bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation
Authors: Henrich Ian C. , Jain Kanika , Young Robert , Quick Laura , Lindsay Jarrett M. , Park Daniel H. , Oliveira Andre M. , Blobel Gerd A. , Chou Margaret M.
Published: March 2023

Abstract
Ewing sarcoma is the second most common pediatric bone cancer, with a 5-year survival rate for metastatic disease of only 20%. Recent work indicates that survival is strongly correlated with high levels of tumor-infiltrating lymphocytes (TIL), whose abundance is associated with IFN-inducible chemokines CXCL10 and CCL5. However, the tumor-intrinsic factors that drive chemokine production and TIL recruitment have not been fully elucidated. We previously showed that ubiquitin-specific protease 6 (USP6) directly deubiquitinates and stabilizes Jak1, thereby inducing an IFN signature in Ewing sarcoma cells. Here, we show that this gene set comprises chemokines associated with immunostimulatory, antitumorigenic functions, including CXCL10 and CCL5. USP6 synergistically enhanced chemokine production in response to exogenous IFN by inducing surface upregulation of IFNAR1 and IFNGR1. USP6-expressing Ewing sarcoma cells stimulated migration of primary human monocytes and T lymphocytes and triggered activation of natural killer (NK) cells in vitro. USP6 inhibited Ewing sarcoma xenograft growth in nude but not NSG mice and was accompanied by increased intratumoral chemokine production and infiltration and activation of NK cells, dendritic cells, and macrophages, consistent with a requirement for innate immune cells in mediating the antitumorigenic effects of USP6. High USP6 expression in patients with Ewing sarcoma was associated with chemokine production, immune infiltration, and improved survival. This work reveals a previously unrecognized tumor-suppressive function for USP6, which engenders an immunostimulatory microenvironment through pleiotropic effects on multiple immune lineages. This further raises the possibility that USP6 activity may be harnessed to create a “hot” tumor microenvironment in immunotherapy.
Significance:
This study reveals a novel tumor-suppressive function for USP6 by inducing an immunostimulatory microenvironment, suggesting that USP6 activity may be exploited to enhance immunotherapy regimens.
Data from Cytoplasmic Localization of Prostate-Specific Membrane Antigen Inhibitors May Confer Advantages for Targeted Cancer Therapies
Authors: Matthias Jessica , Engelhardt Johann , Schäfer Martin , Bauder-Wüst Ulrike , Meyer Philipp T. , Haberkorn Uwe , Eder Matthias , Kopka Klaus , Hell Stefan W. , Eder Ann-Christin
Published: March 2023

Abstract
Targeted imaging and therapy approaches based on novel prostate-specific membrane antigen (PSMA) inhibitors have fundamentally changed the treatment regimen of prostate cancer. However, the exact mechanism of PSMA inhibitor internalization has not yet been studied, and the inhibitors' subcellular fate remains elusive. Here, we investigated the intracellular distribution of peptidomimetic PSMA inhibitors and of PSMA itself by stimulated emission depletion (STED) nanoscopy, applying a novel nonstandard live cell staining protocol. Imaging analysis confirmed PSMA cluster formation at the cell surface of prostate cancer cells and clathrin-dependent endocytosis of PSMA inhibitors. Following the endosomal pathway, PSMA inhibitors accumulated in prostate cancer cells at clinically relevant time points. In contrast with PSMA itself, PSMA inhibitors were found to eventually distribute homogeneously in the cytoplasm, a molecular condition that promises benefits for treatment as cytoplasmic and in particular perinuclear enrichment of the radionuclide carriers may better facilitate the radiation-mediated damage of cancerous cells. This study is the first to reveal the subcellular fate of PSMA/PSMA inhibitor complexes at the nanoscale and aims to inspire the development of new approaches in the field of prostate cancer research, diagnostics, and therapeutics.
Significance:
This study uses STED fluorescence microscopy to reveal the subcellular fate of PSMA/PSMA inhibitor complexes near the molecular level, providing insights of great clinical interest and suggestive of advantageous targeted therapies.
Data from A Combinatorial CRISPR–Cas9 Screen Identifies Ifenprodil as an Adjunct to Sorafenib for Liver Cancer Treatment
Authors: Xu Feng , Tong Man , Tong Cindy S.W. , Chan Becky K.C. , Chu Hoi Yee , Wong Tin Lok , Fong John H.C. , Cheung Maggie S.H. , Mak Kylie Hin-Man , Pardeshi Lakhansing , Huang Yuanhua , Wong Koon Ho , Choi Gigi C.G. , Ma Stephanie , Wong Alan S.L.
Published: March 2023

