bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer
Authors: Paschalis Alec , Welti Jonathan , Neeb Antje J. , Yuan Wei , Figueiredo Ines , Pereira Rita , Ferreira Ana , Riisnaes Ruth , Rodrigues Daniel Nava , Jiménez-Vacas Juan M. , Kim Soojin , Uo Takuma , Micco Patrizio Di , Tumber Anthony , Islam Md. Saiful , Moesser Marc A. , Abboud Martine , Kawamura Akane , Gurel Bora , Christova Rossitza , Gil Veronica S. , Buroni Lorenzo , Crespo Mateus , Miranda Susana , Lambros Maryou B. , Carreira Suzanne , Tunariu Nina , Alimonti Andrea , Al-Lazikani Bissan , Schofield Christopher J. , Plymate Stephen R. , Sharp Adam , de Bono Johann S.
Published: March 2023

Abstract
Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease.
Significance:
This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.
Data from SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
Authors: Martinez Rafael S. , Salji Mark J. , Rushworth Linda , Ntala Chara , Rodriguez Blanco Giovanny , Hedley Ann , Clark William , Peixoto Paul , Hervouet Eric , Renaude Elodie , Kung Sonia H.Y. , Galbraith Laura C.A. , Nixon Colin , Lilla Sergio , MacKay Gillian M. , Fazli Ladan , Gaughan Luke , Sumpton David , Gleave Martin E. , Zanivan Sara , Blomme Arnaud , Leung Hing Y.
Published: March 2023

Abstract
Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC.
Significance:
This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.
Data from Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response
Authors: Choi Hyeongjwa , Kwon Juntae , Cho Min Soon , Sun Yifan , Zheng Xiaofeng , Wang Jing , Bouker Kerrie B. , Casey John L. , Atkins Michael B. , Toretsky Jeffrey , Han Cecil
Published: March 2023

Abstract
Induction of nucleic acid sensing–mediated type I interferon (IFN) has emerged as a novel approach to activate the immune system against cancer. Here we show that the depletion of DEAD-box RNA helicase 3X (DDX3X) triggers a tumor-intrinsic type I IFN response in breast cancer cells. Depletion or inhibition of DDX3X activity led to aberrant cytoplasmic accumulation of cellular endogenous double-stranded RNAs (dsRNA), which triggered type I IFN production through the melanoma differentiation-associated gene 5 (MDA5)-mediated dsRNA-sensing pathway. Furthermore, DDX3X interacted with dsRNA-editing ADAR1 and dual depletion of DDX3X and ADAR1 synergistically activated the cytosolic dsRNA pathway in breast cancer cells. Loss of DDX3X in mouse mammary tumors enhanced antitumor activity by increasing the tumor-intrinsic type I IFN response, antigen presentation, and tumor infiltration of cytotoxic T and dendritic cells. These findings may lead to the development of a novel therapeutic approach for breast cancer by targeting DDX3X in combination with immune-checkpoint blockade.
Significance:
This study elucidates the novel role of DDX3X in regulating endogenous cellular dsRNA homeostasis and type I IFN signaling in breast cancer.
Data from TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors
Authors: Maifrede Silvia , Le Bac Viet , Nieborowska-Skorska Margaret , Golovine Konstantin , Sullivan-Reed Katherine , Dunuwille Wangisa M.B. , Nacson Joseph , Hulse Michael , Keith Kelsey , Madzo Jozef , Caruso Lisa Beatrice , Gazze Zachary , Lian Zhaorui , Padella Antonella , Chitrala Kumaraswamy N. , Bartholdy Boris A. , Matlawska-Wasowska Ksenia , Di Marcantonio Daniela , Simonetti Giorgia , Greiner Georg , Sykes Stephen M. , Valent Peter , Paietta Elisabeth M. , Tallman Martin S. , Fernandez Hugo F. , Litzow Mark R. , Minden Mark D. , Huang Jian , Martinelli Giovanni , Vassiliou George S. , Tempera Italo , Piwocka Katarzyna , Johnson Neil , Challen Grant A. , Skorski Tomasz
Published: March 2023

