bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Transcriptional Activation of MYC-Induced Genes by GCN5 Promotes B-cell Lymphomagenesis
Authors: Farria Aimee T. , Plummer Joshua B. , Salinger Andrew P. , Shen Jianjun , Lin Kevin , Lu Yue , McBride Kevin M. , Koutelou Evangelia , Dent Sharon Y.R.
Published: March 2024

Abstract
Overexpression of the MYC oncoprotein is an initiating step in the formation of several cancers. MYC frequently recruits chromatin-modifying complexes to DNA to amplify the expression of cancer-promoting genes, including those regulating cell cycle, proliferation, and metabolism, yet the roles of specific modifiers in different cancer types are not well defined. Here, we show that GCN5 is an essential coactivator of cell-cycle gene expression driven by MYC overexpression and that deletion of Gcn5 delays or abrogates tumorigenesis in the Eμ-Myc mouse model of B-cell lymphoma. Our results demonstrate that Gcn5 loss impacts both expression and downstream functions of Myc.
Significance:
Our results provide important proof of principle for Gcn5 functions in formation and progression of Myc-driven cancers, suggesting that GCN5 may be a viable target for development of new cancer therapies.
Data from Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer
Authors: Wan Changxin , Keany Matthew P. , Dong Han , Al-Alem Linah F. , Pandya Unnati M. , Lazo Suzan , Boehnke Karsten , Lynch Katherine N. , Xu Rui , Zarrella Dominique T. , Gu Shengqing , Cejas Paloma , Lim Klothilda , Long Henry W. , Elias Kevin M. , Horowitz Neil S. , Feltmate Colleen M. , Muto Michael G. , Worley Michael J. , Berkowitz Ross S. , Matulonis Ursula A. , Nucci Marisa R. , Crum Christopher P. , Rueda Bo R. , Brown Myles , Liu Xiaole Shirley , Hill Sarah J.
Published: March 2024

Abstract
Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC.
Significance:
This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.
Data from The Cancer-Associated ATM R3008H Mutation Reveals the Link between ATM Activation and Its Exchange
Authors: Milanovic Maja , Sprinzen Lisa , Menolfi Demis , Lee Ji-Hoon , Yamamoto Kenta , Li Yang , Lee Brian J. , Xu Jun , Estes Verna M. , Wang Dong , Mckinnon Peter J. , Paull Tanya T. , Zha Shan
Published: March 2024

Abstract
ATM kinase is a tumor suppressor and a master regulator of the DNA damage response. Most cancer-associated alterations to ATM are missense mutations at the PI3-kinase regulatory domain (PRD) or the kinase domain. Expression of kinase-dead (KD) ATM protein solely accelerates lymphomagenesis beyond ATM loss. To understand how PRD suppresses lymphomagenesis, we introduced the cancer-associated PRD mutation R3008H (R3016 in mouse) into mice. R3008H abrogated DNA damage- and oxidative stress-induced activation of ATM without consistently affecting ATM protein stability and recruitment. In contrast to the early embryonic lethality of AtmKD/KD mice, AtmR3016H (AtmR/R) mice were viable, immunodeficient, and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared with Atm−/− controls. Mechanistically, R3008H rescued the tardy exchange of ATM-KD at DNA damage foci, indicating that PRD coordinates ATM activation with its exchange at DNA-breaks. Taken together, our results reveal a unique tumorigenesis profile for PRD mutations that is distinct from null or KD mutations.
Significant:
This study functionally characterizes the most common ATM missense mutation R3008H in cancer and identifies a unique role of PI3-kinase regulatory domain in ATM activation.
Data from Frizzled-7 Identifies Platinum-Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis
Authors: Wang Yinu , Zhao Guangyuan , Condello Salvatore , Huang Hao , Cardenas Horacio , Tanner Edward J. , Wei JianJun , Ji Yanrong , Li Junjie , Tan Yuying , Davuluri Ramana V. , Peter Marcus E. , Cheng Ji-Xin , Matei Daniela
Published: March 2024