Abstract
Systematic testing of existing drugs and their combinations is an attractive strategy to exploit approved drugs for repurposing and identifying the best actionable treatment options. To expedite the search among many possible drug combinations, we designed a combinatorial CRISPR–Cas9 screen to inhibit druggable targets. Coblockade of the N-methyl-d-aspartate receptor (NMDAR) with targets of first-line kinase inhibitors reduced hepatocellular carcinoma (HCC) cell growth. Clinically, HCC patients with low NMDAR1 expression showed better survival. The clinically approved NMDAR antagonist ifenprodil synergized with sorafenib to induce the unfolded protein response, trigger cell-cycle arrest, downregulate genes associated with WNT signaling and stemness, and reduce self-renewal ability of HCC cells. In multiple HCC patient-derived organoids and human tumor xenograft models, the drug combination, but neither single drug alone, markedly reduced tumor-initiating cancer cell frequency. Because ifenprodil has an established safety history for its use as a vasodilator in humans, our findings support the repurposing of this drug as an adjunct for HCC treatment to improve clinical outcome and reduce tumor recurrence. These results also validate an approach for readily discovering actionable combinations for cancer therapy.
Significance:
Combinatorial CRISPR–Cas9 screening identifies actionable targets for HCC therapy, uncovering the potential of combining the clinically approved drugs ifenprodil and sorafenib as a new effective treatment regimen.
Data from Neoadjuvant In Situ Immunomodulation Enhances Systemic Antitumor Immunity against Highly Metastatic Tumors
Authors: Oba Takaaki , Kajihara Ryutaro , Yokoi Toshihiro , Repasky Elizabeth A. , Ito Fumito
Published: March 2023

Abstract
Neoadjuvant immunotherapy, given before surgical resection, is a promising approach to develop systemic antitumor immunity for the treatment of high-risk resectable disease. Here, using syngeneic and orthotopic mouse models of triple-negative breast cancer, we have tested the hypothesis that generation of tumor-specific T-cell responses by induction and activation of tumor-residing Batf3-dependent conventional type 1 dendritic cells (cDC1) before resection improves control of distant metastatic disease and survival. Mice bearing highly metastatic orthotopic tumors were treated with a combinatorial in situ immunomodulation (ISIM) regimen comprised of intratumoral administration of Flt3L, local radiotherapy, and in situ TLR3/CD40 stimulations, followed by surgical resection. Neoadjuvant ISIM (neo-ISIM) generated tumor-specific CD8+ T cells that infiltrated into distant nonirradiated metastatic sites, which delayed the progression of lung metastases and improved survival after the resection of primary tumors. The efficacy of neo-ISIM was dependent on de novo adaptive T-cell immunity elicited by Batf3-dependent dendritic cells and was enhanced by increasing dose and fractionation of radiotherapy, and early surgical resection after the completion of neo-ISIM. Importantly, neo-ISIM synergized with programmed cell death protein-1 ligand-1 (PD-L1) blockade to improve control of distant metastases and prolong survival, while removal of tumor-draining lymph nodes abrogated the antimetastatic efficacy of neo-ISIM. Our findings illustrate the therapeutic potential of neoadjuvant multimodal intralesional therapy for the treatment of resectable tumors with high risk of relapse.
Significance:
Neoadjuvant induction and activation of cDC1s in primary tumors enhances systemic antitumor immunity, suppresses metastatic progression, improves survival, and synergizes with anti–PD-L1 therapy.
Data from A Urinary Drug-Disposing Approach as an Alternative to Intravesical Chemotherapy for Treating Nonmuscle Invasive Bladder Cancer
Authors: Bellat Vanessa , Michel Adam O. , Thomas Charlene , Stokol Tracy , Choi Benjamin B. , Law Benedict
Published: March 2023