Abstract
Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.
Significance:
TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors.
Data from Alteration of MDM2 by the Small Molecule YF438 Exerts Antitumor Effects in Triple-Negative Breast Cancer
Authors: Shan Peipei , Yang Feifei , Qi Hongzhao , Hu Yunjie , Zhu Sujie , Sun Zhenqing , Zhang Zhe , Wang Chuanxiao , Hou Caixia , Yu Jie , Wang Lirong , Zhou Zhixia , Li Peifeng , Zhang Hua , Wang Kun
Published: March 2023

Abstract
Triple-negative breast cancer (TNBC) exhibits a high mortality rate and is the most aggressive subtype of breast cancer. As previous studies have shown that histone deacetylases (HDAC) may represent molecular targets for TNBC treatment, we screened a small library of synthetic molecules and identified a potent HDAC inhibitor (HDACi), YF438, which exerts effective anti-TNBC activity both in vitro and in vivo. Proteomic and biochemical studies revealed that YF438 significantly downregulated mouse double minute 2 homolog (MDM2) expression. In parallel, loss of MDM2 expression or blocking MDM2 E3 ligase activity rendered TNBC cells less sensitive to YF438 treatment, revealing an essential role of MDM2 E3 ligase activity in YF438-induced inhibition of TNBC. Mechanistically, YF438 disturbed the interaction between HDAC1 and MDM2, induced the dissociation of MDM2-MDMX, and subsequently increased MDM2 self-ubiquitination to accelerate its degradation, which ultimately inhibited growth and metastasis of TNBC cells. In addition, analysis of clinical tissue samples demonstrated high expression levels of MDM2 in TNBC, and MDM2 protein levels closely correlated with TNBC progression and metastasis. Collectively, these findings show that MDM2 plays an essential role in TNBC progression and targeting the HDAC1–MDM2–MDMX signaling axis with YF438 may provide a promising therapeutic option for TNBC. Furthermore, this novel underlying mechanism of a hydroxamate-based HDACi in altering MDM2 highlights the need for further development of HDACi for TNBC treatment.
Significance:
This study uncovers the essential role of MDM2 in TNBC progression and suggests that targeting the HDAC1–MDM2–MDMX axis with a hydroxamate-based HDACi could be a promising therapeutic strategy for TNBC.
Data from ALKBH5 Facilitates Hypoxia-Induced Paraspeckle Assembly and IL8 Secretion to Generate an Immunosuppressive Tumor Microenvironment
Authors: Dong Feng , Qin Xiaoyang , Wang Baofeng , Li Qian , Hu Jinyang , Cheng Xuan , Guo Dongsheng , Cheng Fangling , Fang Chuan , Tan Yanli , Yan Han , He You , Sun Xiaoyu , Yuan Ye , Liu Hang , Li Ting , Zhao Yingying , Kang Chunsheng , Wu Xudong
Published: March 2023

Abstract
The dynamic changes of RNA N6-methyl-adenosine (m6A) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer cell m6A dynamics in the hypoxic tumor niche and its pathological consequences in glioblastoma multiforme (GBM). The m6A demethylase ALKBH5 was induced in GBM models under hypoxic conditions and was associated with a hypoxic gene signature in GBM patient samples. Depletion or inactivation of ALKBH5 in GBM cells significantly suppressed hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in allograft tumors. Expression and secretion of CXCL8/IL8 were significantly suppressed in ALKBH5-deficient tumors. However, ALKBH5 did not regulate CXCL8 m6A directly. Instead, hypoxia-induced ALKBH5 erased m6A deposition from the lncRNA NEAT1, stabilizing the transcript and facilitating NEAT1-mediated paraspeckle assembly, which led to relocation of the transcriptional repressor SFPQ from the CXCL8 promoter to paraspeckles and, ultimately, upregulation of CXCL8/IL8 expression. Accordingly, ectopic expression of CXCL8 in ALKBH5-deficient GBM cells partially restored TAM recruitment and tumor progression. Together, this study links hypoxia-induced epitranscriptomic changes to the emergence of an immunosuppressive microenvironment facilitating tumor evasion.
Significance:
Hypoxia induces tumor immune microenvironment remodeling through an ALKBH5-mediated epigenetic and epitranscriptomic mechanism, providing potential immunotherapeutic strategies for treating glioblastoma.
Data from BRAF Inhibitors Reprogram Cancer-Associated Fibroblasts to Drive Matrix Remodeling and Therapeutic Escape in Melanoma
Authors: Liu Tianyi , Zhou Linli , Xiao Yao , Andl Thomas , Zhang Yuhang
Published: March 2023

