Cancer research communications最新文献

{"title":"Auranofin synergizes with cisplatin in reducing tumor burden of Notch-dependent ovarian cancer.","authors":"Robert J Lake, Parisa Nikeghbal, Irina V Lagutina, Kimberly K Leslie, Mara P Steinkamp, Hua-Ying Fan","doi":"10.1158/2767-9764.CRC-25-0190","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0190","url":null,"abstract":"<p><p>The Notch pathway regulates cell proliferation, differentiation, and stem cell maintenance. Thus, aberrant Notch activation plays a key role in cancer initiation, progression, and chemoresistance. Mutations and amplification of Notch pathway genes have been identified in high-grade serous ovarian cancers and are associated with poor clinical outcomes. Among the four Notch receptors, Notch3 alterations were strongly correlated with poor overall survival. Previously, we identified auranofin, an oral gold salt therapeutic compound, as a novel Notch pathway inhibitor that disrupts the DNA binding of RBPJ, the major downstream transcriptional effector of the Notch pathway. Here, we surveyed the response of eight ovarian cancer cell lines to auranofin and found IC50 values ranging from 1.7 to 12 µM, with Notch3-negative SKOV3 cells having the highest IC50 value. In Notch-dependent OVCAR3 cells, auranofin synergized with cisplatin to enhance cell death. Importantly, auranofin treatment led to a dose-dependent decrease in RBPJ occupancy at the Notch-dependent promoters, HES1 and HES4. Furthermore, knocking down Notch3 in OVCAR3 cells significantly decreased sensitivity to auranofin, further supporting the notion that Notch3 signaling is a major target of auranofin. Moreover, auranofin increased cisplatin efficacy in an OVCAR3-derived xenograft mouse model. Using eight patient-derived cancer organoid models, we found that auranofin increased cisplatin efficacy in killing cancer organoids generated from clinically platinum-sensitive patients but also restored platinum response in a subset of organoid models developed from platinum-resistant patients. These studies underscore the potential of auranofin to improve platinum-based cancer therapy, particularly in Notch3-expressing cancers.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic landscapes of endometrioid and mucinous ovarian cancers and morphologically similar tumor types.","authors":"Dorothy Hallberg, Alice C Eastman, Shashikant Koul, Daniel C Bruhm, Eniko Papp, Simon Davenport, Vilmos Adleff, Leonardo Ferreira, Noushin Niknafs, Jamie E Medina, Stephen Cristiano, Carolyn Hruban, Jacob Fiksel, Kaui P Lebarbenchon, Luis Aparicio, Nicholas A Vulpescu, Kuan-Ting Kuo, Nita Ahuja, Ronny Drapkin, Euihye Jung, Sarah H Kim, Mark A Eckert, Ernst Lengyel, Kentaro Nakayama, Ayse Ayhan, Ie-Ming Shih, Tian-Li Wang, Ofer Lavie, Gad Rennert, Hariharan Easwaran, Stephen B Baylin, Michael F Press, Victor E Velculescu, Robert B Scharpf","doi":"10.1158/2767-9764.CRC-25-0147","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0147","url":null,"abstract":"<p><p>While endometrioid and mucinous ovarian carcinomas represent nearly a fifth of ovarian cancers, their molecular characteristics and pathologic origins are poorly understood. To identify the genomic and epigenomic alterations characteristic of these ovarian cancer subtypes and to evaluate links to morphologically similar tumors from other sites, we performed a combination of sequence, copy number, mutation signature, and rearrangement analyses from tumor samples and matched normal tissues of 133 patients, as well as methylation analyses of these tumors and tissues of 150 patients from The Cancer Genome Atlas. Genomic analyses included samples from patients with ovarian endometrioid (n=44), ovarian mucinous (n=43), uterine endometrioid (n=15), and gastrointestinal mucinous carcinomas (n=31), including mucinous carcinomas of the stomach, colon, and pancreas. In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4 and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous carcinomas. Whole genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid carcinomas, and NF1 and MED1 in ovarian mucinous