Cancer research communications最新文献

{"title":"Targeting Pancreatic Cancer Cell Stemness by Blocking Fibronectin-Binding Integrins on Cancer-Associated Fibroblasts.","authors":"Chengsheng Wu, Tami Von Schalscha, Diva Sansanwal, Chen Qian, Qinlin Jiang, Ryan M Shepard, Hiromi I Wettersten, Stephen J McCormack, Sara M Weis, David A Cheresh","doi":"10.1158/2767-9764.CRC-24-0491","DOIUrl":"10.1158/2767-9764.CRC-24-0491","url":null,"abstract":"<p><strong>Abstract: </strong>Cancer-associated fibroblasts (CAF) generate an extracellular matrix (ECM) which provides a repository for factors that promote pancreatic cancer progression. In this study, we establish that CAF contribution to pancreatic tumor initiation, i.e., stemness, depends on fibronectin (FN) as a scaffold required for assembly of a collagen-containing fibrotic ECM with a critical dependence on the FN-binding integrins, α5β1 and αvβ3. CAF matrix assembly can be prevented by knockdown of FN, integrin α5, or integrin β3 or by a bispecific antibody with dual recognition of α5β1 and αvβ3 that can also destabilize a preexisting matrix. In mice, the ability of CAFs to produce a stiff collagenous matrix and accelerate tumor initiation can be blocked by knockdown of FN or FN-binding integrins or systemic treatment with the α5β1/αvβ3 bispecific antibody. Together, these results reveal that dual targeting of the FN-binding integrins, α5β1 and αvβ3, can block the ability of CAFs and their matrix to enhance pancreatic cancer stemness and progression.</p><p><strong>Significance: </strong>Simultaneous targeting of two integrins that function as receptors for FN, a protumor ECM protein, can prevent fibroblasts from supporting the malignant behavior of pancreatic cancer cells.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"195-208"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959791","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":"Claudin-4 Stabilizes the Genome via Nuclear and Cell-Cycle Remodeling to Support Ovarian Cancer Cell Survival.","authors":"Fabian R Villagomez, Julie Lang, Daniel Nunez-Avellaneda, Kian Behbakht, Hannah L Dimmick, Patricia G Webb, Kenneth P Nephew, Margaret Neville, Elizabeth R Woodruff, Benjamin G Bitler","doi":"10.1158/2767-9764.CRC-24-0558","DOIUrl":"10.1158/2767-9764.CRC-24-0558","url":null,"abstract":"<p><strong>Abstract: </strong>Alterations in the interplay between the nucleus and the cell cycle during cancer development lead to a state of genomic instability, often accompanied by observable morphologic aberrations. Tumor cells can regulate these aberrations to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer, overexpression of claudin-4 significantly contributes to therapy resistance through mechanisms associated with genomic instability regulation. However, the molecular mechanisms underlying claudin-4 overexpression in epithelial ovarian cancer remain poorly understood. In this study, we modified claudin-4 expression and employed a unique claudin mimic peptide to investigate claudin-4’s function. Our findings show that claudin-4 supports ovarian cancer cell survival by stabilizing the genome through nuclear and cell-cycle remodeling. Specifically, claudin-4 induced nuclear constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, thereby altering nuclear structure and dynamics. Similarly, cell-cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability in tumors. Importantly, disrupting claudin-4’s biological effects using claudin mimic peptide and forskolin increased the efficacy of PARP inhibitor treatment, correlating with alterations in the oxidative stress response. Our data indicate that claudin-4 protects tumor genome integrity by modulating the crosstalk between the nucleus and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability–inducing agents.</p><p><strong>Significance: </strong>High-grade serous ovarian carcinoma is marked by chromosomal instability, which can serve to promote disease progression and allow cancer to evade therapeutic insults. The report highlights the role of claudin-4 in regulating genomic instability and proposes a novel therapeutic approach to exploit claudin-4-mediated regulation.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"39-53"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775338","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":"Molecular Differences in Pancreatic Ductal Adenocarcinomas from Black versus White Patients.","authors":"Saurabh Mandal, Emily A Teslow, Minxuan Huang, Yingying Yu, Swathi Sridhar, Howard C Crawford, Adam J Hockenberry, Melissa C Stoppler, Albert M Levin, Ling Huang","doi":"10.1158/2767-9764.CRC-24-0376","DOIUrl":"10.1158/2767-9764.CRC-24-0376","url":null,"abstract":"<p><strong>Abstract: </strong>Pancreatic cancer is the third leading cause of cancer-related death in the United States. Black or African American patients have a higher incidence of pancreatic cancer compared with other racial groups. It is