Abstract
The tumor stroma and its cellular components are known to play an important role in tumor response to treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitor (BRAFi)–induced noncanonical activation of nuclear β-catenin signaling in cancer-associated fibroblasts (CAF). Treatment with BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhanced biological properties. This CAF subpopulation is essential for melanoma cells to proliferate and acquire resistance to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF-CRAF heterodimerization and subsequent activation of ERK signaling in CAFs, leading to inactivation of the β-catenin destruction complex. RNA-seq identified periostin (POSTN) as a major downstream effector of β-catenin in CAFs. POSTN compensates for the loss of β-catenin in CAFs and mediates melanoma cell BRAFi/MEKi resistance. In melanoma cells, POSTN activates phosphoinositide 3-kinase (PI3K)/AKT signaling and subsequently reactivates the ERK pathway that was inhibited by BRAFi/MEKi. Collectively, these data underscore the role of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells.
Significance:
β-Catenin activation in cancer-associated fibroblasts in response to BRAF inhibitors stimulates POSTN secretion to promote resistance in cancer cells, revealing POSTN as a potential matrix target in cancer therapy.
Data from LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells
Authors: Han Shujun , Yan Yuwei , Ren Yibo , Hu Yiming , Wang Yan , Chen Lei , Zhi Zhe , Zheng Yan , Shao Yongping , Liu Jiankang
Published: March 2023

Abstract
The long noncoding RNA (lncRNA) SAMMSON is required for human melanoma cell growth and survival. However, whether SAMMSON regulates the response of mutant BRAF melanoma cells to RAF inhibitors remains unknown. In this work, we showed that SAMMSON is rapidly induced upon inhibition of ERK signaling, and SAMMSON overexpression conferred resistance to vemurafenib-induced cytotoxicity in melanoma cells. SOX10 mediated transcriptional induction of SAMMSON by vemurafenib, and SOX10 sumoylation at K55 was essential for this function. In addition, depletion of SAMMSON activated p53 signaling, which is dependent on the SAMMSON-interacting protein CARF. Depletion of SAMMSON sensitized mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo, while CARF knockdown reversed the enhanced sensitivity. In summary, these findings suggest that SAMMSON may function as a new mediator of adaptive resistance to RAF inhibitors in melanoma by modulating CARF-p53 signaling.
Significance:
This study highlights the role of a SAMMSON/CARF/p53 signaling axis in modulating the adaptive resistance of mutant BRAF melanoma to RAF inhibitors.
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 2023

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 CstF64-Induced Shortening of the BID 3′UTR Promotes Esophageal Squamous Cell Carcinoma Progression by Disrupting ceRNA Cross-talk with ZFP36L2
Authors: Lin Ai , Ji Ping , Niu Xiangjie , Zhao Xuan , Chen Yamei , Liu Weiling , Liu Yachen , Fan Wenyi , Sun Yanxia , Miao Chuanwang , Zhang Shaosen , Tan Wen , Lin Dongxin , Wagner Eric J. , Wu Chen
Published: March 2023