carcinomas. The number of alterations, affected genes and genome-wide methylation profiles were not distinguishable between ovarian and uterine endometrioid carcinomas, supporting the hypothesis that these tumors share a tissue of origin. In contrast, mutation and methylation patterns in ovarian mucinous carcinomas were different from gastrointestinal mucinous carcinomas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145114838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Non-Coding Mutational Landscape of Pancreatic Cancer Reveals Recurrent Somatic Mutations in Enhancer Regions.","authors":"Akimasa Hayashi, Yu-Jui Ho, Alvin P Makohon-Moore, Amanda Zucker, Jungeui Hong, Shigeaki Umeda, Elias-Ramzey Karnoub, Jinlong Huang, Priscilla Baez, Rajya Kappagantula, Jerry P Melchor, Wungki Park, Eileen M O'Reilly, Nicholas D Socci, Shinya Oki, Christine A Iacobuzio-Donahue","doi":"10.1158/2767-9764.CRC-24-0167","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-24-0167","url":null,"abstract":"<p><p>While the coding genome of pancreatic cancer has been characterized in detail, features of the noncoding genome remain relatively unexplored. We used whole genome sequencing to study the coding and noncoding genome (promoters, enhancers and noncoding-NOS) in two unique patient cohorts. We find that treated cancers have a significantly higher mutational burden than untreated cancers in all four genomic regions. However, the relative proportion of mutations in each region are preserved despite treatment-induced genetic bottlenecks. Compared to other noncoding regions enhancers have a lower number of mutations/Mb. Enhancers also have a distinct mutational signature with enrichment of SBS39. Enhancer sequences were segregated into conserved and nonconserved regions based on the overlap of predicted orthologous regions in the human and mouse genomes and the conserved regions screened for recurrent somatic mutations. We find recurrent somatic mutations in conserved enhancer regions largely correspond to those associated with known transcription factors with a role in pancreatic development and cancer including KLF5 and TP63. Transcriptional expression based on RNA-seq data of cancers with enhancer mutations showed significantly different levels of expression, most often a loss of expression, compared to cancers without enhancer mutations suggesting a functional effect. These findings expand our knowledge of the noncoding genome in pancreatic cancer and point to an unexplored role of conserved enhancer mutations for pancreatic cancer as well.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Afro-Caribbean Prostate Cancer Model Reveals ancestry-specific Drug Vulnerabilities with Therapeutic Implications for Black Patients.","authors":"Simone Badal, Bor-Jang Hwang, Ashlianne Nelson, Kristoff Frank, Tanisha Maitre, Magdalene Nwokocha, Rory Thompson, Belinda Morison, Rajini Haraksingh, Valerie Odero-Marah, Camille Ragin","doi":"10.1158/2767-9764.CRC-25-0254","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0254","url":null,"abstract":"<p><p>In the era of targeted therapeutics, the inadequate representation of Black populations in prostate cancer (PCa) models limits effective drug screening. Here, we introduce ACRJ-PC28, a novel Afro-Caribbean PCa cell line, and evaluate its responses to five anticancer drugs (docetaxel, cabazitaxel, abiraterone, olaparib, and enzalutamide) and betaine. We compare these responses to those of established PCa cell lines from Black (MDA-PCA-2b) and White (DU-145, PC-3) donors using three distinct viability assays. We observed ancestry-dependent drug sensitivities: Abiraterone showed remarkable selectivity for ACRJ-PC28 (IC₅₀ = 1.10 μM), being 4.6-13.1 fold more potent than in other cell lines, while Enzalutamide demonstrated pronounced racial differences, being 3-5 times less effective in cell lines from Black donors (IC₅₀ = 206 μM for ACRJ-PC28; 104 μM for MDA-PCA-2b) versus cell lines from White donors (IC₅₀ = 37 μM for PC-3; 48 μM for DU-145). RNA-seq analysis revealed consistent underexpression of TNF family genes, particularly TNFRSF14, in