unclear whether distinct molecular mechanisms are involved in the development of pancreatic cancer in different racial groups. To identify tumor molecular features that are distinctly associated with race in Black or African American and White patients with pancreatic ductal adenocarcinoma (the main subtype of pancreatic cancer), we analyzed deidentified patient records, including tumor sequencing data and expression of PD-L1, from the Tempus multimodal database. Patients with a primary diagnosis of pancreatic ductal adenocarcinoma and who received molecular testing between November 2017 and March 2023 were included in analyses. Among 4,249 patients analyzed in this study, 452 (10.6%) were Black or African American, and 3,797 (89.4%) were White. Black patients had a higher prevalence of TP53 mutations compared with White patients (P < 0.001). KRASG12R mutations occurred more frequently in female patients in the Black versus White group (P = 0.007). Compared with White patients, Black patients had a higher tumor mutational burden (P < 0.001) and PD-L1 overexpression (P = 0.047). In a separate analysis of recent clinical trials testing immunotherapies for pancreatic cancer, we found that Black patients and other minorities were underrepresented in most trials. These findings suggest race-associated molecular differences in tumors that may impact patient responses to immunotherapies. Our study also supports the importance of improving patient diversity in clinical trials on pancreatic cancer treatments.</p><p><strong>Significance: </strong>By analyzing the records of patients with pancreatic cancer in the Tempus multimodal database, we identified genomic mutations and PD-L1 overexpression occurred more frequently in Black patients compared with their White counterparts. These molecular features may contribute to racial disparities in pancreatic cancer.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"128-137"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856022","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":"Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia.","authors":"Himangshu Sonowal, William G Rice, Raphael Bejar, Joo-Yun Byun, Seung Hyun Jung, Ranjeet Sinha, Stephen B Howell","doi":"10.1158/2767-9764.CRC-24-0258","DOIUrl":"10.1158/2767-9764.CRC-24-0258","url":null,"abstract":"<p><strong>Abstract: </strong>Tuspetinib (TUS) is a well-tolerated, once daily, oral kinase inhibitor in clinical development for treatment of acute myeloid leukemia (AML). Nonclinical studies show that TUS targets key prosurvival kinases with IC50 values in the low nmol/L range, including SYK, wild-type (WT) and mutant forms of FLT3, mutant but not WT forms of KIT, RSK2, and TAK1–TAB1 kinases, and indirectly suppresses expression of MCL1. Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3-mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax (VEN) or 5-azacytidine. In vitro, TUS demonstrated potent killing of AML lines [concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) = 1.3–5.2 nmol/L] and Ba/F3 cells expressing WT (GI50 = 9.1 nmol/L) or various mutant forms of FLT3 (GI50 = 2.5–56 nmol/L). In AML lines, the multikinase targeting capacity of TUS suppressed phosphorylation of SYK, FLT3, STAT5, MEK, ERK, AKT, mTOR, 4E-BP1, and S6K kinases. Cells selected for stable acquired resistance to TUS exhibited increased BAX and hypersensitivity to VEN (1900 fold), navitoclax, and MCL1 inhibitors. MV-4-11 FLT3-ITD clones expressing NRASG12D revealed that high-level expression of NRASG12D generated modest resistance to TUS and greater resistance to VEN, yet the TUS/VEN combination exhibited synergy in the NRASG12D AML model. Favorable preclinical safety and pharmacology properties, the efficacy of the TUS/VEN combination in a murine model, and the synthetic lethal vulnerability to VEN that accompanies TUS resistance provide the basis for exploration of the TUS/VEN combination in patients with relapsed or refractory AML.</p><p><strong>Significance: </strong>This article reports preclinical development of TUS, an oral kinase inhibitor currently in clinical development for treatment of AML. The article covers the studies of TUS activities on cellular targets and the nonclinical studies that supported the advancement of TUS to a phase I/II trial of TUS/VEN in refractory AML and a phase I/II trial of TUS/VEN/5-azacytidine in newly diagnosed patients with AML (NCT03850574).</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"74-83"},"PeriodicalIF":2.