bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from In Vivo Imaging of Methionine Aminopeptidase II for Prostate Cancer Risk Stratification
Authors: Xie Jinghang , Rice Meghan A. , Chen Zixin , Cheng Yunfeng , Hsu En-Chi , Chen Min , Song Guosheng , Cui Liyang , Zhou Kaixiang , Castillo Jessa B. , Zhang Chiyuan A. , Shen Bin , Chin Frederick T. , Kunder Christian A. , Brooks James D. , Stoyanova Tanya , Rao Jianghong
Published: March 2024

Abstract
Prostate cancer is one of the most common malignancies worldwide, yet limited tools exist for prognostic risk stratification of the disease. Identification of new biomarkers representing intrinsic features of malignant transformation and development of prognostic imaging technologies are critical for improving treatment decisions and patient survival. In this study, we analyzed radical prostatectomy specimens from 422 patients with localized disease to define the expression pattern of methionine aminopeptidase II (MetAP2), a cytosolic metalloprotease that has been identified as a druggable target in cancer. MetAP2 was highly expressed in 54% of low-grade and 59% of high-grade cancers. Elevated levels of MetAP2 at diagnosis were associated with shorter time to recurrence. Controlled self-assembly of a synthetic small molecule enabled design of the first MetAP2-activated PET imaging tracer for monitoring MetAP2 activity in vivo. The nanoparticles assembled upon MetAP2 activation were imaged in single prostate cancer cells with post-click fluorescence labeling. The fluorine-18–labeled tracers successfully differentiated MetAP2 activity in both MetAP2-knockdown and inhibitor-treated human prostate cancer xenografts by micro-PET/CT scanning. This highly sensitive imaging technology may provide a new tool for noninvasive early-risk stratification of prostate cancer and monitoring the therapeutic effect of MetAP2 inhibitors as anticancer drugs.
Significance:
This study defines MetAP2 as an early-risk stratifier for molecular imaging of aggressive prostate cancer and describes a MetAP2-activated self-assembly small-molecule PET tracer for imaging MetAP2 activity in vivo.
Data from Inhibition of the FACT Complex Targets Aberrant Hedgehog Signaling and Overcomes Resistance to Smoothened Antagonists
Authors: Mo Jialin , Liu Fang , Sun Xi , Huang Hongting , Tan Kezhe , Zhao Xiaojing , Li Rui , Jiang Wenyan , Sui Yi , Chen Xiaosong , Shen Kunwei , Zhang Liye , Ma Jie , Zhao Kewen , Tang Yujie
Published: March 2024

Abstract
Hedgehog signaling is aberrantly activated in hematologic malignancies and solid tumors, and targeting it is a promising therapeutic strategy against these cancers. Resistance to clinically available hedgehog-targeted Smoothened inhibitor (SMOi) drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies identified inhibition of BET and CDK7 as two epigenetic/transcriptional-targeted therapeutic strategies for overcoming SMOi resistance, providing a promising direction for anti-hedgehog drug development. To uncover additional strategies for inhibiting aberrant hedgehog activity, here we performed CRISPR-Cas9 screening with an single-guide RNA library targeting epigenetic and transcriptional modulators in hedgehog-driven medulloblastoma cells, combined with tumor dataset analyses. Structure specific recognition protein 1 (SSRP1), a subunit of facilitates chromatin transcription (FACT) complex, was identified as a hedgehog-induced essential oncogene and therapeutic target in hedgehog-driven cancer. The FACT inhibitor CBL0137, which has entered clinical trials for cancer, effectively suppressed in vitro and in vivo growth of multiple SMOi-responsive and SMOi-resistant hedgehog-driven cancer models. Mechanistically, CBL0137 exerted anti-hedgehog activity by targeting transcription of GLI1 and GLI2, which are core transcription factors of the hedgehog pathway. SSRP1 bound the promoter regions of GLI1 and GLI2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 synergized with BET or CDK7 inhibitors to antagonize aberrant hedgehog pathway and growth of hedgehog-driven cancer models. Taken together, these results identify FACT inhibition as a promising epigenetic/transcriptional-targeted therapeutic strategy for treating hedgehog-driven cancers and overcoming SMOi resistance.
Significance:
This study identifies FACT inhibition as an anti-hedgehog therapeutic strategy for overcoming resistance to Smoothened inhibitors and provides preclinical support for initiating clinical trials of FACT-targeted drug CBL0137 against hedgehog-driven cancers.
Data from ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression
Authors: Liu Cuicui , Qiang Jiankun , Deng Qiaodan , Xia Jie , Deng Lu , Zhou Lei , Wang Dong , He Xueyan , Liu Ying , Zhao Botao , Lv Jinhui , Yu Zuoren , Lei Qun-Ying , Shao Zhi-Ming , Zhang Xiao-Yong , Zhang Lixing , Liu Suling
Published: March 2024