PCa cells from Black donors correlating with differential drug responses. Despite underexpressing AR, the ACRJ-PC28 line exhibited exceptional sensitivity to Abiraterone, consistent with clinical observations that Black patients with PCa respond better to this therapy. This aligns with its neuroendocrine phenotype in the source patient, who succumbed within one year despite androgen deprivation therapy. Our findings suggest that incorporating diverse PCa models in preclinical screening could guide personalized treatment strategies for Black patients who experience disproportionate PCa mortality by identifying ancestry-specific drug vulnerabilities that inform optimal therapeutic combinations.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening FDA-Approved Oncology Drugs with Three-Dimensional Spheroids Identifies Romidepsin as a Therapeutic Candidate for Osteosarcoma.","authors":"Emily E Seiden, Spencer M Richardson, Leah A Everitt, Gabrielle J Knafler, Alyssa L Walker, Venetia A Whiteside, Divya Pillutla, Shrey Ramnath, Gavin P Kinsella, Piper A Wilburn, James D Buschbach, Deep A Gandhi, M Reza Saadatzadeh, L Daniel Wurtz, Patrick J Getty, Sheldon L Padgett, Rance M Gamblin, Michael O Childress, Christopher M Fulkerson, Maegan L Capitano, Karen E Pollok, Christopher D Collier, Edward M Greenfield","doi":"10.1158/2767-9764.CRC-25-0121","DOIUrl":"10.1158/2767-9764.CRC-25-0121","url":null,"abstract":"<p><p>Osteosarcoma is the most common primary malignant bone tumor and predominantly affects adolescents and young adults. It is the third most common cause of cancer-related deaths among 9-24-year-olds. Despite aggressive chemotherapeutic and surgical therapies, the survival rate is only 25% for patients with detectable lung metastases at diagnosis and only 70% in patients that present without detectable lung metastases. The poor prognosis is due to growth of metastases irrespective of whether they are initially large enough to detect clinically. It is therefore necessary to develop new methods to target the growth of lung micrometastases. An NCI panel of FDA approved oncology drugs was therefore screened using three highly metastatic human osteosarcoma cell lines. To more closely approximate in vivo micro-metastases, the screen used a 3D multicellular in vitro osteosarcoma spheroid (sarcosphere) model. Among 13 hits from the initial screen, we identified the histone deacetylase inhibitor (HDI) romidepsin as the most promising inhibitor in secondary screens comparing effects on sarcospheres to clinically achievable levels and to effects on non-transformed cells. Romidepsin potency was evident with and without standard-of-care chemotherapeutics (MAP: Methotrexate, Adriamycin, Cisplatin) at romidepsin concentrations that are clinically achievable and did not affect non transformed cells. Romidepsin also substantially outperformed the other three FDA approved HDIs and eight HDIs in clinical trials. The effects of romidepsin were a transient cell cycle block at G2/M and cell death. Importantly, sarcospheres derived from ~30% of human and 50% of canine patient samples responded to romidepsin at clinically tolerable concentrations (ED50s<70nM).</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic cells are resistant to KRAS(Q61L) expression due to hyperactive ERK/MAPK signaling and apoptosis induction.","authors":"Rachel A Burge, Lucas Bialousow, Thomas McFall, Logan Bamonte, Grayson Johnson, Merissa Smith, Silvia G Vaena, Susana Comte-Walters, Lauren E Ball, Stefano Berto, John P O'Bryan, G Aaron Hobbs","doi":"10.1158/2767-9764.CRC-25-0281","DOIUrl":"https://doi.org/10.1158/2767-9764.CRC-25-0281","url":null,"abstract":"<p><p>The RAS family of small GTPases is among the most frequently mutated gene families in human cancer. In pancreatic ductal adenocarcinoma (PDAC), ~95% of cases harbor an activating KRAS mutation, primarily at codon 12, 13, or 61, with G12D the most common overall (40%). In contrast, the KRASQ61L mutation, though constitutively active, is virtually absent in PDAC patient tumors. This suggests that KRASQ61L may engage in distinct, allele-specific