Abstract
The majority of human genes have multiple polyadenylation sites, which are differentially used through the process of alternative polyadenylation (APA). Dysregulation of APA contributes to numerous diseases, including cancer. However, specific genes subject to APA that impact oncogenesis have not been well characterized, and many cancer APA landscapes remain underexplored. Here, we used dynamic analyses of APA from RNA-seq (DaPars) to define both the 3′UTR APA profile in esophageal squamous cell carcinoma (ESCC) and to identify 3′UTR shortening events that may drive tumor progression. In four distinct squamous cell carcinoma datasets, BID 3′UTRs were recurrently shortened and BID mRNA levels were significantly upregulated. Moreover, system correlation analysis revealed that CstF64 is a candidate upstream regulator of BID 3′UTR length. Mechanistically, a shortened BID 3′UTR promoted proliferation of ESCC cells by disrupting competing endogenous RNA (ceRNA) cross-talk, resulting in downregulation of the tumor suppressor gene ZFP36L2. These in vitro and in vivo results were supported by human patient data whereby 3′UTR shortening of BID and low expression of ZFP36L2 are prognostic factors of survival in ESCC. Collectively, these findings demonstrate that a key ceRNA network is disrupted through APA and promotes ESCC tumor progression.

Significance: High-throughput analysis of alternative polyadenylation in esophageal squamous cell carcinoma identifies recurrent shortening of the BID 3′UTR as a driver of disease progression.
Data from PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer
Authors: Yu Tian-Jian , Liu Ying-Ying , Li Xiao-Guang , Lian Bi , Lu Xun-Xi , Jin Xi , Shao Zhi-Ming , Hu Xin , Di Gen-Hong , Jiang Yi-Zhou
Published: March 2023

Abstract
Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC.
Significance:
A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.
Data from A Dual PI3K/HDAC Inhibitor Induces Immunogenic Ferroptosis to Potentiate Cancer Immune Checkpoint Therapy
Authors: Fan Fushun , Liu Pei , Bao Rudi , Chen Jian , Zhou Minhua , Mo Zhenxian , Ma Yaru , Liu Haiqi , Zhou Yiping , Cai Xiong , Qian Changgeng , Liu Xinjian
Published: March 2023

Abstract
The capacity of targeted anticancer agents to exert immunomodulatory effects provides a strong rationale to develop novel agents suitable for combinatorial regimens with immunotherapy to improve clinical outcomes. In this study, we developed a dual-targeting PI3K and HDAC inhibitor BEBT-908 that potently inhibits tumor cell growth and potentiates anti-PD1 therapy in mice by inducing immunogenic ferroptosis in cancer cells. Treatment with BEBT-908 promoted ferroptotic cell death of cancer cells by hyperacetylating p53 and facilitating the expression of ferroptotic signaling. Furthermore, BEBT-908 promoted a proinflammatory tumor microenvironment that activated host antitumor immune responses and potentiated immune checkpoint blockade therapy. Mechanistically, BEBT-908–induced ferroptosis led to upregulation of MHC class I and activation of endogenous IFNγ signaling in cancer cells via the STAT1 signaling pathway. The dual PI3K/HDAC inhibitor BEBT-908 is a promising targeted therapeutic agent against multiple cancer types that promotes immunogenic ferroptosis and enhances the efficacy of immunotherapy.
Significance:
The dual PI3K/HDAC inhibitor BEBT-908 elicits potent antitumor responses, effectively inducing immunogenic ferroptosis of tumor cells and potentiating cancer immunotherapy.
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 2023

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 Epigenetic and Posttranscriptional Modulation of SOS1 Can Promote Breast Cancer Metastasis through Obesity-Activated c-Met Signaling in African-American Women
Authors: Xing Fei , Zhao Dan , Wu Shih-Ying , Tyagi Abhishek , Wu Kerui , Sharma Sambad , Liu Yin , Deshpande Ravindra , Wang Yuezhu , Cleary Jacob , Miller Lance D. , Chittiboyina Amar G. , Yalamanchili Chinni , Mo Yin-Yuan , Watabe Kounosuke
Published: March 2023