Abstract
Defining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using in vitro and in vivo ovarian cancer models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH+ cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared with parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor Frizzled-7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7+ from FZD7− cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation-enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7+ platinum-tolerant ovarian cancer cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, and glutathione metabolism gene sets were strongly correlated in the ovarian cancer Tumor Cancer Genome Atlas (TCGA) database and in residual human ovarian cancer specimens after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial cancer stem cell features, characterized by FZD7 expression and dependent on the FZD7–β-catenin–Tp63–GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum-tolerant cancer cells and provide new insight into a potential “persister cancer cell” phenotype.
Significance:
Frizzled-7 marks platinum-tolerant cancer cells harboring stemness features and altered glutathione metabolism that depend on GPX4 for survival and are highly susceptible to ferroptosis.
Data from A Notch-Dependent Inflammatory Feedback Circuit between Macrophages and Cancer Cells Regulates Pancreatic Cancer Metastasis
Authors: Geng Yawen , Fan Jie , Chen Lianyu , Zhang Chenyue , Qu Chao , Qian Ling , Chen Kun , Meng Zhiqiang , Chen Zhen , Wang Peng
Published: March 2024

Abstract
Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages, which contributes to PDAC metastasis. In this circuit, miR-124 regulated Notch signaling in cancer cells by directly targeting the Notch ligand Jagged 1. Autoamplified Notch signaling promoted the recruitment and activation of macrophages to a tumor-supporting M2-like phenotype via downstream IL8, CCL2, IL1α, and uPA paracrine signaling. In turn, activated macrophage-derived IL6 activated the oncogenic transcription factor STAT3 that directly repressed miR-124 genes via a conserved STAT3-binding site in their promoters, thereby promoting cancer cell epithelial–mesenchymal transition and invasion. Disrupting this circuit suppressed liver metastasis in mouse models. Thus, our study suggests that manipulation of this Notch-dependent circuit has a therapeutic potential for the treatment of PDAC metastasis.
Significance:
This study provided potential therapeutic targets and robust preclinical evidence for PDAC treatment by interrupting feedback signaling between cancer cells and macrophages with targeted inhibitors.
Data from Transcriptional Repression of SIRT3 Potentiates Mitochondrial Aconitase Activation to Drive Aggressive Prostate Cancer to the Bone
Authors: Sawant Dessai Abhisha , Dominguez Mayrel Palestino , Chen Uan-I , Hasper John , Prechtl Christian , Yu Cuijuan , Katsuta Eriko , Dai Tao , Zhu Bokai , Jung Sung Yun , Putluri Nagireddy , Takabe Kazuaki , Zhang Xiang H.-F. , O'Malley Bert W. , Dasgupta Subhamoy
Published: March 2024

