L Banerjee, Hannah N Robeson, Nicolas Bisson, Anne-Claude Gingras, Jasmin Lalonde, Nina Jones","doi":"10.1002/1878-0261.70022","DOIUrl":"https://doi.org/10.1002/1878-0261.70022","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is highly metastatic and presents clinical challenges given the lack of targeted therapies. Here, we report that the ShcD phosphotyrosine adaptor protein is upregulated in TNBC, and its expression correlates with overall reduced patient survival and decreased response to chemotherapy. In human breast cancer cells, we demonstrate that ShcD expression promotes cell invasion and reduces adhesion, and that these effects are abrogated by mutating the ShcD phosphotyrosine binding (PTB) domain. Similarly, in a three-dimensional assembloid model, ShcD-expressing spheroids derived from brain metastatic TNBC cells show enhanced infiltration into cerebral organoids. Using a proteomic screen for ShcD binding partners, we identify multiple components of epidermal growth factor receptor (EGFR) signaling and confirm these interactions with ShcD but not the PTB mutant. Interestingly, the ShcD interactome correlates with EGFR tyrosine kinase inhibitor resistance, in line with our findings that ShcD overexpression results in hyperphosphorylation of EGFR while ShcD knockout or PTB mutation reverts this response. Lastly, pharmacological inhibition of the ShcD PTB domain using indomethacin in TNBC cells decreases EGFR binding and hyperphosphorylation and reduces cell invasion. Altogether, our results identify ShcD as a potential contributor to metastasis in TNBC, and they provide a molecular basis for clinical targeting of adaptor proteins.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting the AKT/mTOR pathway attenuates the metastatic potential of colorectal carcinoma circulating tumor cells in a murine xenotransplantation model. 在小鼠异种移植模型中,靶向 AKT/mTOR 通路可减轻结直肠癌循环肿瘤细胞的转移潜力。
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-25 DOI: 10.1002/1878-0261.70024
Daniel J Smit, Thais Pereira-Veiga, Helena Brauer, Michael Horn, Paula Nissen, Thomas Mair, Bente Siebels, Hannah Voß, Ruimeng Zhuang, Marie-Therese Haider, Desiree Loreth, Margarita Iskhakova, Bele Lindemann, Julian Kött, Laure Cayrefourcq, Jasmin Wellbrock, Hartmut Schlüter, Klaus Pantel, Catherine Alix-Panabières, Manfred Jücker

Circulating tumor cells (CTCs) play an important role in metastasis formation. Aberrant signaling of oncogenic pathways (e.g., PI3K/AKT/mTOR pathway) drives tumor progression. In this work, the susceptibility of the colon cancer CTC-derived cell line CTC-MCC-41 to AKT and mammalian target of rapamycin (mTOR) inhibitors was evaluated. Additionally, the functional role of the expressed AKT isoforms was characterized in this cell line. The efficacy of the AKT inhibitor MK2206, the mTOR inhibitor RAD001, and the combination was examined in CTC-MCC-41 cells in a murine intracardiac xenotransplantation model. Furthermore, stable isoform-specific AKT1 or AKT2 knockdowns (KDs) as well as AKT1/AKT2 double-KD cells were generated. Differentially regulated proteins and phospho-peptides were identified using liquid chromatography coupled mass spectrometry (LC-MS). CTC-MCC-41 cells showed a high susceptibility for dual targeting of AKT and mTOR in vivo, indicating that selective eradication of CTCs by AKT/mTOR inhibitors may be considered a new treatment option in cancer. KD of AKT1 or AKT2 significantly reduced the proliferation of CTC-MCC-41 cells. AKT KDs share commonly regulated proteins and phospho-proteins, but also regulate a large number uniquely. AKT1/AKT2 double-KD cells show a strongly dysregulated replication machinery, as well as a decrease in cell cycle activity and stem-cell-associated processes, underlining the non-redundant role of AKT isoforms.