Abstract
Tumor-initiating cells (TIC) are associated with tumor initiation, growth, metastasis, and recurrence. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker in many cancers, including breast cancer. However, the molecular mechanisms underlying ALDH1A1 functions in solid tumors remain largely unknown. Here we demonstrate that ALDH1A1 enzymatic activity facilitates breast tumor growth. Mechanistically, ALDH1A1 decreased the intracellular pH in breast cancer cells to promote phosphorylation of TAK1, activate NFκB signaling, and increase the secretion of GM-CSF, which led to myeloid-derived suppressor cell expansion and immunosuppression. Furthermore, the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ TICs and activating T-cell immunity. These findings elucidate how active ALDH1A1 modulates the immune system to promote tumor development, highlighting new therapeutic strategies for malignant breast cancer.
Significance:
ALDH1A1 enzyme activity induces MDSC expansion and triggers a procancer immune microenvironment to facilitate breast cancer progression, providing a novel therapeutic vulnerability in this disease.
Data from Label-Free Deep Profiling of the Tumor Microenvironment
Authors: You Sixian , Chaney Eric J. , Tu Haohua , Sun Yi , Sinha Saurabh , Boppart Stephen A.
Published: March 2024

Abstract
Label-free nonlinear microscopy enables nonperturbative visualization of structural and metabolic contrast within living cells in their native tissue microenvironment. Here a computational pipeline was developed to provide a quantitative view of the microenvironmental architecture within cancerous tissue from label-free nonlinear microscopy images. To enable single-cell and single-extracellular vesicle (EV) analysis, individual cells, including tumor cells and various types of stromal cells, and EVs were segmented by a multiclass pixelwise segmentation neural network and subsequently analyzed for their metabolic status and molecular structure in the context of the local cellular neighborhood. By comparing cancer tissue with normal tissue, extensive tissue reorganization and formation of a patterned cell–EV neighborhood was observed in the tumor microenvironment. The proposed analytic pipeline is expected to be useful in a wide range of biomedical tasks that benefit from single-cell, single–EV, and cell-to-EV analysis.
Significance:
The proposed computational framework allows label-free microscopic analysis that quantifies the complexity and heterogeneity of the tumor microenvironment and opens possibilities for better characterization and utilization of the evolving cancer landscape.
Data from Oncostatin M Receptor–Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth
Authors: Geethadevi Anjali , Nair Ajay , Parashar Deepak , Ku Zhiqiang , Xiong Wei , Deng Hui , Li Yongsheng , George Jasmine , McAllister Donna M. , Sun Yunguang , Kadamberi Ishaque P. , Gupta Prachi , Dwinell Michael B. , Bradley William H. , Rader Janet S. , Rui Hallgeir , Schwabe Robert F. , Zhang Ningyan , Pradeep Sunila , An Zhiqiang , Chaluvally-Raghavan Pradeep
Published: March 2024

Abstract
Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR–IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR–IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling in vitro. Importantly, these antibody clones inhibited the growth of ovarian cancer cells in vitro and in vivo by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR–IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer.
Significance:
This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment.
Data from Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis
Authors: Tang Donge , Dai Yong , Xu Songhui
Published: March 2024

The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance.
Significance:
These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.
Data from Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models
Authors: Campbell Joseph R. , McDonald Bryan R. , Mesko Paul B. , Siemers Nathan O. , Singh Priti B. , Selby Mark , Sproul Tim W. , Korman Alan J. , Vlach Logan M. , Houser Jeff , Sambanthamoorthy Sharmila , Lu Kai , Hatcher Sandra V. , Lohre Jack , Jain Renu , Lan Ruth Y.
Published: March 2024