Abstract
Metabolic dysregulation is a known hallmark of cancer progression, yet the oncogenic signals that promote metabolic adaptations to drive metastatic cancer remain unclear. Here, we show that transcriptional repression of mitochondrial deacetylase sirtuin 3 (SIRT3) by androgen receptor (AR) and its coregulator steroid receptor coactivator-2 (SRC-2) enhances mitochondrial aconitase (ACO2) activity to favor aggressive prostate cancer. ACO2 promoted mitochondrial citrate synthesis to facilitate de novo lipogenesis, and genetic ablation of ACO2 reduced total lipid content and severely repressed in vivo prostate cancer progression. A single acetylation mark lysine258 on ACO2 functioned as a regulatory motif, and the acetylation-deficient Lys258Arg mutant was enzymatically inactive and failed to rescue growth of ACO2-deficient cells. Acetylation of ACO2 was reversibly regulated by SIRT3, which was predominantly repressed in many tumors including prostate cancer. Mechanistically, SRC-2–bound AR formed a repressive complex by recruiting histone deacetylase 2 to the SIRT3 promoter, and depletion of SRC-2 enhanced SIRT3 expression and simultaneously reduced acetylated ACO2. In human prostate tumors, ACO2 activity was significantly elevated, and increased expression of SRC-2 with concomitant reduction of SIRT3 was found to be a genetic hallmark enriched in prostate cancer metastatic lesions. In a mouse model of spontaneous bone metastasis, suppression of SRC-2 reactivated SIRT3 expression and was sufficient to abolish prostate cancer colonization in the bone microenvironment, implying this nuclear-mitochondrial regulatory axis is a determining factor for metastatic competence.
Significance:
This study highlights the importance of mitochondrial aconitase activity in the development of advanced metastatic prostate cancer and suggests that blocking SRC-2 to enhance SIRT3 expression may be therapeutically valuable.
Data from MYC-Activated LncRNA MNX1-AS1 Promotes the Progression of Colorectal Cancer by Stabilizing YB1
Authors: Wu Qi-Nian , Luo Xiao-Jing , Liu Jia , Lu Yun-Xin , Wang Yun , Qi Jingjing , Liu Ze-Xian , Huang Qi-Tao , Liu Ze-Kun , Lu Jia-Bin , Jin Ying , Pu Heng-Ying , Hu Pei-Shan , Zheng Jia-Bo , Zeng Zhao-Lei , Ju Huai-Qiang , Xie Dan , Zhao Qi , Xu Ruihua
Published: March 2024

Abstract
Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer–related lncRNA, MNX1-AS1. MNX1-AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1-AS1 promotes the proliferation of colorectal cancer cells. MNX1-AS1 bound to and activated Y-box-binding protein 1 (YB1), a multifunctional RNA/DNA-binding protein, and prevented its ubiquitination and degradation. A marked overlap between genes that are differentially expressed in MNX1-AS1 knockdown cells and transcriptional targets of YB1 was observed. YB1 knockdown mimicked the loss of viability phenotype observed upon depletion of MNX1-AS1. In addition, MYC bound the promoter of the MNX1-AS1 locus and activated its transcription. In vivo experiments showed that ASO inhibited MNX1-AS1, which suppressed the proliferation of colorectal cancer cells in both cell-based and patient-derived xenograft models. Collectively, these findings suggest that the MYC–MNX1-AS1–YB1 axis might serve as a potential biomarker and therapeutic target in colorectal cancer.
Significance:
This study highlights the discovery of a novel colorectal cancer biomarker and therapeutic target, MNX1-AS1, a long noncoding RNA that drives proliferation via a MYC/MNX1-AS1/YB1 signaling pathway.
Data from HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness
Authors: Bi Lei , Ren Yidan , Feng Maoxiao , Meng Peng , Wang Qin , Chen Weiping , Jiao Qinlian , Wang Yuli , Du Lutao , Zhou Fuqiong , Jiang Yucui , Chen Feiyan , Wang Chuanxin , Tang Bo , Wang Yunshan
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC.
Significance:
This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.
Data from NPM–ALK-Induced Reprogramming of Mature TCR-Stimulated T Cells Results in Dedifferentiation and Malignant Transformation
Authors: Pawlicki Jan M. , Cookmeyer David L. , Maseda Damian , Everett John K. , Wei Fang , Kong Hong , Zhang Qian , Wang Hong Y. , Tobias John W. , Walter David M. , Zullo Kelly M. , Javaid Sarah , Watkins Amanda , Wasik Mariusz A. , Bushman Frederic D. , Riley James L.
Published: March 2024

Abstract
Fusion genes including NPM–ALK can promote T-cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM–ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T-cell effector programs, reemergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM–ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Finally, T-cell receptor (TCR)–generated signals were required to achieve T-cell transformation, explaining how healthy individuals can harbor T cells with NPM–ALK translocations. These findings describe the fundamental mechanisms of NPM–ALK-mediated oncogenesis and may serve as a model to better understand factors that regulate tumor formation.
Significance:
This investigation into malignant transformation of T cells uncovers a requirement for TCR triggering, elucidates integral signaling complexes nucleated by NPM–ALK, and delineates dynamic transcriptional changes as a T cell transforms.