signaling that limits its ability to drive tumorigenesis. Determining the mechanisms that limit the occurrence of this mutation will aid in our understanding of the critical KRAS effectors and pathways that drive tumorigenesis. To investigate these mechanisms, we utilized a tightly controlled doxycycline-inducible KRAS expression system in an isogenic, immortalized pancreatic cell line, enabling direct comparison of KRASQ61L to the common PDAC mutant KRASG12D. Using TurboID proximity labeling alongside RNA sequencing, we mapped early effector interactions and transcriptional responses, revealing that KRASQ61L induces greater hyperactivation of the ERK/MAPK pathway, resulting in increased nuclear translocation of ERK1/2. Finally, pancreatic cells are highly tolerant to overexpression of KRASG12D, but KRASQ61L overexpression leads to impaired proliferation and increased apoptosis. These findings provide experimental support for the long-standing \"Goldilocks\" model of oncogenic signaling, where too much ERK/MAPK pathway activation is detrimental to tumorigenesis. Our work offers a mechanistic explanation for the relative absence of KRASQ61L in PDAC and contributes to our understanding of KRAS allele-specific vulnerabilities, which can inform future therapeutic strategies targeting KRAS-driven pancreatic cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Pretreatment Autoantibodies Correlate with Enfortumab Vedotin-Related Dermatologic Events in Patients with Advanced Urothelial Cancer.","authors":"Evangelia Vlachou, Burles A Johnson, David J McConkey, Noah M Hahn, Yuezhou Jing, Stephanie Russell, Daniel Stairiker, Antony Rosen, Livia A Casciola-Rosen, Jean Hoffman-Censits","doi":"10.1158/2767-9764.CRC-25-0039","DOIUrl":"10.1158/2767-9764.CRC-25-0039","url":null,"abstract":"<p><p>Enfortumab vedotin (EV) plus pembrolizumab (P) is the first-line treatment for patients with advanced urothelial cancer (aUC). No biomarker for EV toxicity or response has been prospectively validated. EV-related dermatologic events (EVDE) are common and correlate with improved outcomes in retrospective studies. Immune checkpoint inhibitor-related toxicity also correlates with improved outcomes, and the presence of autoantibodies correlates with improved responses. We hypothesized that EV unmasks preexisting subclinical autoimmune responses leading to EVDEs in the setting of EV or EV/P. Our goal was to determine whether novel autoantibodies, if detected, correlate with EVDEs. We screened for novel autoantibodies using an immunoprecipitation-based approach in a pilot retrospective cohort (A) and a prospective longitudinal cohort (B) of patients with aUC who were treated with EV or EV/P and experienced EVDEs. Incidence of EVDEs, radiographic response, and progression-free and overall survival were compared between patients with and without autoantibodies. Two of six cohort A patients had pretreatment autoantibodies [Rho-associated coiled-coil containing protein kinase 2 (one patient) and target of Myb1-like 1 membrane trafficking protein (one patient)]. Pretreatment autoantibodies were also identified in 6/23 cohort B patients [mitochondrial complex 3 - M2 antigen (four patients), NMD3 ribosome export adapter (two patients), and carnitine palmitoyltransferase (one patient)]. All six (100%) cohort B antibody-positive patients developed EVDEs during treatment. To our knowledge, this is the first study correlating EVDEs with novel pretreatment autoantibodies in patients with mUC. Further studies are needed to confirm that they are biomarkers of EV-related skin toxicity and/or response.</p><p><strong>Significance: </strong>EV is approved alone and with pembrolizumab (EV/P) for aUC. EV-related dermatologic events (EVDEs) have been correlated with improved outcomes. We identified novel pre- and on-treatment autoantibodies in sera of patients with mUC treated with EV or EV/P which correlated with EVDEs.