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814921","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":"Single-Cell Analysis of Bone Marrow CD8+ T Cells in Myeloid Neoplasms Reveals Pathways Associated with Disease Progression and Response to Treatment with Azacitidine.","authors":"Athanasios Tasis, Nikos E Papaioannou, Maria Grigoriou, Nikolaos Paschalidis, Catherine Loukogiannaki, Anastasia Filia, Kyriaki Katsiki, Eleftheria Lamprianidou, Vasileios Papadopoulos, Christina Maria Rimpa, Antonios Chatzigeorgiou, Ioannis Kourtzelis, Petroula Gerasimou, Ioannis Kyprianou, Paul Costeas, Panagiotis Liakopoulos, Konstantinos Liapis, Petros Kolovos, Triantafyllos Chavakis, Themis Alissafi, Ioannis Kotsianidis, Ioannis Mitroulis","doi":"10.1158/2767-9764.CRC-24-0310","DOIUrl":"10.1158/2767-9764.CRC-24-0310","url":null,"abstract":"<p><strong>Abstract: </strong>CD8+ T cells are crucial for antitumor immunity. However, their functionality is often altered in higher-risk myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). To understand their role in disease progression, we conducted a comprehensive immunophenotypic analysis of 104 pretreatment bone marrow (BM) samples using mass and flow cytometry. Our findings revealed an increased frequency of CD57+CXCR3+ subset of CD8+ T cells in patients who did not respond to azacitidine (AZA) therapy. Furthermore, an increased baseline frequency (>29%) of the CD57+CXCR3+CD8+ T-cell subset was correlated with poor overall survival. We performed single-cell RNA sequencing to assess the transcriptional profile of BM CD8+ T cells from treatment-naïve patients. The response to AZA was linked to an enrichment of IFN-mediated pathways, whereas nonresponders exhibited a heightened TGF-β signaling signature. These findings suggest that combining AZA with TGF-β signaling inhibitors targeting CD8+ T cells could be a promising therapeutic strategy for patients with higher-risk MDS and AML.</p><p><strong>Significance: </strong>Immunophenotypic analysis identified a BM CD57+CXCR3+ subset of CD8+ T cells associated with response to AZA in patients with MDS and AML. Single-cell RNA sequencing analysis revealed that IFN signaling is linked to the response to treatment, whereas TGF-β signaling is associated with treatment failure, providing insights into new therapeutic approaches.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"3067-3083"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559622","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":"Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma.","authors":"Todd Shearer, Melissa Comstock, Rex L Williams, Mark C Johnson, Ewa Cendrowicz, Cathrine Leonowens, Margaret Smith, Todd M Baughman, Caroline J Breitbach, Shinta Cheng, Damian J Green","doi":"10.1158/2767-9764.CRC-24-0075","DOIUrl":"10.1158/2767-9764.CRC-24-0075","url":null,"abstract":"<p><strong>Abstract: </strong>B-cell maturation antigen (BCMA) is the target of several investigational and approved drugs for multiple myeloma. BCMA expressed on plasma cells (PC) and multiple myeloma cells is cleaved by the enzyme γ-secretase, reducing membrane-bound BCMA (mbBCMA) receptor density. γ-Secretase inhibitors (GSI) have been shown to increase mbBCMA density and may enhance efficacy of BCMA-targeted therapies. The pharmacodynamic profile of the GSI nirogacestat was evaluated in multiple myeloma cell lines and a phase I study in healthy volunteers. In multiple myeloma cell lines, mbBCMA density and soluble BCMA concentrations were measured before and after short-duration nirogacestat exposure and at serial time points following washout. In the phase I study, 23 participants were administered a single oral dose of nirogacestat 50, 150, or 300 mg or repeated doses of 100 mg every 12 hours for up to 48 hours; mbBCMA density on PCs (from whole blood and bone marrow) and nirogacestat plasma concentrations were measured at baseline and postdose. After single-dose administration, serum nirogacestat concentrations rapidly increased (Tmax ∼1 hour), and a two-compartment model with linear absorption and clearance best described nirogacestat pharmacokinetics. In multiple myeloma cells and healthy volunteers’ PCs, nirogacestat resulted in rapid and robust increases in mbBCMA density, with increases up to 20-fold within 4 to 8 hours of exposure. Concomitant decreases in soluble BCMA were observed. Nirogacestat is currently being evaluated in combination with several BCMA-directed therapeutic agents in patients with multiple myeloma. Elucidating the kinetics of BCMA in response to nirogacestat is key to guiding dosing and therapeutic strategies in multiple myeloma.</p><p><strong>Significance: </strong>GSIs can enhance multiple myeloma therapies targeting BCMA by increasing mbBCMA on plasma cells. In response to the GSI nirogacestat, mbBCMA rapidly and robustly increased in vitro and in vivo. Elucidating nirogacestat's effects on BCMA kinetics will guide potential multiple myeloma dosing strategies.