See related commentary by Spasevska and Myklebust, p. 3160
Data from EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma
Authors: Gao Minling , Fu Yi , Zhou Weiqiang , Gui Gege , Lal Bachuchu , Li Yunqing , Xia Shuli , Ji Hongkai , Eberhart Charles G. , Laterra John , Ying Mingyao
Published: March 2024

Abstract
Hyperactivated EGFR signaling is a driver of various human cancers, including glioblastoma (GBM). Effective EGFR-targeted therapies rely on knowledge of key signaling hubs that transfer and amplify EGFR signaling. Here we focus on the transcription factor TAZ, a potential signaling hub in the EGFR signaling network. TAZ expression was positively associated with EGFR expression in clinical GBM specimens. In patient-derived GBM neurospheres, EGF induced TAZ through EGFR–ERK and EGFR–STAT3 signaling, and the constitutively active EGFRvIII mutation caused EGF-independent hyperactivation of TAZ. Genome-wide analysis showed that the EGFR–TAZ axis activates multiple oncogenic signaling mechanisms, including an EGFR–TAZ–RTK positive feedback loop, as well as upregulating HIF1α and other oncogenic genes. TAZ hyperactivation in GBM stem-like cells induced exogenous mitogen-independent growth and promoted GBM invasion, radioresistance, and tumorigenicity. Screening a panel of brain-penetrating EGFR inhibitors identified osimertinib as the most potent inhibitor of the EGFR–TAZ signaling axis. Systemic osimertinib treatment inhibited the EGFR–TAZ axis and in vivo growth of GBM stem-like cell xenografts. Overall these results show that the therapeutic efficacy of osimertinib relies on effective TAZ inhibition, thus identifying TAZ as a potential biomarker of osimertinib sensitivity.
Significance:
This study establishes a genome-wide map of EGFR–TAZ signaling in glioblastoma and finds osimertinib effectively inhibits this signaling, justifying its future clinical evaluation to treat glioblastoma and other cancers with EGFR/TAZ hyperactivation.
Data from MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis
Authors: Floros Konstantinos V. , Cai JinYang , Jacob Sheeba , Kurupi Richard , Fairchild Carter K. , Shende Mayuri , Coon Colin M. , Powell Krista M. , Belvin Benjamin R. , Hu Bin , Puchalapalli Madhavi , Ramamoorthy Sivapriya , Swift Kimberly , Lewis Janina P. , Dozmorov Mikhail G. , Glod John , Koblinski Jennifer E. , Boikos Sosipatros A. , Faber Anthony C.
Published: March 2024

Abstract
MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer–related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway.
Significance:
This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.
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 2024

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 Multilevel Regulation of β-Catenin Activity by SETD2 Suppresses the Transition from Polycystic Kidney Disease to Clear Cell Renal Cell Carcinoma
Authors: Rao Hanyu , Li Xiaoxue , Liu Min , Liu Jing , Feng Wenxin , Tang Huayuan , Xu Jin , Gao Wei-Qiang , Li Li
Published: March 2024