Abstract
The standard treatment of nonmuscle invasive bladder cancer (NMIBC) is transurethral resection of the tumors, followed by intravesical therapy (IT), which comprises a direct instillation of a solution of Bacillus Calmette-Guérin vaccine or chemotherapy into the bladder. However, the recurrence rate in this disease remains unacceptably high. IT is a local treatment that fails to reach tumors developed in the upper urinary tract (ureter and renal pelvis). The catheterization procedure required for IT is invasive, painful, and poses an increased infection risk, resulting in poor patient quality of life and compliance. There is an unmet need for a potent, comprehensive, and noninvasive option. Without chemical modifications, peptides are rapidly removed by renal clearance. This “shortcoming” can be advantageous when used as a drug carrier for directing therapy to NMIBC. Here we develop a urinary drug-disposing (UDD) approach to improve NMIBC treatment. A 12-amino acid bio-inert peptide (Bdd) that can be exclusively eliminated via renal filtration was generated for delivering the microtubule inhibitor DM1 to NMIBC with minimal nonspecific accumulation in other organs. The UDD approach prolonged survival of mice bearing human bladder tumors. Unlike IT, the treatment was given noninvasively (intravenously). Furthermore, it was more effective at suppressing tumor growth than clinically used IT (mitomycin) and safer than free DM1. The application of this UDD approach to treat kidney tumors and deliver other drugs such as doxorubicin was also demonstrated. Overall, the rapid renal clearance of peptides can be exploited to direct cancer therapies to the urinary system.
Significance:
A noninvasive drug delivery approach that targets the urinary system overcomes the current barriers facing effective treatment of bladder cancer.
Data from A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer
Authors: Rodríguez Yara , Unno Kenji , Truica Mihai I. , Chalmers Zachary R. , Yoo Young A. , Vatapalli Rajita , Sagar Vinay , Yu Jindan , Lysy Barbara , Hussain Maha , Han Huiying , Abdulkadir Sarki A.
Published: March 2023

Abstract
Androgen receptor (AR) pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance to therapy is common. Here, we used a CRISPR activation screen in metastatic castration-sensitive prostate cancer cells to identify genes that promote resistance to AR inhibitors. Activation of the TGFβ target gene paired-related homeobox2 (PRRX2) promoted enzalutamide resistance. PRRX2 expression was the highest in double-negative prostate cancer (DNPC), which lack AR signaling and neuroendocrine differentiation, and a PRRX2-related gene signature identified a subset of patients with DNPC with reduced overall survival. PRRX2-expressing cells showed alterations in the CDK4/6/Rb/E2F and BCL2 pathways. Accordingly, treatment with CDK4/6 and BCL2 inhibitors sensitized PRRX2-expressing, castration-resistant tumors to enzalutamide. Overall, PRRX2 was identified as a driver of enzalutamide resistance. The PRRX2 signature merits investigation as a biomarker of enzalutamide resistance in prostate cancer that could be reversed with CDK4/6 and BCL2 inhibitors.
Significance:
PRRX2 mediates enzalutamide resistance via activation of the E2F and BCL2 pathways, which can be targeted with CDK4/6 and BCL2 inhibitors to reverse resistance.
Data from Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy
Authors: Quintanal-Villalonga Alvaro , Taniguchi Hirokazu , Hao Yuan , Chow Andrew , Zhan Yingqian A. , Chavan Shweta S. , Uddin Fathema , Allaj Viola , Manoj Parvathy , Shah Nisargbhai S. , Chan Joseph M. , Offin Michael , Ciampricotti Metamia , Ray-Kirton Jordana , Egger Jacklynn , Bhanot Umesh , Linkov Irina , Asher Marina , Roehrl Michael H. , Qiu Juan , de Stanchina Elisa , Hollmann Travis J. , Koche Richard P. , Sen Triparna , Poirier John T. , Rudin Charles M.
Published: March 2023

Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1, as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC, with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease.
Significance:
CRISPR-Cas9 screening nominates exportin-1 as a therapeutic target in SCLC, and exportin-1 inhibition enhances chemotherapy efficacy in patient-derived xenografts, providing a novel therapeutic opportunity in this disease.
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 2023

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 Prostaglandin Pathways: Opportunities for Cancer Prevention and Therapy
Authors: Wang Qiushi , Morris Rebecca J. , Bode Ann M. , Zhang Tianshun
Published: March 2023

Abstract
Because of profound effects observed in carcinogenesis, prostaglandins (PG), prostaglandin-endoperoxide synthases, and PG receptors are implicated in cancer development and progression. Understanding the molecular mechanisms of PG actions has potential clinical relevance for cancer prevention and therapy. This review focuses on the current status of PG signaling pathways in modulating cancer progression and aims to provide insights into the mechanistic actions of PGs and their receptors in influencing tumor progression. We also examine several small molecules identified as having anticancer activity that target prostaglandin receptors. The literature suggests that targeting PG pathways could provide opportunities for cancer prevention and therapy.
Data from PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer
Authors: Ghilardi Carmen , Moreira-Barbosa Catarina , Brunelli Laura , Ostano Paola , Panini Nicolò , Lupi Monica , Anastasia Alessia , Fiordaliso Fabio , Salio Monica , Formenti Laura , Russo Massimo , Arrigoni Edoardo , Chiaradonna Ferdinando , Chiorino Giovanna , Draetta Giulio , Marszalek Joseph R. , Vellano Christopher P. , Pastorelli Roberta , Bani MariaRosa , Decio Alessandra , Giavazzi Raffaella
Published: March 2023

Abstract
Ovarian cancer is the deadliest gynecologic cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control ovarian cancer progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC1α and PGC1β. In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1α and PGC1β (PGC1α/β) fostered a unique transcriptional signature, leading to increased mitochondrial abundance, enhanced tricarboxylic acid cycling, and elevated cellular respiration that ultimately conferred vulnerability to OXPHOS inhibition. Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling and ATP depletion that consequently delayed malignant progression and prolonged the lifespan of high PGC1α/β-expressing OC-PDX-bearing mice. Conversely, low PGC1α/β OC-PDXs were not affected by IACS-010759, thus pinpointing a selective antitumor effect of OXPHOS inhibition. The clinical relevance of these findings was substantiated by analysis of ovarian cancer patient datasets, which showed that 25% of all cases displayed high PGC1α/β expression along with an activated mitochondrial gene program. This study endorses the use of OXPHOS inhibitors to manage ovarian cancer and identifies the high expression of both PGC1α and β as biomarkers to refine the selection of patients likely to benefit most from this therapy.
Significance:
OXPHOS inhibition in ovarian cancer can exploit the metabolic vulnerabilities conferred by high PGC1α/β expression and offers an effective approach to manage patients on the basis of PGC1α/β expression.
Data from Comprehensive Evaluation of Machine Learning Models and Gene Expression Signatures for Prostate Cancer Prognosis Using Large Population Cohorts
Authors: Li Ruidong , Zhu Jianguo , Zhong Wei-De , Jia Zhenyu
Published: March 2023