Abstract
FOXP3+ regulatory T cells (Treg) play a critical role in mediating tolerance to self-antigens and can repress antitumor immunity through multiple mechanisms. Therefore, targeted depletion of tumor-resident Tregs is warranted to promote effective antitumor immunity while preserving peripheral homeostasis. Here, we propose the chemokine receptor CCR8 as one such optimal tumor Treg target. CCR8 was expressed by Tregs in both murine and human tumors, and unlike CCR4, a Treg depletion target in the clinic, CCR8 was selectively expressed on suppressive tumor Tregs and minimally expressed on proinflammatory effector T cells (Teff). Preclinical mouse tumor modeling showed that depletion of CCR8+ Tregs through an FcyR-engaging anti-CCR8 antibody, but not blockade, enabled dose-dependent, effective, and long-lasting antitumor immunity that synergized with PD-1 blockade. This depletion was tumor Treg-restricted, sparing CCR8+ T cells in the spleen, thymus, and skin of mice. Importantly, Fc-optimized, nonfucosylated (nf) anti-human CCR8 antibodies specifically depleted Tregs and not Teffs in ex vivo tumor cultures from primary human specimens. These findings suggest that anti–CCR8-nf antibodies may deliver optimal tumor-targeted Treg depletion in the clinic, providing long-term antitumor memory responses while limiting peripheral toxicities.
Significance:
These findings show that selective depletion of regulatory T cells with an anti-CCR8 antibody can improve antitumor immune responses as a monotherapy or in combination with other immunotherapies.
Data from Exogenous and Endogenous Sources of Serine Contribute to Colon Cancer Metabolism, Growth, and Resistance to 5-Fluorouracil
Authors: Montrose David C. , Saha Suchandrima , Foronda Miguel , McNally Erin M. , Chen Justin , Zhou Xi Kathy , Ha Taehoon , Krumsiek Jan , Buyukozkan Mustafa , Verma Akanksha , Elemento Olivier , Yantiss Rhonda K. , Chen Qiuying , Gross Steven S. , Galluzzi Lorenzo , Dow Lukas E. , Dannenberg Andrew J.
Published: March 2024

Abstract
Serine is a nonessential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition, cancer cells can harness exogenous serine to enhance their metabolism and proliferation. Here we tested the relative contributions of exogenous and endogenous sources of serine on the biology of colorectal cancer. In murine tumors, Apc status was identified as a determinant of the expression of genes controlling serine synthesis. In patient samples, PSAT1 was overexpressed in both colorectal adenomas and adenocarcinomas. Combining genetic deletion of PSAT1 with exogenous serine deprivation maximally suppressed the proliferation of colorectal cancer cells and induced profound metabolic defects including diminished nucleotide production. Inhibition of serine synthesis enhanced the transcriptional changes following exogenous serine removal as well as alterations associated with DNA damage. Both loss of PSAT1 and removal of serine from the diet were necessary to suppress colorectal cancer xenograft growth and enhance the antitumor activity of 5-fluorouracil (5-FU). Restricting endogenous and exogenous serine in vitro augmented 5-FU–induced cell death, DNA damage, and metabolic perturbations, likely accounting for the observed antitumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to colorectal cancer growth and resistance to 5-FU.
Significance:
These findings provide insights into the metabolic requirements of colorectal cancer and reveal a novel approach for its treatment.
Data from Engineering T Cells to Express Tumoricidal MDA-7/IL24 Enhances Cancer Immunotherapy
Authors: Liu Zheng , Guo Chunqing , Das Swadesh K. , Yu Xiaofei , Pradhan Anjan K. , Li Xia , Ning Yanxia , Chen Shixian , Liu Wenjie , Windle Jolene J. , Bear Harry D. , Manjili Masoud H. , Fisher Paul B. , Wang Xiang-Yang
Published: March 2024

Abstract
Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation–associated gene-7/IL24 (MDA-7/IL24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL24-potentiated T-cell expansion was dependent on T-cell–intrinsic STAT3 signaling. Finally, MDA-7/IL24-modified T-cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T-cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape.
Significance:
This research describes a novel strategy to overcome the antigenic heterogeneity of solid cancers and prevent tumor escape by engineering T lymphocytes to produce a broad-spectrum tumoricidal agent.
Data from KMT9 Controls Stemness and Growth of Colorectal Cancer
Authors: Berlin Christopher , Cottard Félicie , Willmann Dominica , Urban Sylvia , Tirier Stephan M. , Marx Lisa , Rippe Karsten , Schmitt Mark , Petrocelli Valentina , Greten Florian R. , Fichtner-Feigl Stefan , Kesselring Rebecca , Metzger Eric , Schüle Roland
Published: March 2024