Abstract
Patients with polycystic kidney disease (PKD) are at a high risk of developing renal cell carcinoma (RCC). However, little is known about genetic alterations or changes in signaling pathways during the transition from PKD to RCC. SET domain–containing 2 (SETD2) is a histone methyltransferase, which catalyzes tri-methylation of H3K36 (H3K36me3) and has been identified as a tumor suppressor in clear cell renal cell carcinoma (ccRCC), but the underlying mechanism remains largely unexplored. Here we report that knockout of SETD2 in a c-MYC–driven PKD mouse model drove the transition to ccRCC. SETD2 inhibited β-catenin activity at transcriptional and posttranscriptional levels by competing with β-catenin for binding promoters of target genes and maintaining transcript levels of members of the β-catenin destruction complex. Thus, SETD2 deficiency enhanced the epithelial-to-mesenchymal transition and tumorigenesis through the hyperactivation of Wnt/β-catenin signaling. Our findings reveal previously unrecognized roles of SETD2-mediated competitive DNA binding and H3K36me3 modification in regulating Wnt/β-catenin signaling during the transition from PKD to ccRCC. The novel autochthonous mouse models of PKD and ccRCC will be useful for preclinical research into disease progression.
Significance:
These findings characterize multiple mechanisms by which SETD2 inhibits β-catenin activity during the transition of polycystic kidney disease to renal cell carcinoma, providing a potential therapeutic strategy for high-risk patients.
Data from Susceptibility-Associated Genetic Variation in NEDD9 Contributes to Prostate Cancer Initiation and Progression
Authors: Han Dong , Owiredu Jude N. , Healy Bridget M. , Li Muqing , Labaf Maryam , Steinfeld Jocelyn S. , Patalano Susan , Gao Shuai , Liu Mingyu , Macoska Jill A. , Zarringhalam Kourosh , Siegfried Kellee R. , Yuan Xin , Rebbeck Timothy R. , Cai Changmeng
Published: March 2024

Abstract
Although American men of European ancestry represent the largest population of patients with prostate cancer, men of African ancestry are disproportionately affected by prostate cancer, with higher prevalence and worse outcomes. These racial disparities in prostate cancer are due to multiple factors, but variations in genomic susceptibility such as SNP may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, we have identified a prostate cancer susceptibility SNP at an intronic enhancer of the neural precursor expressed, developmentally downregulated 9 (NEDD9) gene, which is strongly associated with increased risk of patients with African ancestry. This genetic variation increased expression of NEDD9 by modulating the chromatin binding of certain transcription factors, including ERG and NANOG. Moreover, NEDD9 displayed oncogenic activity in prostate cancer cells, promoting prostate cancer tumor growth and metastasis in vitro and in vivo. Together, our study provides novel insights into the genetic mechanisms driving prostate cancer racial disparities.
Significance:
A prostate cancer susceptibility genetic variation in NEDD9, which is strongly associated with the increased risk of patients with African ancestry, increases NEDD9 expression and promotes initiation and progression of prostate cancer.

See related commentary by Mavura and Huang, p. 3764
Data from CDK6 Is a Therapeutic Target in Myelofibrosis
Authors: Dutta Avik , Nath Dipmoy , Yang Yue , Le Bao T. , Mohi Golam
Published: March 2024

Abstract
Myelofibrosis (myelofibrosis) is a deadly blood neoplasia with the worst prognosis among myeloproliferative neoplasms (MPN). The JAK2 inhibitors ruxolitinib and fedratinib have been approved for treatment of myelofibrosis, but they do not offer significant improvement of bone marrow fibrosis. CDK6 expression is significantly elevated in MPN/myelofibrosis hematopoietic progenitor cells. In this study, we investigated the efficacy of CDK4/6 inhibitor palbociclib alone or in combination with ruxolitinib in Jak2V617F and MPLW515L murine models of myelofibrosis. Treatment with palbociclib alone significantly reduced leukocytosis and splenomegaly and inhibited bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of myelofibrosis. Combined treatment of palbociclib and ruxolitinib resulted in normalization of peripheral blood leukocyte counts, marked reduction of spleen size, and abrogation of bone marrow fibrosis in murine models of myelofibrosis. Palbociclib treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, treatment with palbociclib or depletion of CDK6 inhibited Aurora kinase, NF-κB, and TGFβ signaling pathways in Jak2V617F mutant hematopoietic cells and attenuated expression of fibrotic markers in the bone marrow. Overall, these data suggest that palbociclib in combination with ruxolitinib may have therapeutic potential for treatment of myelofibrosis and support the clinical investigation of this drug combination in patients with myelofibrosis.
Significance:
These findings demonstrate that CDK6 inhibitor palbociclib in combination with ruxolitinib ameliorates myelofibrosis, suggesting this drug combination could be an effective therapeutic strategy against this devastating blood disorder.
Data from GAS7 Deficiency Promotes Metastasis in MYCN-Driven Neuroblastoma
Authors: Dong Zhiwei , Yeo Kok Siong , Lopez Gonzalo , Zhang Cheng , Dankert Eggum Erin N. , Rokita Jo Lynne , Ung Choong Yong , Levee Taylor M. , Her Zuag Paj , Howe Cassie J. , Hou Xiaonan , van Ree Janine H. , Li Shuai , He Shuning , Tao Ting , Fritchie Karen , Torres-Mora Jorge , Lehman Julia S. , Meves Alexander , Razidlo Gina L. , Rathi Komal S. , Weroha S. John , Look A. Thomas , van Deursen Jan M. , Li Hu , Westendorf Jennifer J. , Maris John M. , Zhu Shizhen
Published: March 2024