Abstract
Ethnicity is considered to be one of the major risk factors in certain subtypes of breast cancer. However, the mechanism of this racial disparity remains poorly understood. Here, we demonstrate that SOS1, a key regulator of Ras pathway, is highly expressed in African-American (AA) patients with breast cancer compared with Caucasian-American patients. Because of the higher obesity rate in AA women, increased levels of SOS1 facilitated signal transduction of the c-Met pathway, which was highly activated in AA patients with breast cancer via hepatocyte growth factor secreted from adipocytes. Elevated expression of SOS1 also enhanced cancer stemness through upregulation of PTTG1 and promoted M2 polarization of macrophages by CCL2 in metastatic sites. SOS1 was epigenetically regulated by a super-enhancer identified by H3K27ac in AA patients. Knockout of the super-enhancer by CRISPR in AA cell lines significantly reduced SOS1 expression. Furthermore, SOS1 was posttranscriptionally regulated by miR-483 whose expression is reduced in AA patients through histone trimethylation (H3K27me3) on its promoter. The natural compound, taxifolin, suppressed signaling transduction of SOS1 by blocking the interaction between SOS1 and Grb2, suggesting a potential utility of this compound as a therapeutic agent for AA patients with breast cancer.
Significance:
These findings elucidate the signaling network of SOS1-mediated metastasis in African-American patients, from the epigenetic upregulation of SOS1 to the identification of taxifolin as a potential therapeutic strategy against SOS1-driven tumor progression.
Data from Combined Inactivation of CTPS1 and ATR Is Synthetically Lethal to MYC-Overexpressing Cancer Cells
Authors: Sun Zhe , Zhang Ziheng , Wang Qiao-Qi , Liu Ji-Long
Published: March 2023

Abstract
The “undruggable” oncogene MYC supports cancer cell proliferation and survival through parallel induction of multiple anabolic processes. Here we find that inhibiting CTP synthase (CTPS) selectively decreases cell viability and induces DNA replication stress in MYC-overexpressing cells. MYC-driven rRNA synthesis caused the selective DNA replication stress upon CTPS inhibition. Combined inhibition of CTPS and ataxia telangiectasia and Rad3-related protein (ATR) is synthetically lethal in MYC-overexpressing cells, promoting cell death in vitro and decreasing tumor growth in vivo. Unexpectedly, interfering with CTPS1 but not CTPS2 is required to induce replication stress in MYC-deregulated cancer cells and consequent cell death in the presence of an ATR inhibitor. These results highlight a specific and key role of CTPS1 in MYC-driven cancer, suggesting that selectively inhibiting CTPS1 in combination with ATR could be a promising strategy to combat disease progression.
Significance:
Inhibition of CTPS in MYC-overexpressing cells blocks pyrimidine synthesis while maintaining ribosome synthesis activity to create an anabolic imbalance that induces replication stress, providing a new approach to selectively target MYC-driven cancer.

See related commentary by Chabanon and Postel-Vinay, p. 969
Data from Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer
Authors: Javellana Melissa , Eckert Mark A. , Heide Janna , Zawieracz Katarzyna , Weigert Melanie , Ashley Sarah , Stock Elizabeth , Chapel David , Huang Lei , Yamada S. Diane , Ahmed Ahmed Ashour , Lastra Ricardo R. , Chen Mengjie , Lengyel Ernst
Published: March 2023

Abstract
The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (FOS, FOSB, FRA-1) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses SIK2. In vitro, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and SIK2 copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance.
Significance:
Genomic and transcriptomic analyses identify increased AP-1 activity and SIK2 copy-number amplifications in resistant ovarian cancer following neoadjuvant chemotherapy, uncovering synergistic effects of AP-1 and SIK2 inhibitors with chemotherapy.
Data from Rab13 Sustains Breast Cancer Stem Cells by Supporting Tumor–Stroma Cross-talk
Authors: Wang Hui , Xu Haibo , Chen Wei , Cheng Mei , Zou Li , Yang Qin , Chan Chi Bun , Zhu Hao , Chen Ceshi , Nie Jianyun , Jiao Baowei
Published: March 2023