Abstract
Colorectal cancer is among the leading causes of cancer-associated deaths worldwide. Treatment failure and tumor recurrence due to survival of therapy-resistant cancer stem/initiating cells represent major clinical issues to overcome. In this study, we identified lysine methyltransferase 9 (KMT9), an obligate heterodimer composed of KMT9α and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1), as an important regulator in colorectal tumorigenesis. KMT9α and KMT9β were overexpressed in colorectal cancer and colocalized with H4K12me1 at promoters of target genes involved in the regulation of proliferation. Ablation of KMT9α drastically reduced colorectal tumorigenesis in mice and prevented the growth of murine as well as human patient-derived tumor organoids. Moreover, loss of KMT9α impaired the maintenance and function of colorectal cancer stem/initiating cells and induced apoptosis specifically in this cellular compartment. Together, these data suggest that KMT9 is an important regulator of colorectal carcinogenesis, identifying KMT9 as a promising therapeutic target for the treatment of colorectal cancer.
Significance:
The H4K12 methyltransferase KMT9 regulates tumor cell proliferation and stemness in colorectal cancer, indicating that targeting KMT9 could be a useful approach for preventing and treating this disease.
Data from Single-Cell Analysis Unveils the Role of the Tumor Immune Microenvironment and Notch Signaling in Dormant Minimal Residual Disease
Authors: Janghorban Mahnaz , Yang Yuchen , Zhao Na , Hamor Clark , Nguyen Tuan M. , Zhang Xiang H.-F. , Rosen Jeffrey M.
Published: March 2024

Abstract
Tumor dormancy is a stage in which residual cancer cells remain inactive, but regrowth of dormant cancer cells contributes to recurrence. The complex ecosystem in cancer that promotes cell survival and the factors that eventually overcome growth constraints and result in proliferation remain to be fully elucidated. Doing so may provide new insights and help identify novel strategies to prolong cancer dormancy and prevent disease recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of dormancy, we utilized a novel immunocompetent transgenic model to study minimal residual disease and relapse. This model revealed a significant reorganization of cancer cell structures, stroma, and immune cells, with cancer cells showing dormant cell signatures. Single-cell RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. In addition, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis, including stem cell development, epithelial-to-mesenchymal transition, and immune cell homeostasis during minimal residual disease. Treatment with an anti–Jagged-1 antibody inhibited the Jagged-1/Notch signaling pathway in tumor cells and the microenvironment, delaying tumor recurrence. These findings uncover a cascade of regulatory changes in the microenvironment during dormancy and identify a therapeutic strategy to undercut these changes.
Significance:
Single-cell RNA-sequencing analysis reveals dormancy-associated changes in immune and stromal cells and demonstrates a rationale to pursue Jagged-1/Notch pathway inhibition as a viable therapeutic strategy to reduce disease recurrence.
Data from Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors
Authors: Westerhout Ellen M. , Hamdi Mohamed , Stroeken Peter , Nowakowska Natalia E. , Lakeman Arjan , van Arkel Jennemiek , Hasselt Nancy E. , Bleijlevens Boris , Akogul Nurdan , Haneveld Franciska , Chan Alvin , van Sluis Peter , Zwijnenburg Danny , Volckmann Richard , van Noesel Carel J.M. , Adameyko Igor , van Groningen Tim , Koster Jan , Valentijn Linda J. , van Nes Johan , Versteeg Rogier
Published: March 2024

Abstract
Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors.
Significance:
In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell–targeting TRAIL delays tumor relapse.
Data from Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors
Authors: Lappin Katrina M. , Barros Eliana M. , Jhujh Satpal S. , Irwin Gareth W. , McMillan Hayley , Liberante Fabio G. , Latimer Cheryl , La Bonte Melissa J. , Mills Ken I. , Harkin D. Paul , Stewart Grant S. , Savage Kienan I.
Published: March 2024