Abstract
Overtreatment remains a pervasive problem in prostate cancer management due to the highly variable and often indolent course of disease. Molecular signatures derived from gene expression profiling have played critical roles in guiding prostate cancer treatment decisions. Many gene expression signatures have been developed to improve the risk stratification of prostate cancer and some of them have already been applied to clinical practice. However, no comprehensive evaluation has been performed to compare the performance of these signatures. In this study, we conducted a systematic and unbiased evaluation of 15 machine learning (ML) algorithms and 30 published prostate cancer gene expression–based prognostic signatures leveraging 10 transcriptomics datasets with 1,558 primary patients with prostate cancer from public data repositories. This analysis revealed that survival analysis models outperformed binary classification models for risk assessment, and the performance of the survival analysis methods—Cox model regularized with ridge penalty (Cox-Ridge) and partial least squares (PLS) regression for Cox model (Cox-PLS)—were generally more robust than the other methods. Based on the Cox-Ridge algorithm, several top prognostic signatures displayed comparable or even better performance than commercial panels. These findings will facilitate the identification of existing prognostic signatures that are promising for further validation in prospective studies and promote the development of robust prognostic models to guide clinical decision-making. Moreover, this study provides a valuable data resource from large primary prostate cancer cohorts, which can be used to develop, validate, and evaluate novel statistical methodologies and molecular signatures to improve prostate cancer management.
Significance:
This systematic evaluation of 15 machine learning algorithms and 30 published gene expression signatures for the prognosis of prostate cancer will assist clinical decision-making.
Data from NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression
Authors: Qin Qizhi , Gomez-Salazar Mario , Tower Robert J. , Chang Leslie , Morris Carol D. , McCarthy Edward F. , Ting Kang , Zhang Xinli , James Aaron W.
Published: March 2023

Abstract
Sarcomas produce an abnormal extracellular matrix (ECM), which in turn provides instructive cues for cell growth and invasion. Neural EGF like-like molecule 1 (NELL1) is a secreted glycoprotein characterized by its nonneoplastic osteoinductive effects, yet it is highly expressed in skeletal sarcomas. Here, we show that genetic deletion of NELL1 markedly reduces invasive behavior across human osteosarcoma (OS) cell lines. NELL1 deletion resulted in reduced OS disease progression, inhibiting metastasis and improving survival in a xenograft mouse model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb-driven sarcomagenesis, which reduced tumor frequency and extended tumor-free survival. Transcriptomic and phosphoproteomic analyses demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culturing NELL1 knockout sarcoma cells on wild-type OS-enriched matricellular proteins reversed the phenotypic and signaling changes induced by NELL1 deficiency. In sarcoma patients, high expression of NELL1 correlated with decreased overall survival. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma ECM, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short-circuit sarcoma disease progression.
Significance:
NELL1 modulates the sarcoma matrisome to promote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell–ECM interactions in sarcomagenesis and disease progression.
Data from PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma
Authors: Yi Jiaqing , Kim BongWoo , Shi Xuanming , Zhan Xiaoming , Lu Q. Richard , Xuan Zhenyu , Wu Jiang
Published: March 2023

Abstract
Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated sonic hedgehog (SHH) signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here, we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wild-type tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. Insulin-like growth factor 2 (IGF2) mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non–cell autonomous mechanisms in distinct tumor subclones.
Significance:
The identification of an oncogenic function of PRC2 heterogeneity in medulloblastoma provides insights into subclone competition and cooperation during heterogeneous tumor evolution.
Data from Selenium Modulates Cancer Cell Response to Pharmacologic Ascorbate
Authors: Jankowski Connor S.R. , Rabinowitz Joshua D.
Published: March 2023