循环肿瘤细胞(CTCs)在转移形成中发挥着重要作用。致癌通路(如 PI3K/AKT/mTOR 通路)信号的异常会推动肿瘤进展。本研究评估了结肠癌 CTC 衍生细胞系 CTC-MCC-41 对 AKT 和哺乳动物雷帕霉素靶标(mTOR)抑制剂的敏感性。此外,还对该细胞系中表达的 AKT 异构体的功能作用进行了鉴定。在小鼠心内异种移植模型中,研究人员检测了 AKT 抑制剂 MK2206、mTOR 抑制剂 RAD001 及其组合对 CTC-MCC-41 细胞的疗效。此外,还生成了稳定的同工酶特异性 AKT1 或 AKT2 基因敲除(KD)细胞以及 AKT1/AKT2 双 KD 细胞。使用液相色谱耦合质谱法(LC-MS)鉴定了受不同调控的蛋白质和磷酸化肽。CTC-MCC-41 细胞在体内对 AKT 和 mTOR 的双重靶向显示出高度敏感性,这表明通过 AKT/mTOR 抑制剂选择性地消灭 CTC 可被视为癌症治疗的一种新选择。AKT1或AKT2的KD能显著减少CTC-MCC-41细胞的增殖。AKT KDs具有共同的调控蛋白和磷酸化蛋白,但也有大量独特的调控蛋白。AKT1/AKT2双KD细胞显示出强烈的复制机制失调,以及细胞周期活性和干细胞相关过程的降低,强调了AKT同工酶的非冗余作用。
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引用次数: 0
MIF as an oncogenic driver of low-heterogeneity melanomas. MIF 是低异质性黑色素瘤的致癌驱动因素。
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-25 DOI: 10.1002/1878-0261.70031
Thuy T Tran, Gabriela Athziri Sánchez-Zuno, Rajan P Kulkarni, Harriet M Kluger, Richard Bucala

Identifying targets involved in tumor evolution and immune escape is an active area of research in oncology. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine that promotes transformed cell proliferation and survival, and generates a tumor-permissive immune landscape of immunosuppressive myeloid and T cells. Shvefel and colleagues have identified a key role for MIF in tumor progression in melanoma clones with low tumor heterogeneity. These findings provide important insights into the potential therapeutic utility of MIF antagonists and support ongoing research to utilize MIF pathway inhibitors for improved therapeutic outcomes.

{"title":"MIF as an oncogenic driver of low-heterogeneity melanomas.","authors":"Thuy T Tran, Gabriela Athziri Sánchez-Zuno, Rajan P Kulkarni, Harriet M Kluger, Richard Bucala","doi":"10.1002/1878-0261.70031","DOIUrl":"https://doi.org/10.1002/1878-0261.70031","url":null,"abstract":"<p><p>Identifying targets involved in tumor evolution and immune escape is an active area of research in oncology. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine that promotes transformed cell proliferation and survival, and generates a tumor-permissive immune landscape of immunosuppressive myeloid and T cells. Shvefel and colleagues have identified a key role for MIF in tumor progression in melanoma clones with low tumor heterogeneity. These findings provide important insights into the potential therapeutic utility of MIF antagonists and support ongoing research to utilize MIF pathway inhibitors for improved therapeutic outcomes.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages.
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-25 DOI: 10.1002/1878-0261.70032
Paula Díez, Pablo Juanes-Velasco, Marina L García-Vaquero, Conrad Droste, Alicia Landeira-Viñuela, Miguel Alcoceba, Helena Fidalgo-Gómez, Sara Misiego-Herrero, Almudena Navarro-Bailón, Mónica Baile, José M Bastida, Jose Manuel Sanchez-Santos, Rafael Góngora, Julia Almeida, Marcos Gonzalez-Diaz, Alberto Orfao, Javier De Las Rivas, Manuel Fuentes

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B-CLL and CLL-like monoclonal B-cell lymphocytosis (MBL) primary cells. Using high-resolution mass spectrometry, we identified 2970 proteins and 316 phosphoproteins across five tumor samples, including 55 newly identified phosphopeptides (ProteomeXchange-PXD005997). Our multifaceted approach also integrated protein microarrays and western blotting for further data validation in a new patient cohort of 14 patients. Despite sharing 73% of their proteomes, the phosphoproteomes varied significantly among samples, independent of cytogenetic alterations and immunoglobulin heavy variable cluster (IGHV) mutational status. We identified common functional hallmarks in B-CLL and MBL phosphoproteomes, notably tonic signaling (low-level, constitutive signaling) of the B-cell antigen-specific receptor (BCR) and nuclear factor NF-kappa-B (NF-kβ)/signal transducer and activator of transcription 3 (STAT3) pathways. Nine phosphoproteins involved in BCR signaling were further validated, showing a high correlation with early disease stages. Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B-CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.