Abstract
Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response to DNA damage. Here, we demonstrate that depletion of SF3B1 specifically compromises homologous recombination (HR) and is epistatic with loss of BRCA1. More importantly, the most prevalent cancer-associated mutation in SF3B1, K700E, also affects HR efficiency and as a consequence, increases the cellular sensitivity to ionizing radiation and a variety of chemotherapeutic agents, including PARP inhibitors. In addition, the SF3B1 K700E mutation induced unscheduled R-loop formation, replication fork stalling, increased fork degradation, and defective replication fork restart. Taken together, these data suggest that tumor-associated mutations in SF3B1 induce a BRCA-like cellular phenotype that confers synthetic lethality to DNA-damaging agents and PARP inhibitors, which can be exploited therapeutically.
Significance:
The cancer-associated SF3B1K700E mutation induces DNA damage via generation of genotoxic R-loops and stalled replication forks, defective homologous recombination, and increased replication fork degradation, which can be targeted with PARP inhibitors.
Data from Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies
Authors: Szydłowski Maciej , Garbicz Filip , Jabłońska Ewa , Górniak Patryk , Komar Dorota , Pyrzyńska Beata , Bojarczuk Kamil , Prochorec-Sobieszek Monika , Szumera-Ciećkiewicz Anna , Rymkiewicz Grzegorz , Cybulska Magdalena , Statkiewicz Małgorzata , Gajewska Marta , Mikula Michał , Gołas Aniela , Domagała Joanna , Winiarska Magdalena , Graczyk-Jarzynka Agnieszka , Białopiotrowicz Emilia , Polak Anna , Barankiewicz Joanna , Puła Bartosz , Pawlak Michał , Nowis Dominika , Golab Jakub , Tomirotti Andrea M. , Brzózka Krzysztof , Pacheco-Blanco Mariana , Kupcova Kristyna , Green Michael R. , Havranek Ondrej , Chapuy Bjoern , Juszczyński Przemysław
Published: March 2024

Abstract
The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase–associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition–induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies.
Significance:
These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.
Data from Prostate Cancer Risk Stratification via Nondestructive 3D Pathology with Deep Learning–Assisted Gland Analysis
Authors: Xie Weisi , Reder Nicholas P. , Koyuncu Can , Leo Patrick , Hawley Sarah , Huang Hongyi , Mao Chenyi , Postupna Nadia , Kang Soyoung , Serafin Robert , Gao Gan , Han Qinghua , Bishop Kevin W. , Barner Lindsey A. , Fu Pingfu , Wright Jonathan L. , Keene C. Dirk , Vaughan Joshua C. , Janowczyk Andrew , Glaser Adam K. , Madabhushi Anant , True Lawrence D. , Liu Jonathan T.C.
Published: March 2024

Abstract
Prostate cancer treatment planning is largely dependent upon examination of core-needle biopsies. The microscopic architecture of the prostate glands forms the basis for prognostic grading by pathologists. Interpretation of these convoluted three-dimensional (3D) glandular structures via visual inspection of a limited number of two-dimensional (2D) histology sections is often unreliable, which contributes to the under- and overtreatment of patients. To improve risk assessment and treatment decisions, we have developed a workflow for nondestructive 3D pathology and computational analysis of whole prostate biopsies labeled with a rapid and inexpensive fluorescent analogue of standard hematoxylin and eosin (H&E) staining. This analysis is based on interpretable glandular features and is facilitated by the development of image translation–assisted segmentation in 3D (ITAS3D). ITAS3D is a generalizable deep learning–based strategy that enables tissue microstructures to be volumetrically segmented in an annotation-free and objective (biomarker-based) manner without requiring immunolabeling. As a preliminary demonstration of the translational value of a computational 3D versus a computational 2D pathology approach, we imaged 300 ex vivo biopsies extracted from 50 archived radical prostatectomy specimens, of which, 118 biopsies contained cancer. The 3D glandular features in cancer biopsies were superior to corresponding 2D features for risk stratification of patients with low- to intermediate-risk prostate cancer based on their clinical biochemical recurrence outcomes. The results of this study support the use of computational 3D pathology for guiding the clinical management of prostate cancer.
Significance:
An end-to-end pipeline for deep learning–assisted computational 3D histology analysis of whole prostate biopsies shows that nondestructive 3D pathology has the potential to enable superior prognostic stratification of patients with prostate cancer.
Data from CDK4/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade
Authors: Tong Jingshan , Tan Xiao , Song Xiangping , Gao Man , Risnik Denise , Hao Suisui , Ermine Kaylee , Wang Peng , Li Hua , Huang Yi , Yu Jian , Zhang Lin
Published: March 2024

Abstract
Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TRAIL, 5-fluorouracil chemotherapy, and anti–PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.
Significance:
This work demonstrates how inhibition of CDK4/6 sensitizes cancer cells to chemotherapy and immune checkpoint blockade and may provide a new molecular marker for improving CDK4/6-targeted cancer therapies.