Abstract
High-dose ascorbate (vitamin C) has shown promising anticancer activity. Two redox mechanisms have been proposed: hydrogen peroxide generation by ascorbate itself or glutathione depletion by dehydroascorbate (formed by ascorbate oxidation). Here we show that the metabolic effects and cytotoxicity of high-dose ascorbate in vitro result from hydrogen peroxide independently of dehydroascorbate. These effects were suppressed by selenium through antioxidant selenoenzymes including glutathione peroxidase 1 (GPX1) but not the classic ferroptosis-inhibiting selenoenzyme GPX4. Selenium-mediated protection from ascorbate was powered by NADPH from the pentose phosphate pathway. In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts. These data establish selenoproteins as key mediators of cancer redox homeostasis. Cancer sensitivity to free radical-inducing therapies, including ascorbate, may depend on selenium, providing a dietary approach for improving their anticancer efficacy.
Significance:
Selenium restriction augments ascorbate efficacy and extends lifespan in a mouse xenograft model of glioblastoma, suggesting that targeting selenium-mediated antioxidant defenses merits clinical evaluation in combination with ascorbate and other pro-oxidant therapies.
Data from Benign SNPs in the Coding Region of TP53: Finding the Needles in a Haystack of Pathogenic Variants
Authors: Soussi Thierry
Published: March 2023

Abstract
With the recent explosion in high-throughput genotyping technology, the amount and quality of SNP data have increased exponentially, facilitating the discovery of multiple uncommon SNPs in the human population. To provide unified and centralized resources for the scientific community, several repositories have been developed that aggregate numerous population studies and serve widely as references to filter natural variants in genetic analyses. However, they are largely biased toward European populations. TP53 gene is the most frequently mutated gene in human cancer, and pathogenic germline TP53 variants are associated with several cancer susceptibility disorders such as Li–Fraumeni syndrome. For these reasons, it is essential that TP53 SNPs are rigorously evaluated to avoid misclassifications that could impair patient management. The recent discovery of numerous benign SNPs within the coding region of TP53 can be attributed to surveillance of both global repositories and population-specific databases, with the latter enabling the recognition of additional TP53 SNPs in Japanese, African, and Indian populations. This review summarizes the body of evidence behind the identification of 21 TP53 variants and the information defining them as bona fide SNPs. This illustrates the need to include populations of different ethnic origins in genetic studies and the substantial benefits that can be derived from the information.
Data from Squalene Epoxidase Metabolic Dependency Is a Targetable Vulnerability in Castration-Resistant Prostate Cancer
Authors: Shangguan Xun , Ma Zehua , Yu Minghao , Ding Jie , Xue Wei , Qi Jun
Published: March 2023

Abstract
Considering the dismal prognosis of castration-resistant prostate cancer (CRPC), it is critical to identify novel therapeutic targets in this disease. Malignant cells have metabolic dependencies distinct from their healthy counterparts, resulting in therapeutic vulnerabilities. Although PTEN and TP53 are the most frequently comutated or codeleted driver genes in lethal CRPC, the metabolic dependencies underlying PTEN/p53 deficiency-driven CRPC for therapeutic intervention remain largely elusive. In this study, PTEN/p53 deficient tumors were determined to be reliant on cholesterol metabolism. Moreover, PTEN/p53 deficiency transcriptionally upregulated squalene epoxidase (SQLE) via activation of sterol regulatory element-binding protein 2 (SREBP2). In addition, PTEN deficiency enhanced the protein stability of SQLE by inhibiting the PI3K/Akt/GSK3β-mediated proteasomal pathway. Consequently, SQLE increased cholesterol biosynthesis to facilitate tumor cell growth and survival. Pharmacologic blockade of SQLE with FR194738 profoundly suppressed the invasive program of CRPC. Collectively, these results demonstrate a synergistic relationship between SQLE and PTEN/p53 deficiency in CRPC development and progression. Therefore, pharmacologic interventions targeting SQLE may hold promise for the treatment of patients with CRPC.
Significance:
This study reveals PTEN and p53 deficiency confers a dependence on SQLE-mediated cholesterol metabolism, providing insights for new therapeutic strategies for treating castration-resistant prostate cancer.
Data from Therapy-Induced Senescence Enhances the Efficacy of HER2-Targeted Antibody–Drug Conjugates in Breast Cancer
Authors: Duro-Sánchez Santiago , Nadal-Serrano Mercedes , Lalinde-Gutiérrez Marta , Arenas Enrique Javier , Bernadó Morales Cristina , Morancho Beatriz , Escorihuela Marta , Pérez-Ramos Sandra , Escrivá-de-Romaní Santiago , Gandullo-Sánchez Lucía , Pandiella Atanasio , Esteve-Codina Anna , Rodilla Verónica , Dijcks Fred A. , Dokter Wim H.A. , Cortés Javier , Saura Cristina , Arribas Joaquín
Published: March 2023