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"3114-3123"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11632591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633110","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":"Nuclear Focal Adhesion Kinase Protects against Cisplatin Stress in Ovarian Carcinoma.","authors":"Yichi Zhang, Marjaana Ojalill, Antonia Boyer, Xiao Lei Chen, Elise Tahon, Gaëtan Thivolle Lioux, Marvin Xia, Maryam Abbas, Halime Meryem Soylu, Douglas B Flieder, Denise C Connolly, Alfredo A Molinolo, Michael T McHale, Dwayne G Stupack, David D Schlaepfer","doi":"10.1158/2767-9764.CRC-24-0382","DOIUrl":"10.1158/2767-9764.CRC-24-0382","url":null,"abstract":"<p><strong>Abstract: </strong>Tumor chemotherapy resistance arises frequently and limits high-grade serous ovarian cancer (HGSOC) patient survival. Focal adhesion kinase (FAK) is an intracellular protein–tyrosine kinase encoded by PTK2, a gene that is often gained in HGSOC. Canonically, FAK functions at the cell periphery. However, FAK also transits to the nucleus to modulate gene expression. We find that FAK is tyrosine-phosphorylated and nuclear-localized in tumors of patients with HGSOC surviving neoadjuvant platinum–paclitaxel chemotherapy and that FAK nuclear accumulation occurs upon subcytotoxic cisplatin exposure to ovarian tumor cells in vitro. FAK nuclear localization sequence (NLS) mutational inactivation resulted in tumor cell sensitization to cisplatin in vitro and in vivo relative to wild-type FAK-reconstituted ovarian tumor cells. Cisplatin cytotoxicity was associated with elevated ERK MAPK activation in FAK NLS− cells, cisplatin-stimulated ERK activation was also enhanced upon loss of FAK activity or expression, and cisplatin-stimulated cell death was prevented by an inhibitor of ERK signaling. MAPK phosphastase-1 (MKP1) negatively regulates ERK signaling, and cisplatin-induced MKP1 levels were significantly elevated in wild-type FAK compared with FAK NLS− ovarian tumor cells. Notably, small-molecule MKP1 inhibition enhanced both cisplatin-stimulated ERK phosphorylation and ovarian tumor cell death. Together, our results show that FAK expression, activity, and nuclear localization limit cisplatin cytotoxicity in part by regulating MKP1 levels and preventing noncanonical ERK/MAPK activation.</p><p><strong>Significance: </strong>FAK inhibitors are in combinatorial clinical testing with agents that prevent Ras-Raf-MAPK pathway activation in various cancers. This study suggests that nuclear FAK limits ERK/MAPK activation in supporting HGSOC cell survival to cisplatin stress. Overall, it is likely that targets of FAK-mediated survival signaling may be tumor type- and context-dependent.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"3165-3179"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710432","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":"Beyond HRD Status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer.","authors":"Maj K Kjeldsen, Morten Jørgensen, Dina Sofie B Grønseth, Martin Schønemann-Lund, Gitte-Bettina Nyvang, Charlotte Aaquist Haslund, Anja Oer Knudsen, Anne Krejbjerg Motavaf, Susanne Malander, Maarit Anttila, Gabriel Lindahl, Johanna Mäenpää, Maria Dimoula, Theresa L Werner, Trine Zeeberg Iversen, Sakari Hietanen, Lars Fokdal, Hanna Dahlstrand, Line Bjørge, Michael J Birrer, Mansoor R Mirza, Maria Rossing","doi":"10.1158/2767-9764.CRC-24-0294","DOIUrl":"10.1158/2767-9764.CRC-24-0294","url":null,"abstract":"<p><strong>Abstract: </strong>The management of advanced epithelial ovarian cancer (AOC) has undergone significant advancements with the emergence of molecular diagnostics, particularly in predicting responses to PARP inhibitors (PARPi) based on homologous recombination deficiency (HRD) status. However, understanding sensitivity and resistance beyond HRD status remains elusive. This study aims to explore molecular factors that may elucidate why HRD status does not consistently predict PARPi sensitivity. Therefore, we conducted a post hoc translational analysis of formalin-fixed paraffin-embedded tumor samples from the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial (NCT02354131), focusing on alterations pertaining radiologic response and progression-free survival (PFS). DNA sequencing was performed using the TruSight Oncology 500 HT gene panel, with variants classified according to recent guidelines. HRD status had been assessed by Myriad MyChoice CDx. We identified, among 92 patients in the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial, 151 pathogenic or likely pathogenic variants across 81 samples. PARPi-sensitizing variants were found in two out of 10 HRD-negative samples from patients with clinical benefit (PFS ≥12 months), whereas three out of 10 HRD-positive samples from patients having no benefit (PFS ≤6 months) harbored variants associated with PARPi resistance. Additionally, analysis of BRCA1 variants revealed that truncating variants in exon 11 correlated with clinical benefit when niraparib was combined with bevacizumab. Conclusively, our findings highlight the complexity of PARPi response in AOC and underscore the importance of exploring somatic variants beyond HRD status. Further investigation into exon 11 variants of BRCA1 and the potential of combination treatment is warranted.