See related commentary by Frank, p. 1170
Data from Aberrant RNA Splicing Is a Primary Link between Genetic Variation and Pancreatic Cancer Risk
Authors: Tian Jianbo , Chen Can , Rao Meilin , Zhang Ming , Lu Zequn , Cai Yimin , Ying Pingting , Li Bin , Wang Haoxue , Wang Lu , Li Yao , Huang Jinyu , Fan Linyun , Cai Xiaomin , Ning Caibo , Li Yanmin , Zhang Fuwei , Wang Wenzhuo , Jiang Yuan , Liu Yizhuo , Wang Min , Li Heng , Huang Chaoqun , Yang Zhiyong , Chang Jiang , Zhu Ying , Yang Xiaojun , Miao Xiaoping
Published: March 2024

Abstract
Understanding the genetic variation underlying transcript splicing is essential for fully dissecting the molecular mechanisms of common diseases. The available evidence from splicing quantitative trait locus (sQTL) studies using pancreatic ductal adenocarcinoma (PDAC) tissues have been limited to small sample sizes. Here we present a genome-wide sQTL analysis to identify SNP that control mRNA splicing in 176 PDAC samples from TCGA. From this analysis, 16,175 sQTLs were found to be significantly enriched in RNA-binding protein (RBP) binding sites and chromatin regulatory elements and overlapped with known loci from PDAC genome-wide association studies (GWAS). sQTLs and expression quantitative trait loci (eQTL) showed mostly nonoverlapping patterns, suggesting sQTLs provide additional insights into the etiology of disease. Target genes affected by sQTLs were closely related to cancer signaling pathways, high mutational burden, immune infiltration, and pharmaceutical targets, which will be helpful for clinical applications. Integration of a large-scale population consisting of 2,782 patients with PDAC and 7,983 healthy controls identified an sQTL variant rs1785932-T allele that promotes alternative splicing of ELP2 exon 6 and leads to a lower level of the ELP2 full-length isoform (ELP2_V1) and a higher level of a truncated ELP2 isoform (ELP2_V2), resulting in decreased risk of PDAC [OR = 0.83; 95% confidence interval (CI), 0.77–0.89; P = 1.16 × 10−6]. The ELP2_V2 isoform functioned as a potential tumor suppressor gene, inhibiting PDAC cell proliferation by exhibiting stronger binding affinity to JAK1/STAT3 than ELP2_V1 and subsequently blocking the pathologic activation of the phosphorylated STAT3 (pSTAT3) pathway. Collectively, these findings provide an informative sQTL resource and insights into the regulatory mechanisms linking splicing variants to PDAC risk.
Significance:
In pancreatic cancer, splicing quantitative trait loci analysis identifies a rs1785932 variant that contributes to decreased risk of disease by influencing ELP2 mRNA splicing and blocking the STAT3 oncogenic pathway.
Data from Myeloid-Derived Suppressive Cell Expansion Promotes Melanoma Growth and Autoimmunity by Inhibiting CD40/IL27 Regulation in Macrophages
Authors: Valencia Julio C. , Erwin-Cohen Rebecca A. , Clavijo Paul E. , Allen Clint , Sanford Michael E. , Day Chi-Ping , Hess Megan M. , Johnson Morgan , Yin Jie , Fenimore John M. , Bettencourt Ian A. , Tsuneyama Koichi , Romero Maria E. , Klarmann Kimberly D. , Jiang Peng , Bae Heekyong R. , McVicar Daniel W. , Merlino Glenn , Edmondson Elijah F. , Anandasabapathy Niroshana , Young Howard A.
Published: March 2024