Abstract
Antibody–drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression.
Significance:
Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells.
Data from Pan-Cancer Analysis of Microbiome Quantitative Trait Loci
Authors: Chen Can , Cai Yimin , Liu Yizhuo , Chen Shuoni , Li Yanmin , Zhang Fuwei , Zhang Ming , Lu Zequn , Ying Pingting , Huang Jinyu , Fan Linyun , Cai Xiaomin , Ning Caibo , Wang Wenzhuo , Jiang Yuan , Zhang Heng , Yang Shuhui , Wang Zhihua , Wang Xiaoyang , Zhang Shaokai , Huang Chaoqun , Xu Bin , Fu Zhenming , Song Qibin , Jin Mingjuan , Chen Kun , Chen Hongda , Dai Min , Miao Xiaoping , Yang Xiaojun , Zhu Ying , Tian Jianbo
Published: March 2023

Abstract
Microorganisms are commonly detected in tumor tissues, and the species and abundance have been reported to affect cancer initiation, progression, and therapy. Host genetics have been associated with gut microbial abundances, while the relationships between genetic variants and the cancer microbiome still require systematic interrogation. Therefore, identification of cancer microbiome quantitative trait loci (mbQTL) across cancer types might elucidate the contributions of genetic variants to tumor development. Using genotype data from The Cancer Genome Atlas and microbial abundance levels from Kraken-derived data, we developed a computational pipeline to identify mbQTLs in 32 cancer types. This study systematically identified 38,660 mbQTLs across cancers, ranging 50 in endometrial carcinoma to 3,133 in thyroid carcinoma. Furthermore, a strong enrichment of mbQTLs was observed among transcription factor binding sites and chromatin regulatory elements, such as H3K27ac. Notably, mbQTLs were significantly enriched in cancer genome-wide association studies (GWAS) loci and explained an average of 2% for cancer heritability, indicating that mbQTLs could provide additional insights into cancer etiology. Correspondingly, 24,443 mbQTLs overlapping with GWAS linkage disequilibrium regions were identified. Survival analyses identified 318 mbQTLs associated with patient overall survival. Moreover, we uncovered 135,248 microbiome–immune infiltration associations and 166,603 microbiome–drug response associations that might provide clues for microbiome-based biomarkers. Finally, a user-friendly database, Cancer-mbQTL (http://canmbqtl.whu.edu.cn/#/), was constructed for users to browse, search, and download data of interest. This study provides a valuable resource for investigating the roles of genetics and microorganisms in human cancer.
Significance:
This study provides insights into the host–microbiome interactions for multiple cancer types, which could help the research community understand the effects of inherited variants in tumorigenesis and development.
Data from Loss of NF1 in Melanoma Confers Sensitivity to SYK Kinase Inhibition
Authors: Abecunas Cara , Whitehead Christopher E. , Ziemke Elizabeth K. , Baumann Douglas G. , Frankowski-McGregor Christy L. , Sebolt-Leopold Judith S. , Fallahi-Sichani Mohammad
Published: March 2023

Abstract
Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single-cell analysis indicated that drug-induced cytotoxicity was linked to effective cosuppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The antitumor efficacy of MTX-216 was dependent on its ability to inhibit not only PI3K, its nominal target, but also SYK. MTX-216 suppressed expression of a group of genes that regulate mitochondrial electron transport chain and are associated with poor survival in patients with NF1LoF melanoma. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1LoF melanoma cells.
Significance:
A kinase inhibitor screen identifies SYK as a targetable vulnerability in melanoma cells with NF1 loss of function.
Data from The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression
Authors: Hong Yun-Guang , Yang Zhigang , Chen Yan , Liu Tian , Zheng Yuyuan , Zhou Chun , Wu Guo-Cai , Chen Yinhui , Xia Juan , Wen Ruiting , Liu Wenxin , Zhao Yi , Chen Jin , Gao Xiangwei , Chen Zhanghui
Published: March 2023