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1674-1680"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12444012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating Treatment Outcomes of Patients with Solid Tumors in Immunotherapy Trials: A Drug Interaction Analysis from a Phase I Unit.","authors":"Camila Braganca Xavier, Clark R Andersen, JoAnn Lim, Julian H Slade, Stacie A Bean, Lei Kang, Hung Le, Apostolia M Tsimberidou, Aung Naing, David S Hong, Ecaterina E Dumbrava, Jordi Rodon Ahnert, Paula R Pohlmann, Sarina A Piha-Paul, Stephane Champiat, Timothy A Yap, Tin-Yun Tang, Funda Meric-Bernstam, Siqing Fu","doi":"10.1158/2767-9764.CRC-25-0033","DOIUrl":"10.1158/2767-9764.CRC-25-0033","url":null,"abstract":"<p><strong>Purpose: </strong>Concurrent use of medications can modulate the effectiveness of immunotherapy. Although this interaction is well documented for immune checkpoint inhibitors, whether this occurs with new experimental compounds has not been evaluated.</p><p><strong>Patients and methods: </strong>A computerized data extraction tool was used to collect clinical data and identify the prescription of a predefined set of medications within 30 days of immunotherapy infusion in the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center. The primary endpoints were median overall survival (OS) and progression-free survival. Tumor responses were assessed using RECIST.</p><p><strong>Results: </strong>We identified 897 patients. The most prevalent tumor types were colorectal (24.5%), head and neck (10.5%), and pancreatic (9.4%). The immunotherapy administered consisted of monoclonal antibodies and fusion proteins (64.7%), immune modulators (IM; 20.8%), combinations of IMs and antibodies (9.2%), and oncolytic viruses and cancer vaccines (5.3%). The most frequently prescribed drugs were narcotics (70.5%), antiemetics (49.1%), antihistamines (34.6%), antibiotics (31.2%), and proton pump inhibitors (PPI; 28.7%). Patients receiving antihistamines exhibited increased rates of stable disease and partial response (χ2 8.48; P = 0.014) on the IMs and antibodies combination. The benefit of antihistamines was confirmed in a multivariate analysis of OS [HR, 0.752 (95% CI, 0.603-0.938); P = 0.012]. For patients with colorectal cancer, PPI use was associated with shortened survival, with a median OS of 5.2 months with PPI use and 8.6 months without it (P < 0.001).</p><p><strong>Conclusions: </strong>Our findings highlight the need for strategies to guide concurrent medication choices for patients receiving immunotherapy in early-phase trials.</p><p><strong>Significance: </strong>Concurrent administration of antihistamines correlates with enhanced survival in patients receiving experimental immunotherapy for cancer. Conversely, PPI use diminishes survival in patients with colorectal cancer. These findings highlight how tumor immunogenicity and drug interactions can modulate response and survival outcomes, offering new insights to optimize investigational immunotherapy.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1631-1641"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SALL4 Is Required for YAP1-Dependent Malignant and Regenerative Hepatocyte-to-Cholangiocyte Reprogramming.","authors":"Minwook Kim, Yoojeong Park, Rachel Covitz, Joseph Kwon, Jia-Jun Liu, Silvia Liu, Sungjin Ko","doi":"10.1158/2767-9764.CRC-25-0172","DOIUrl":"10.1158/2767-9764.CRC-25-0172","url":null,"abstract":"<p><p>Hepatocytes (HC), which share a developmental origin with cholangiocytes (CC), have the capacity to undergo reparative reprogramming into CCs in response to liver injury and, under specific conditions, can also transform malignantly into cholangiocarcinoma (CCA). However, the molecular mechanisms governing HC plasticity in liver diseases remain poorly understood. In this study, we investigated the role of spalt-like transcription factor 4 (SALL4), an oncofetal transcription factor, in both malignant and regenerative HC fate transitions toward the biliary lineage. Using Sleeping Beauty hydrodynamic tail vein injection-mediated murine liver cancer models, we explored HC-to-CCA transformation, whereas the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced cholestasis model was used to investigate regenerative HC-to-CC reprogramming. Our findings reveal that