Abstract
The relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces de novo autoinflammation and exacerbates underlying AID, even without evident antitumor responses. Recently, systemic lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier to healthy immune surveillance and successful cancer immunotherapy. Cross-talk between MDSCs and macrophages generally drives immune suppressive activity in the tumor microenvironment. However, it remains unclear how peripheral pregenerated MDSC under chronic inflammatory conditions modulates global macrophage immune functions and the impact it could have on existing tumors and underlying lupus nephritis. Here we show that pathogenic expansion of SLE-generated MDSCs by melanoma drives global macrophage polarization and simultaneously impacts the severity of lupus nephritis and tumor progression in SLE-prone mice. Molecular and functional data showed that MDSCs interact with autoimmune macrophages and inhibit cell surface expression of CD40 and the production of IL27. Moreover, low CD40/IL27 signaling in tumors correlated with high tumor-associated macrophage infiltration and ICB therapy resistance both in murine and human melanoma exhibiting active IFNγ signatures. These results suggest that preventing global macrophage reprogramming induced by MDSC-mediated inhibition of CD40/IL27 signaling provides a precision melanoma immunotherapy strategy, supporting an original and advantageous approach to treat solid tumors within established autoimmune landscapes.
Significance:
Myeloid-derived suppressor cells induce macrophage reprogramming by suppressing CD40/IL27 signaling to drive melanoma progression, simultaneously affecting underlying autoimmune disease and facilitating resistance to immunotherapy within preexisting autoimmune landscapes.
Data from The Protein Kinase Activity of NME7 Activates Wnt/β-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma
Authors: Ren Xinxin , Rong Zhuoxian , Liu Xiaoyu , Gao Jie , Xu Xu , Zi Yuyuan , Mu Yun , Guan Yidi , Cao Zhen , Zhang Yuefang , Zeng Zimei , Fan Qi , Wang Xitao , Pei Qian , Wang Xiang , Xin Haiguang , Li Zhi , Nie Yingjie , Qiu Zilong , Li Nan , Sun Lunquan , Deng Yuezhen
Published: March 2024

Abstract
Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/β-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/β-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, whereas overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and to promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3β to promote β-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of β-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. In addition, expression levels of NME7, β-catenin, and MTHFD2 correlated with each other and with poor prognosis in patients with HCC. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/β-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC.
Significance:
The identification of NME7 as an activator of Wnt/β-catenin signaling and MTHFD2 expression in HCC reveals a mechanism regulating one-carbon metabolism and potential therapeutic strategies for treating this disease.
Data from Proteomic Mapping and Targeting of Mitotic Pericentriolar Material in Tumors Bearing Centrosome Amplification
Authors: Xie Bingteng , Pu Yang , Yang Fan , Chen Wei , Yue Wei , Ma Jihong , Zhang Na , Jiang Yuening , Wu Jiegen , Lin Yihan , Liang Xin , Wang Chu , Zou Peng , Li Mo
Published: March 2024

Abstract
Recent work has made it clear that pericentriolar material (PCM), the matrix of proteins surrounding centrioles, contributes to most functions of centrosomes. Given the occurrence of centrosome amplification in most solid tumors and the unconventional survival of these tumor cells, it is tempting to hypothesize that gel-like mitotic PCM would cluster extra centrosomes to defend against mitotic errors and increase tumor cell survival. However, because PCM lacks an encompassing membrane, is highly dynamic, and is physically connected to centrioles, few methods can decode the components of this microscale matrix. In this study, we took advantage of differential labeling between two sets of APEX2-centrosome reactions to design a strategy for acquiring the PCM proteome in living undisturbed cells without synchronization treatment, which identified 392 PCM proteins. Localization of ubiquitination promotion proteins away from PCM was a predominant mechanism to maintain the large size of PCM for centrosome clustering during mitosis in cancer cells. Depletion of PCM gene kinesin family member 20A (KIF20A) caused centrosome clustering failure and apoptosis in cancer cells in vitro and in vivo. Thus, our study suggests a strategy for targeting a wide range of tumors exhibiting centrosome amplification and provides a proteomic resource for future mining of PCM proteins.
Significance:
This study identifies the proteome of pericentriolar material and reveals therapeutic vulnerabilities in tumors bearing centrosome amplification.
Data from TRAF4 Maintains Deubiquitination of Caveolin-1 to Drive Glioblastoma Stemness and Temozolomide Resistance
Authors: Li Yongxu , Wang Tiepeng , Wan Quan , Wang Qing , Chen Zhenzhong , Gao Yuan , Ye Yuchen , Lin Jiusheng , Zhao Bihuan , Wang Huaile , Yang Jinming , Zhao Kai , Lu Na
Published: March 2024

Abstract
Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified risperidone interaction with TRAF4, and risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacologic inhibition of TRAF4 with risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes.
Significance:
The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.
Polo-like Kinase 1 Inhibition inKRAS-Mutated Metastatic Colorectal Cancer
Authors: Stebbing Justin , Bullock Andrea J.
Published: March 2024

Inhibition of Polo-like kinase 1 (Plk1) is a promising new target and therapeutic strategy in metastatic colorectal cancer, especially those with KRAS mutations. New data support further development of onvansertib, and highlights the role of circulating tumor DNA in phase I clinical trials.