Abstract
Cancer stem cells (CSC) are supported by the tumor microenvironment, and non-CSCs can regain CSC phenotypes in certain niches, leading to limited clinical benefits of CSC-targeted therapy. A better understanding of the mechanisms governing the orchestration of the CSC niche could help improve the therapeutic targeting of CSCs. Here, we report that Rab13, a small GTPase, is highly expressed in breast CSCs (BCSC). Rab13 depletion suppressed breast cancer cell stemness, tumorigenesis, and chemoresistance by reducing tumor-stroma cross-talk. Accordingly, Rab13 controlled the membrane translocation of C-X-C chemokine receptor type 1/2 (CXCR1/2), allowing tumor cells to interact with tumor-associated macrophages and cancer-associated fibroblasts to establish a supportive BCSC niche. Targeting the Rab13-mediated BCSC niche with bardoxolone-methyl (C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid; CDDO-Me) prevented BCSC stemness in vitro and in vivo. These findings highlight the novel regulatory mechanism of Rab13 in BCSC, with important implications for the development of therapeutic strategies for disrupting the BCSC niche.
Significance:
Targeting Rab13 perturbs formation of the breast cancer stem cell niche by inhibiting cross-talk between cancer cells and the tumor microenvironment, providing a therapeutic opportunity for niche-targeted breast cancer treatment.
Data from Cardiac Dysfunction Promotes Cancer Progression via Multiple Secreted Factors
Authors: Awwad Lama , Aronheim Ami
Published: March 2023

Abstract
Heart failure and cancer are the leading cause of deaths worldwide. While heart failure and cancer have been considered separate diseases, it is becoming evident that they are highly connected and affect each other's outcomes. Recent studies using experimental mouse models have suggested that heart failure promotes tumor progression. The mouse models used involve major irreversible surgery. Here, we induced heart hypertrophy via expression of activating transcription factor 3 (ATF3) in cardiomyocytes, followed by cancer cells’ implantation. Tumors developing in ATF3-transgenic mice grew larger and displayed a more highly metastatic phenotype compared with tumors in wild-type mice. To address whether ATF3 expression or the cardiac outcome are necessary for tumor progression, ATF3 expression was turned off after cardiac hypertrophy development followed by cancer cell implantation. The tumor promotion phenotype and the enhancement of metastatic properties were preserved, suggesting that the failing heart per se is sufficient to promote tumor progression. Serum derived from ATF3-transgenic mice enhanced cancer cell proliferation and increased cancer cell metastatic properties in vitro. Using a cytokine array panel, multiple factors responsible for promoting tumor cell proliferation and the metastatic phenotype were identified. Interestingly, the failing heart and the tumor separately and simultaneously contributed to higher levels of these factors in the serum as well as other tissues and organs. These data suggest the existence of intimate cross-talk between the hypertrophied heart and the tumor that is mediated by secreted factors, leading to cancer promotion and disease deterioration.
Significance:
This work highlights the importance of early diagnosis and treatment of heart failure prior to reaching the irreversible stage that can exacerbate cancer progression.
Data from ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib
Authors: Wilson Zena , Odedra Rajesh , Wallez Yann , Wijnhoven Paul W.G. , Hughes Adina M. , Gerrard Joe , Jones Gemma N. , Bargh-Dawson Hannah , Brown Elaine , Young Lucy A. , O'Connor Mark J. , Lau Alan
Published: March 2023