{"title":"Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages.","authors":"Paula Díez, Pablo Juanes-Velasco, Marina L García-Vaquero, Conrad Droste, Alicia Landeira-Viñuela, Miguel Alcoceba, Helena Fidalgo-Gómez, Sara Misiego-Herrero, Almudena Navarro-Bailón, Mónica Baile, José M Bastida, Jose Manuel Sanchez-Santos, Rafael Góngora, Julia Almeida, Marcos Gonzalez-Diaz, Alberto Orfao, Javier De Las Rivas, Manuel Fuentes","doi":"10.1002/1878-0261.70032","DOIUrl":"https://doi.org/10.1002/1878-0261.70032","url":null,"abstract":"<p><p>B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B-CLL and CLL-like monoclonal B-cell lymphocytosis (MBL) primary cells. Using high-resolution mass spectrometry, we identified 2970 proteins and 316 phosphoproteins across five tumor samples, including 55 newly identified phosphopeptides (ProteomeXchange-PXD005997). Our multifaceted approach also integrated protein microarrays and western blotting for further data validation in a new patient cohort of 14 patients. Despite sharing 73% of their proteomes, the phosphoproteomes varied significantly among samples, independent of cytogenetic alterations and immunoglobulin heavy variable cluster (IGHV) mutational status. We identified common functional hallmarks in B-CLL and MBL phosphoproteomes, notably tonic signaling (low-level, constitutive signaling) of the B-cell antigen-specific receptor (BCR) and nuclear factor NF-kappa-B (NF-kβ)/signal transducer and activator of transcription 3 (STAT3) pathways. Nine phosphoproteins involved in BCR signaling were further validated, showing a high correlation with early disease stages. Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B-CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Time, the final frontier.
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-24 DOI: 10.1002/1878-0261.70025
Gautier Follain, Michal Dibus, Omkar Joshi, Guillaume Jacquemet

Cancer's notorious heterogeneity poses significant challenges, as each tumor comprises a unique ecosystem. While single-cell and spatial transcriptomics advancements have transformed our understanding of spatial diversity within tumors, the temporal dimension remains underexplored. Tumors are dynamic entities that continuously evolve and adapt, and relying solely on static snapshots obscures the intricate interplay between cancer cells and their microenvironment. Here, we advocate for integrating temporal dynamics into cancer research, emphasizing a fundamental shift from traditional endpoint experiments to data-driven, continuous approaches. This integration involves, for instance, the development of advanced live imaging techniques, innovative temporal omics methodologies, and novel computational tools.

{"title":"Time, the final frontier.","authors":"Gautier Follain, Michal Dibus, Omkar Joshi, Guillaume Jacquemet","doi":"10.1002/1878-0261.70025","DOIUrl":"https://doi.org/10.1002/1878-0261.70025","url":null,"abstract":"<p><p>Cancer's notorious heterogeneity poses significant challenges, as each tumor comprises a unique ecosystem. While single-cell and spatial transcriptomics advancements have transformed our understanding of spatial diversity within tumors, the temporal dimension remains underexplored. Tumors are dynamic entities that continuously evolve and adapt, and relying solely on static snapshots obscures the intricate interplay between cancer cells and their microenvironment. Here, we advocate for integrating temporal dynamics into cancer research, emphasizing a fundamental shift from traditional endpoint experiments to data-driven, continuous approaches. This integration involves, for instance, the development of advanced live imaging techniques, innovative temporal omics methodologies, and novel computational tools.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibitor of DNA binding-1 is a key regulator of cancer cell vasculogenic mimicry.
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-21 DOI: 10.1002/1878-0261.70027
Emma J Thompson, Emma L Dorward, Kristyn Jurrius, Nathalie Nataren, Markus Tondl, Kay K Myo Min, Michaelia P Cockshell, Anahita Fouladzadeh, John Toubia, Mark DeNichilo, Delphine Merino, Claudine S Bonder