SALL4 is specifically required for myristoylated Akt-YAP1S127A-driven HC-to-CCA transformation, as its loss significantly suppressed malignant reprogramming and clonal expansion. Surprisingly, Sall4 overexpression also prevented YAP1S127A-driven CCA development while promoting the expansion of liver progenitor cell (LPC)-like fatty HCs. Mechanistically, we propose Bmi1 as a key downstream effector of SALL4 in YAP1-dependent HC-to-CCA transformation. Additionally, in the DDC-fed cholestasis model, Sall4 deletion enhanced HC-to-LPC activation while impairing LPC differentiation into mature CCs. These findings establish SALL4 as a critical regulator of HC plasticity in both malignant and regednerative contexts and highlight its potential as a therapeutic target for specific liver cancer subtypes.</p><p><strong>Significance: </strong>HC plasticity supports repair but can drive malignancy, acting as a double-edged sword. We identify SALL4 as regulator of YAP1-driven HC-to-CC reprogramming, revealing the YAP1-SALL4-BMI1 axis as a therapeutic target for CCA.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1714-1727"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Validity of FoundationOne Liquid CDx for Detection of BRAFV600E in Colorectal Cancer.","authors":"Rona Yaeger, Jean-François Martini, Lincoln Pasquina, Brian Tunquist, Xiaosong Zhang, Fatima Kaiser, Norberto Pantoja Galicia, Shibing Deng, Siliang Gong, Cui Guo, Jimmy Kiely, Ta-Chou Vincent Ng, Graham Ferrier, Josep Tabernero, Scott Kopetz","doi":"10.1158/2767-9764.CRC-25-0002","DOIUrl":"10.1158/2767-9764.CRC-25-0002","url":null,"abstract":"<p><strong>Purpose: </strong>The BRAF inhibitor encorafenib (Enco) plus the anti-EGFR antibody cetuximab (Cetux) improved overall survival, objective response rate, and progression-free survival in previously treated BRAFV600E-mutant metastatic colorectal cancer in BEACON, a phase III randomized trial, leading to regulatory approval for this indication. To support rapid, plasma-based testing for BRAFV600E identification, clinical validity of a ctDNA-based assay, FoundationOneLiquid CDx (F1LCDx), was assessed against the reference tumor-based clinical trial assay (CTA) in liquid biopsy-evaluable samples from BEACON and commercially obtained tissue-matched plasma samples.</p><p><strong>Patients and methods: </strong>Pretreatment tissue samples were collected in BEACON to confirm BRAF mutational status using the central single gene PCR assay. Concordance between the CTA and liquid biopsy tests was assessed, and clinical validity of liquid biopsy testing was examined using clinical outcomes from BEACON.</p><p><strong>Results: </strong>Of the 523 evaluable patients, 433 with matched tissue and plasma samples had CTA and F1LCDx results available (BEACON, n = 328; commercial, n = 105). A strong concordance in detecting BRAFV600E was found between F1LCDx and CTA, with a positive percent agreement of 87.2% and negative percent agreement of 97.1%. Among 42 F1LCDx-/CTA+ samples, 41 (97.6%) had ctDNA tumor fraction <1%. Among samples with ctDNA tumor fraction >1%, the positive percent agreement was 99.4% and negative percent agreement was 86.7%. Clinical outcomes with Enco plus Cetux were similar between those identified as F1LCDx+/CTA+ and CTA+ overall.</p><p><strong>Conclusions: </strong>This study supports using liquid biopsies as a clinically valid assay for identifying BRAFV600E alterations in patients with metastatic colorectal cancer, particularly when ctDNA tumor fraction was >1%.</p><p><strong>Significance: </strong>In the phase III BEACON trial, which established Enco plus Cetux as a standard of care for previously treated BRAFV600E-mutant metastatic colorectal cancer, mutational status was confirmed through testing of tumor tissue. To support rapid, less invasive testing for BRAFV600E in plasma, this retrospective study assessed a ctDNA-based assay and found strong concordance between the liquid biopsy test and the tumor-based assay in detecting BRAFV600E.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"1566-1573"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}