</p><p><strong>Significance: </strong>The irregular response to PARPi in HRD-positive and -negative tumors highlights the need for identifying additional biomarkers. This study explores the mutational landscape beyond HRD status in AOC, ultimately advancing precision oncology in future clinical practice.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"3190-3200"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735176","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":"DeePathNet: A Transformer-Based Deep Learning Model Integrating Multiomic Data with Cancer Pathways.","authors":"Zhaoxiang Cai, Rebecca C Poulos, Adel Aref, Phillip J Robinson, Roger R Reddel, Qing Zhong","doi":"10.1158/2767-9764.CRC-24-0285","DOIUrl":"10.1158/2767-9764.CRC-24-0285","url":null,"abstract":"<p><strong>Abstract: </strong>Multiomic data analysis incorporating machine learning has the potential to significantly improve cancer diagnosis and prognosis. Traditional machine learning methods are usually limited to omic measurements, omitting existing domain knowledge, such as the biological networks that link molecular entities in various omic data types. Here, we develop a transformer-based explainable deep learning model, DeePathNet, which integrates cancer-specific pathway information into multiomic data analysis. Using a variety of big datasets, including ProCan-DepMapSanger, Cancer Cell Line Encyclopedia, and The Cancer Genome Atlas, we demonstrate and validate that DeePathNet outperforms traditional methods for predicting drug response and classifying cancer type and subtype. Combining biomedical knowledge and state-of-the-art deep learning methods, DeePathNet enables biomarker discovery at the pathway level, maximizing the power of data-driven approaches to cancer research. DeePathNet is available on GitHub at https://github.com/CMRI-ProCan/DeePathNet.</p><p><strong>Significance: </strong>DeePathNet integrates cancer-specific biological pathways using transformer-based deep learning for enhanced cancer analysis. It outperforms existing models in predicting drug responses, cancer types, and subtypes. By enabling pathway-level biomarker discovery, DeePathNet represents a significant advancement in cancer research and could lead to more effective treatments.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"3151-3164"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633089","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":"Tumor Expression of CD83 Reduces Glioma Progression and Is Associated with Reduced Immunosuppression.","authors":"Malcolm F McDonald, Rachel Naomi Curry, Isabella O'Reilly, Brittney Lozzi, Alexis Cervantes, Zhung-Fu Lee, Anna Rosenbaum, Peihao He, Carrie Mohila, Arif O Harmanci, Akdes Serin Harmanci, Benjamin Deneen, Ganesh Rao","doi":"10.1158/2767-9764.CRC-24-0281","DOIUrl":"10.1158/2767-9764.CRC-24-0281","url":null,"abstract":"<p><strong>Abstract: </strong>Malignant glioma, the most lethal form of brain cancer, presents with an immunosuppressive microenvironment that obstructs tumor cell clearance and hampers immunotherapeutic interventions. Despite advancements in characterizing cellular and extracellular profiles in cancer, the immunosuppressive mechanisms specific to glioma remain poorly understood. We conducted single-cell RNA sequencing of glioma samples, which revealed a select subset of human and mouse glioma cells that express CD83, a marker associated with mature antigen-presenting cells. To investigate the impact of tumor cell CD83 expression on glioma outcomes, we used an immunocompetent mouse model of glioma, bioinformatic analyses of human samples, and in vitro assays. Our findings revealed that CD83+ tumor cells contribute to tumor growth suppression and are associated with enhanced cytotoxic T-cell profiles and activated CD8+ T cells. Increased proinflammatory cytokines were identified in CD83-overexpressing tumor conditions, which were also correlated with long-term CD8+ antitumor responses. Importantly, tumor-derived CD83 could mediate communication with T cells, altering the immune microenvironment to potentially enhance immune-related tumor clearance. Collectively, our data suggest that tumor cell expression of CD83 supports the endogenous antitumor T-cell constituency in malignant glioma. Future research endeavors may aim to further investigate whether CD83 expression can enhance immunotherapeutic approaches and improve patient outcomes.</p><p><strong>Significance: </strong>Immunosuppression in malignant glioma remains a barrier to therapeutic development. CD83 overexpression in human and mouse glioma increases survival. CD83+ tumor cells promote signatures related to cytotoxic T cells, enhanced activation of CD8+ T cells, and increased proinflammatory cytokines. These findings suggest that tumor-expressed CD83 could mediate tumor-immune communications.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":"3209-3223"},"PeriodicalIF":2.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735178","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}