Solid tumours routinely access the blood supply by promoting endothelium-dependent angiogenesis; but tumour vasculature can also be formed by cancer cells themselves via vasculogenic mimicry (VM). Investigation of the gene expression profile during the early stages of VM formation by MDA-MB-231-LM2 breast cancer cells identified the transcriptional regulator inhibitor of DNA binding 1 (ID1) to be elevated ~ 10-fold within the first 2 hours. This role for ID1 in promoting VM was supported by ID1 genetic knockdown or chemical inhibition interrupting VM formation by MDA-MB-231-LM2 (breast) and BxPC-3 (pancreatic) cancer cells. More specifically, reducing ID1 lowered cancer cell expression of endothelial cell genes (e.g. CDH5, TIE2) and production of pro-angiogenic proteins (e.g. VEGF, CD31, MMP9 and IL-8). In silico analysis of MDA-MB-231 cells engrafted into mice identified elevated ID1 expression in cancer cells that had metastasised to the lungs or liver, and an enrichment of pro-angiogenic genes. Additionally, Id1 knockdown in 4T1.13 murine breast cancer cells demonstrated reduced tumour growth and metastasis in vivo. Taken together, this study further implicates ID1 in a vascular program within cancer cells that supports disease progression.

{"title":"Inhibitor of DNA binding-1 is a key regulator of cancer cell vasculogenic mimicry.","authors":"Emma J Thompson, Emma L Dorward, Kristyn Jurrius, Nathalie Nataren, Markus Tondl, Kay K Myo Min, Michaelia P Cockshell, Anahita Fouladzadeh, John Toubia, Mark DeNichilo, Delphine Merino, Claudine S Bonder","doi":"10.1002/1878-0261.70027","DOIUrl":"https://doi.org/10.1002/1878-0261.70027","url":null,"abstract":"<p><p>Solid tumours routinely access the blood supply by promoting endothelium-dependent angiogenesis; but tumour vasculature can also be formed by cancer cells themselves via vasculogenic mimicry (VM). Investigation of the gene expression profile during the early stages of VM formation by MDA-MB-231-LM2 breast cancer cells identified the transcriptional regulator inhibitor of DNA binding 1 (ID1) to be elevated ~ 10-fold within the first 2 hours. This role for ID1 in promoting VM was supported by ID1 genetic knockdown or chemical inhibition interrupting VM formation by MDA-MB-231-LM2 (breast) and BxPC-3 (pancreatic) cancer cells. More specifically, reducing ID1 lowered cancer cell expression of endothelial cell genes (e.g. CDH5, TIE2) and production of pro-angiogenic proteins (e.g. VEGF, CD31, MMP9 and IL-8). In silico analysis of MDA-MB-231 cells engrafted into mice identified elevated ID1 expression in cancer cells that had metastasised to the lungs or liver, and an enrichment of pro-angiogenic genes. Additionally, Id1 knockdown in 4T1.13 murine breast cancer cells demonstrated reduced tumour growth and metastasis in vivo. Taken together, this study further implicates ID1 in a vascular program within cancer cells that supports disease progression.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Microglial reprogramming: a potential new frontier in enhancing immunotherapy for melanoma brain metastasis.
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-20 DOI: 10.1002/1878-0261.70028
Noam Savion-Gaiger, Dorin Bar-Ziv, Harriet Kluger

The brain is a common site of metastatic dissemination in advanced melanoma. Due to limited access to samples from human brain metastases, our understanding of the tumor microenvironment in the brain lags behind that of other sites, and murine studies are therefore highly informative. Rodriguez-Baena et al. conducted elegant studies of myeloid cells within melanoma brain metastases, demonstrating their plasticity and changes before and after colonization by melanoma cells. The immune-inhibitory changes in microglial cells may be reversed or mitigated by inhibition of RelA/NF-κB.