Abstract
One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell–cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression.
Significance:
Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma.

See related commentary by Menard, p. 2815
Data from Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner
Authors: McDonald James I. , Diab Noor , Arthofer Elisa , Hadley Melissa , Kanholm Tomas , Rentia Uzma , Gomez Stephanie , Yu Angela , Grundy Erin E. , Cox Olivia , Topper Michael J. , Xing Xiaoyun , Strissel Pamela L. , Strick Reiner , Wang Ting , Baylin Stephen B. , Chiappinelli Katherine B.
Published: March 2024

Abstract
Epithelial ovarian carcinomas are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the ovarian carcinoma epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8+ T cells and natural killer cells to fight ovarian carcinoma in murine models. This increased immune activity is caused by increased transcription of repetitive elements (RE) that form double-stranded RNA (dsRNA) and trigger an IFN response. To understand which REs are affected by epigenetic therapies in ovarian carcinoma, we assessed the effect of DNMTi and HDACi on ovarian carcinoma cell lines and patient samples. Subfamily-level (TEtranscripts) and individual locus-level (Telescope) analysis of REs showed that DNMTi treatment upregulated more REs than HDACi treatment. Upregulated REs were predominantly LTR and SINE subfamilies, and SINEs exhibited the greatest loss of DNA methylation upon DNMTi treatment. Cell lines with TP53 mutations exhibited significantly fewer upregulated REs with epigenetic therapy than wild-type TP53 cell lines. This observation was validated using isogenic cell lines; the TP53-mutant cell line had significantly higher baseline expression of REs but upregulated fewer upon epigenetic treatment. In addition, p53 activation increased expression of REs in wild-type but not mutant cell lines. These data give a comprehensive, genome-wide picture of RE chromatin and transcription-related changes in ovarian carcinoma after epigenetic treatment and implicate p53 in RE transcriptional regulation.
Significance:
This study identifies the repetitive element targets of epigenetic therapies in ovarian carcinoma and indicates a role for p53 in this process.

See interview with Katherine B. Chiappinelli, PhD, recipient of the 2022 Cancer Research Early Career Award: https://vimeo.com/720726570
Data from Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment
Authors: Wang Hui Qin , Mulford Iain J. , Sharp Fiona , Liang Jinsheng , Kurtulus Sema , Trabucco Gina , Quinn David S. , Longmire Tyler A. , Patel Nidhi , Patil Roshani , Shirley Matthew D. , Chen Yan , Wang Hao , Ruddy David A. , Fabre Claire , Williams Juliet A. , Hammerman Peter S. , Mataraza Jennifer , Platzer Barbara , Halilovic Ensar
Published: March 2024