Abstract
AZD6738 (ceralasertib) is a potent and selective orally bioavailable inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. ATR is activated in response to stalled DNA replication forks to promote G2–M cell-cycle checkpoints and fork restart. Here, we found AZD6738 modulated CHK1 phosphorylation and induced ATM-dependent signaling (pRAD50) and the DNA damage marker γH2AX. AZD6738 inhibited break-induced replication and homologous recombination repair. In vitro sensitivity to AZD6738 was elevated in, but not exclusive to, cells with defects in the ATM pathway or that harbor putative drivers of replication stress such as CCNE1 amplification. This translated to in vivo antitumor activity, with tumor control requiring continuous dosing and free plasma exposures, which correlated with induction of pCHK1, pRAD50, and γH2AX. AZD6738 showed combinatorial efficacy with agents associated with replication fork stalling and collapse such as carboplatin and irinotecan and the PARP inhibitor olaparib. These combinations required optimization of dose and schedules in vivo and showed superior antitumor activity at lower doses compared with that required for monotherapy. Tumor regressions required at least 2 days of daily dosing of AZD6738 concurrent with carboplatin, while twice daily dosing was required following irinotecan. In a BRCA2-mutant patient-derived triple-negative breast cancer (TNBC) xenograft model, complete tumor regression was achieved with 3 to5 days of daily AZD6738 per week concurrent with olaparib. Increasing olaparib dosage or AZD6738 dosing to twice daily allowed complete tumor regression even in a BRCA wild-type TNBC xenograft model. These preclinical data provide rationale for clinical evaluation of AZD6738 as a monotherapy or combinatorial agent.
Significance:
This detailed preclinical investigation, including pharmacokinetics/pharmacodynamics and dose–schedule optimizations, of AZD6738/ceralasertib alone and in combination with chemotherapy or PARP inhibitors can inform ongoing clinical efforts to treat cancer with ATR inhibitors.
Data from Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy
Authors: Fernandez Mario R. , Schaub Franz X. , Yang Chunying , Li Weimin , Yun Seongseok , Schaub Stephanie K. , Dorsey Frank C. , Liu Min , Steeves Meredith A. , Ballabio Andrea , Tzankov Alexandar , Chen Zhihua , Koomen John M. , Berglund Anders E. , Cleveland John L.
Published: March 2023

Abstract
MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, AA transport, and AA and nucleotide metabolism, leading to metabolic anergy, growth arrest, and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors.
Significance:
MYC suppresses TFEB and autophagy and controls amino acid homeostasis by upregulating amino acid transport and the proteasome, and reactivation of TFEB disables the metabolism of MYC-driven tumors.
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 2023

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 Caspase-3–Induced Activation of SREBP2 Drives Drug Resistance via Promotion of Cholesterol Biosynthesis in Hepatocellular Carcinoma
Authors: Mok Etienne Ho Kit , Leung Carmen Oi Ning , Zhou Lei , Lei Martina Mang Leng , Leung Hoi Wing , Tong Man , Wong Tin Lok , Lau Eunice Yuen Ting , Ng Irene Oi Lin , Ding Jin , Yun Jing Ping , Yu Jun , Zhu Hui Lian , Lin Chi Ho , Lindholm Dan , Leung Kit Sum , Cybulski Jonathan D. , Baker David M. , Ma Stephanie , Lee Terence Kin Wah
Published: March 2023