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引用次数: 0
Targeting PRAME directly or via EZH2 inhibition overcomes retinoid resistance and represents a novel therapy for keratinocyte carcinoma.
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-18 DOI: 10.1002/1878-0261.13820
Brandon Ramchatesingh, Amelia Martinez Villarreal, Philippe Lefrançois, Jennifer Gantchev, Sriraam Sivachandran, Samy Abou Setah, Ivan V Litvinov

Retinoids have demonstrated efficacy as preventative/treatment agents for keratinocyte carcinomas (KCs): basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). However, retinoid resistance mechanisms limit the efficacy of these compounds. A subset of KCs expresses Preferentially Expressed Antigen in Melanoma (PRAME): a retinoid signaling corepressor. PRAME is proposed to repress retinoid signaling by guiding enhancer of zeste homolog 2 (EZH2) to retinoic acid response elements (RARE) in promoters. We investigated the effects of PRAME on KC pathogenesis and retinoid response. High-PRAME expression in tumors was negatively correlated with epidermal differentiation gene signatures. PRAME overexpression downregulated epidermal differentiation gene signatures and impaired differentiation in 3D culture. PRAME overexpression attenuated retinoid-induced RARE activation, growth suppression, and differentiation responses. Conversely, low-PRAME tumors and PRAME-depleted KC cells demonstrated enriched epidermal differentiation gene signatures. PRAME downregulation restored retinoid-induced RARE activation, growth suppression, keratinization in SCC, and cell death signaling in BCC. Furthermore, combined retinoid and EZH2 inhibitor treatment augmented RARE activation and suppressed PRAME-expressing KC cell growth. Hence, PRAME confers retinoid resistance in KC, which may be overcome by EZH2 inhibition.

{"title":"Targeting PRAME directly or via EZH2 inhibition overcomes retinoid resistance and represents a novel therapy for keratinocyte carcinoma.","authors":"Brandon Ramchatesingh, Amelia Martinez Villarreal, Philippe Lefrançois, Jennifer Gantchev, Sriraam Sivachandran, Samy Abou Setah, Ivan V Litvinov","doi":"10.1002/1878-0261.13820","DOIUrl":"https://doi.org/10.1002/1878-0261.13820","url":null,"abstract":"<p><p>Retinoids have demonstrated efficacy as preventative/treatment agents for keratinocyte carcinomas (KCs): basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). However, retinoid resistance mechanisms limit the efficacy of these compounds. A subset of KCs expresses Preferentially Expressed Antigen in Melanoma (PRAME): a retinoid signaling corepressor. PRAME is proposed to repress retinoid signaling by guiding enhancer of zeste homolog 2 (EZH2) to retinoic acid response elements (RARE) in promoters. We investigated the effects of PRAME on KC pathogenesis and retinoid response. High-PRAME expression in tumors was negatively correlated with epidermal differentiation gene signatures. PRAME overexpression downregulated epidermal differentiation gene signatures and impaired differentiation in 3D culture. PRAME overexpression attenuated retinoid-induced RARE activation, growth suppression, and differentiation responses. Conversely, low-PRAME tumors and PRAME-depleted KC cells demonstrated enriched epidermal differentiation gene signatures. PRAME downregulation restored retinoid-induced RARE activation, growth suppression, keratinization in SCC, and cell death signaling in BCC. Furthermore, combined retinoid and EZH2 inhibitor treatment augmented RARE activation and suppressed PRAME-expressing KC cell growth. Hence, PRAME confers retinoid resistance in KC, which may be overcome by EZH2 inhibition.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cell-free DNA aneuploidy score as a dynamic early response marker in prostate cancer. 作为前列腺癌早期反应动态标记物的无细胞 DNA 非整倍体评分
IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2025-03-14 DOI: 10.1002/1878-0261.13797
Khrystany T Isebia, Anouk C de Jong, Lisanne F van Dessel, Vanja de Weerd, Corine Beaufort, Jean Helmijr, José Alberto Nakauma-González, Job van Riet, Paul Hamberg, Daniel Vis, Michiel S van der Heijden, Nick Beije, Martijn P Lolkema, Teoman Deger, Saskia M Wilting, Ronald de Wit, Maurice P H M Jansen, John W M Martens