Abstract
N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myelogenous leukemia (AML). Identification of the key regulators of m6A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for patients with AML. Here, we report overexpression of YTHDF1, an m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Whereas YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m6A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m6A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m6A-modified mRNAs, which might serve as a potential therapeutic target for AML.
Significance:
The m6A reader YTHDF1 is required for progression of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.
Data from JAK–STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States
Authors: Stevens Laura E. , Peluffo Guillermo , Qiu Xintao , Temko Daniel , Fassl Anne , Li Zheqi , Trinh Anne , Seehawer Marco , Jovanović Bojana , Alečković Maša , Wilde Callahan M. , Geck Renee C. , Shu Shaokun , Kingston Natalie L. , Harper Nicholas W. , Almendro Vanessa , Pyke Alanna L. , Egri Shawn B. , Papanastasiou Malvina , Clement Kendell , Zhou Ningxuan , Walker Sarah , Salas Jacqueline , Park So Yeon , Frank David A. , Meissner Alexander , Jaffe Jacob D. , Sicinski Piotr , Toker Alex , Michor Franziska , Long Henry W. , Overmoyer Beth A. , Polyak Kornelia
Published: March 2023

Abstract
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24− cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24−pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24− cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.
Significance:
Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.
Data from VRK1 Is a Synthetic–Lethal Target in VRK2-Deficient Glioblastoma
Authors: Shields Julie A. , Meier Samuel R. , Bandi Madhavi , Mulkearns-Hubert Erin E. , Hajdari Nicole , Ferdinez Maria Dam , Engel Justin L. , Silver Daniel J. , Shen Binzhang , Zhang Wenhai , Hubert Christopher G. , Mitchell Kelly , Shakya Sajina , Zhao Shan-Chuan , Bejnood Alborz , Zhang Minjie , Tjin Tham Sjin Robert , Wilker Erik , Lathia Justin D. , Andersen Jannik N. , Chen Yingnan , Li Fang , Weber Barbara , Huang Alan , Emmanuel Natasha
Published: March 2023

Abstract
Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic–lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2–M arrest and DNA damage. The VRK1–VRK2 synthetic–lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line–derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.
Significance:
A paralog synthetic–lethal interaction between VRK1 and VRK2 sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease.
Data from Postoperative Plasmacytoid Dendritic Cells Secrete IFNα to Promote Recruitment of Myeloid-Derived Suppressor Cells and Drive Hepatocellular Carcinoma Recurrence
Authors: Pang Li , Yeung Oscar W.H. , Ng Kevin T.P. , Liu Hui , Zhu Jiye , Liu Jiang , Yang Xinxiang , Ding Tao , Qiu Wenqi , Wang Yuewen , Chiu T.L. Shirley , Chen Zhiwei , Lo Chung-Mau , Man Kwan
Published: March 2023

Abstract
Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. Although it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFNα serve as an independent risk factor for tumor recurrence in 100 patients with HCC with curative hepatectomy. Plasmacytoid dendritic cells (pDC), the major source of IFNα, were activated after surgery and correlated with poor disease-free survival. Functionally, IFNα was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFNα-treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFNα upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1+ monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFNα, or CX3CR1 could restore the tumor-killing activity of CD8+ T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFNα-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFNα/CX3CL1/CX3CR1 axis could inhibit surgical stress–induced HCC recurrence by attenuating postoperative immunosuppression.
Significance:
IFNα secreted by plasmacytoid dendritic cells drives postoperative immunosuppression and early recurrence of hepatocellular carcinoma, providing new biomarkers and therapeutic targets to improve patient outcomes after surgical resection.