Abstract
Accumulating evidence has demonstrated that drug resistance can be acquired in cancer through the repopulation of tumors by cancer stem cell (CSC) expansion. Here, we investigated mechanisms driving resistance and CSC repopulation in hepatocellular carcinoma (HCC) as a cancer model using two drug-resistant, patient-derived tumor xenografts that mimicked the development of acquired resistance to sorafenib or lenvatinib treatment observed in patients with HCC. RNA sequencing analysis revealed that cholesterol biosynthesis was most commonly enriched in the drug-resistant xenografts. Comparison of the genetic profiles of CD133+ stem cells and CD133− bulk cells from liver regeneration and HCC mouse models showed that the cholesterol pathway was preferentially upregulated in liver CSCs compared with normal liver stem cells. Consistently, SREBP2-mediated cholesterol biosynthesis was crucial for the augmentation of liver CSCs, and loss of SREBP2 conferred sensitivity to tyrosine kinase inhibitors, suggesting a role in regulation of acquired drug resistance in HCC. Similarly, exogenous cholesterol-treated HCC cells showed enhanced cancer stemness abilities and drug resistance. Mechanistically, caspase-3 (CASP3) mediated cleavage of SREBP2 from the endoplasmic reticulum to promote cholesterol biosynthesis, which consequently caused resistance to sorafenib/lenvatinib treatment by driving activation of the sonic hedgehog signaling pathway. Simvastatin, an FDA-approved cholesterol-lowering drug, not only suppressed HCC tumor growth but also sensitized HCC cells to sorafenib. These findings demonstrate that CSC populations in HCC expand via CASP3-dependent, SREBP2-mediated cholesterol biosynthesis in response to tyrosine kinase inhibitor therapy and that targeting cholesterol biosynthesis can overcome acquired drug resistance.
Significance:
This study finds that cholesterol biosynthesis supports the expansion of cancer stem cell populations to drive resistance to tyrosine kinase inhibitor therapy in hepatocellular carcinoma, identifying potential therapeutic approaches for improving cancer treatment.
Data from Anti-HIV Drug Elvitegravir Suppresses Cancer Metastasis via Increased Proteasomal Degradation of m6A Methyltransferase METTL3
Authors: Liao Long , He Yan , Li Shu-Jun , Zhang Guo-Geng , Yu Wei , Yang Jing , Huang Zi-Jia , Zheng Can-Can , He Qing-Yu , Li Yan , Li Bin
Published: March 2023

Abstract
N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into the regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3, whereas SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration–approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC.
Significance:
This study finds that METTL3 promotes cancer metastasis by activating EGR1/Snail signaling in an m6A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.
Data from CDK4/6 Inhibition Enhances Oncolytic Virus Efficacy by Potentiating Tumor-Selective Cell Killing and T-cell Activation in Refractory Glioblastoma
Authors: Xiao Jingshu , Liang Jiaming , Fan Junjie , Hou Panpan , Li Xiaodong , Zhang Haipeng , Li Kai , Bu Lang , Li Ping , He Miao , Zhong Yongheng , Guo Liping , Jia Penghui , Xiao Qiaoqiao , Wu Junyu , Peng Hong , Li Chunmei , Xing Fan , Guo Deyin
Published: March 2023

Abstract
Glioblastoma (GBM) is among the most aggressive human cancers. Although oncolytic virus (OV) therapy has been proposed as a potential approach to treat GBM, it frequently fails because GBM cells are usually nonpermissive to OV. Here, we describe a dual-step drug screen for identifying chemical enhancers of OV in GBM. From a high-throughput screen of 1416 FDA-approved drugs, an inhibitor of CDK4/6 was identified as the top enhancer, selectively increasing potency of two OV strains, VSVΔ51 and Zika virus. Mechanistically, CDK4/6 inhibition promoted autophagic degradation of MAVS, resulting in impaired antiviral responses and enhanced tumor-selective replication of VSVΔ51 in vitro and in vivo. CDK4/6 inhibition cooperated with VSVΔ51 to induce severe DNA damage stress and amplify oncolysis. In GBM xenograft models, combined treatment with CDK4/6 inhibitor and VSVΔ51 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice. Further investigation revealed that CDK4/6 inhibitor and VSVΔ51 synergistically induced immunogenic cell death and boosted antitumor immunity. Together, this study features a promising approach of treating aggressive GBM through the combination of CDK4/6 inhibitor with OV.
Significance:
This study proposes inhibition of cyclin-dependent kinases as a clinically translatable combinatorial strategy to enhance the efficacy of oncolytic virotherapy in GBM.