See related article by Ahn et al., p. 2039
Data from Bortezomib Sensitizes Malignant Human Glioma Cells to TRAIL, Mediated by Inhibition of the NF-κB Signaling Pathway
Authors: Jane Esther P. , Premkumar Daniel R. , Pollack Ian F.
Published: March 2024

Abstract
Previous studies have shown that the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has significant apoptosis-inducing activity in some glioma cell lines, although many lines are either moderately or completely resistant, which has limited the therapeutic applicability of this agent. Because our recent studies showed that inhibition of proteasomal function may be independently active as an apoptosis-inducing stimulus in these tumors, we investigated the sensitivity of a panel of glioma cell lines (U87, T98G, U373, A172, LN18, LN229, LNZ308, and LNZ428) to TRAIL alone and in combination with the proteasome inhibitor bortezomib. Analysis of these cell lines revealed marked differences in their sensitivity to these treatments, with two (LNZ308 and U373) of the eight cell lines revealing no significant induction of cell death in response to TRAIL alone. No correlation was found between sensitivity of cells to TRAIL and expression of TRAIL receptors DR4, DR5, and decoy receptor DcR1, caspase 8, apoptosis inhibitory proteins XIAP, survivin, Mcl-1, Bcl-2, Bcl-Xl, and cFLIP. However, TRAIL-resistant cell lines exhibited a high level of basal NF-κB activity. Bortezomib was capable of potentiating TRAIL-induced apoptosis in TRAIL-resistant cells in a caspase-dependent fashion. Bortezomib abolished p65/NF-κB DNA-binding activity, supporting the hypothesis that inhibition of the NF-κB pathway is critical for the enhancement of TRAIL sensitization in glioma cells. Moreover, knockdown of p65/NF-κB by shRNA also enhanced TRAIL-induced apoptosis, indicating that p65/NF-κB may be important in mediating TRAIL sensitivity and the effect of bortezomib in promoting TRAIL sensitization and apoptosis induction. Mol Cancer Ther; 10(1); 198–208. ©2011 AACR.
Data from Targeting the Intracellular MUC1 C-terminal Domain Inhibits Proliferation and Estrogen Receptor Transcriptional Activity in Lung Adenocarcinoma Cells
Authors: Klinge Carolyn M. , Radde Brandie N. , Imbert-Fernandez Yoannis , Teng Yun , Ivanova Margarita M. , Abner Sabra M. , Martin Alexandra L.
Published: March 2024

Abstract
Mucin 1 (MUC1) is a diagnostic factor and therapy target in lung adenocarcinoma. MUC1 C-terminal intracellular domain (CD) interacts with estrogen receptor (ER) α and increases gene transcription in breast cancer cells. Because lung adenocarcinoma cells express functional ERα and ERβ, we examined MUC1 expression and MUC1–ER interaction. Because blocking MUC1 CD with an inhibitory peptide (PMIP) inhibited breast tumor growth, we tested whether PMIP would inhibit lung adenocarcinoma cell proliferation. We report that MUC1 interacts with ERα and ERβ within the nucleus of H1793 lung adenocarcinoma cells in accordance with MUC1 expression. PMIP was taken up by H23 and H1793 cells and inhibited the proliferation of H1793, but not H23 cells, concordant with higher MUC1 protein expression in H1793 cells. Lower MUC1 protein expression in H23 does not correspond to microRNAs miR-125b and miR-145 that have been reported to reduce MUC1 expression. PMIP had no effect on the viability of normal human bronchial epithelial cells, which lack MUC1 expression. PMIP inhibited estradiol-activated reporter gene transcription and endogenous cyclin D1 and nuclear respiratory factor-1 gene transcription in H1793 cells. These results indicate MUC1–ER functional interaction in lung adenocarcinoma cells and that inhibiting MUC1 inhibits lung adenocarcinoma cell viability. Mol Cancer Ther; 10(11); 2062–71. ©2011 AACR.