Cell-free circulating tumor DNA (ctDNA) has emerged as a promising biomarker for response evaluation in metastatic castration-resistant prostate cancer (mCRPC). The current study evaluated the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), a quick, tumor-agnostic and affordable ctDNA assay that requires a small input of DNA, to generate a genome-wide aneuploidy (GWA) score in mCRPC patients, and correlated this to matched metastatic tumor biopsies. In this prospective multicenter study, GWA scores were evaluated from blood samples of 196 mCRPC patients prior to treatment (baseline) with taxanes (docetaxel and cabazitaxel) and androgen receptor signaling inhibitors (ARSI; abiraterone and enzalutamide), and from 74 mCRPC patients at an early timepoint during treatment (early timepoint; median 21 days). Z-scores per chromosome arm were tested for their association with tumor tissue genomic alterations. We found that a high tumor load in blood (GWAhigh) at baseline was associated with poor response to ARSI [HR: 2.63 (95% CI: 1.86-3.72) P < 0.001] but not to taxanes. Interestingly, GWAhigh score at the early timepoint was associated with poor response to both ARSIs [HR: 6.73 (95% CI: 2.60-17.42) P < 0.001] and taxanes [2.79 (95% CI: 1.34-5.78) P = 0.006]. A significant interaction in Cox proportional hazards analyses was seen when combining GWA status and type of treatment (at baseline P = 0.008; early timepoint P = 0.018). In summary, detection of ctDNA in blood by mFast-SeqS is cheap, fast and feasible, and could be used at different timepoints as a potential predictor for outcome to ARSI and taxane treatment in mCRPC.

{"title":"Cell-free DNA aneuploidy score as a dynamic early response marker in prostate cancer.","authors":"Khrystany T Isebia, Anouk C de Jong, Lisanne F van Dessel, Vanja de Weerd, Corine Beaufort, Jean Helmijr, José Alberto Nakauma-González, Job van Riet, Paul Hamberg, Daniel Vis, Michiel S van der Heijden, Nick Beije, Martijn P Lolkema, Teoman Deger, Saskia M Wilting, Ronald de Wit, Maurice P H M Jansen, John W M Martens","doi":"10.1002/1878-0261.13797","DOIUrl":"https://doi.org/10.1002/1878-0261.13797","url":null,"abstract":"<p><p>Cell-free circulating tumor DNA (ctDNA) has emerged as a promising biomarker for response evaluation in metastatic castration-resistant prostate cancer (mCRPC). The current study evaluated the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), a quick, tumor-agnostic and affordable ctDNA assay that requires a small input of DNA, to generate a genome-wide aneuploidy (GWA) score in mCRPC patients, and correlated this to matched metastatic tumor biopsies. In this prospective multicenter study, GWA scores were evaluated from blood samples of 196 mCRPC patients prior to treatment (baseline) with taxanes (docetaxel and cabazitaxel) and androgen receptor signaling inhibitors (ARSI; abiraterone and enzalutamide), and from 74 mCRPC patients at an early timepoint during treatment (early timepoint; median 21 days). Z-scores per chromosome arm were tested for their association with tumor tissue genomic alterations. We found that a high tumor load in blood (GWA<sup>high</sup>) at baseline was associated with poor response to ARSI [HR: 2.63 (95% CI: 1.86-3.72) P < 0.001] but not to taxanes. Interestingly, GWA<sup>high</sup> score at the early timepoint was associated with poor response to both ARSIs [HR: 6.73 (95% CI: 2.60-17.42) P < 0.001] and taxanes [2.79 (95% CI: 1.34-5.78) P = 0.006]. A significant interaction in Cox proportional hazards analyses was seen when combining GWA status and type of treatment (at baseline P = 0.008; early timepoint P = 0.018). In summary, detection of ctDNA in blood by mFast-SeqS is cheap, fast and feasible, and could be used at different timepoints as a potential predictor for outcome to ARSI and taxane treatment in mCRPC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Molecular Oncology
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