Abstract
p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell-cycle arrest or induction of apoptosis. However, the effects of p53 in antitumor immunity are poorly understood. To investigate the role of p53 in controlling tumor-immune cell cross-talk, we studied murine syngeneic models treated with HDM201, a potent and selective second-generation MDM2 inhibitor. In response to HDM201 treatment, the percentage of dendritic cells increased, including the CD103+ antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet+Eomes+ CD8+ T cells and the CD8+/Treg ratio within the tumor. These immunophenotypic changes were eliminated with the knockout of p53 in tumor cells. Enhanced expression of CD80 on tumor cells was observed in vitro and in vivo, which coincided with T-cell–mediated tumor cell killing. Combining HDM201 with PD-1 or PD-L1 blockade increased the number of complete tumor regressions. Responding mice developed durable, antigen-specific memory T cells and rejected subsequent tumor implantation. Importantly, antitumor activity of HDM201 in combination with PD-1/PD-L1 blockade was abrogated in p53-mutated and knockout syngeneic tumor models, indicating the effect of HDM201 on the tumor is required for triggering antitumor immunity. Taken together, these results demonstrate that MDM2 inhibition triggers adaptive immunity, which is further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in patients with wild-type p53 tumors.
Significance:
This study provides a mechanistic rationale for combining checkpoint blockade immunotherapy with MDM2 inhibitors in patients with wild-type p53 tumors.
Data from SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243
Authors: Murai Yasuhisa , Jo Ukhyun , Murai Junko , Jenkins Lisa M. , Huang Shar-Yin N. , Chakka Sirisha , Chen Lu , Cheng Ken , Fukuda Shinsaku , Takebe Naoko , Pommier Yves
Published: March 2024

Abstract
Schlafen11 (SLFN11) inactivation occurs in approximately 50% of cancer cell lines and in a large fraction of patient tumor samples, which leads to chemoresistance. Therefore, new therapeutic approaches are needed to target SLFN11-deficient cancers. To that effect, we conducted a drug screen with the NCATS mechanistic drug library of 1,978 compounds in isogenic SLFN11-knockout (KO) and wild-type (WT) leukemia cell lines. Here we report that TAK-243, a first-in-class ubiquitin activating enzyme UBA1 inhibitor in clinical development, causes preferential cytotoxicity in SLFN11-KO cells; this effect is associated with claspin-mediated DNA replication inhibition by CHK1 independently of ATR. Additional analyses showed that SLFN11-KO cells exhibit consistently enhanced global protein ubiquitylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and protein aggregation. TAK-243 suppressed global protein ubiquitylation and activated the UPR transducers PERK, phosphorylated eIF2α, phosphorylated IRE1, and ATF6 more effectively in SLFN11-KO cells than in WT cells. Proteomic analysis using biotinylated mass spectrometry and RNAi screening also showed physical and functional interactions of SLFN11 with translation initiation complexes and protein folding machinery. These findings uncover a previously unknown function of SLFN11 as a regulator of protein quality control and attenuator of ER stress and UPR. Moreover, they suggest the potential value of TAK-243 in SLFN11-deficient tumors.
Significance:
This study uncovers that SLFN11 deficiency induces proteotoxic stress and sensitizes cancer cells to TAK-243, suggesting that profiling SLFN11 status can serve as a therapeutic biomarker for cancer therapy.
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 2024

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 Low Glucose–Induced Overexpression of HOXC-AS3 Promotes Metabolic Reprogramming of Breast Cancer
Authors: Zhu Wenjie , Chen Xu , Guo Xiangyu , Liu Haiting , Ma Ranran , Wang Yawen , Liang Yahang , Sun Ying , Wang Mengqi , Zhao Ruinan , Gao Peng
Published: March 2024

Abstract
Breast cancer is the most common malignancy in women worldwide. However, the mechanisms underlying breast cancer energy metabolism and progression remain obscure. Cancer cells rapidly adapt to microenvironments with fluctuating nutrient levels. Here, we characterized a long noncoding RNA (lncRNA), HOXC-AS3, which is activated upon glucose deprivation to trigger a nutrient-stress response and a switch in glucose metabolism. Upregulation of HOXC-AS3 in breast cancer was identified by in published microarray and RNA-sequencing datasets, and then confirmed by qRT-PCR in fresh breast cancer tissues. Glucose deprivation induced HOXC-AS3 overexpression in a dose- and time-dependent manner in breast cancer cells. Gain- and loss-of-function experiments in vitro and in vivo showed that HOXC-AS3 triggers energy metabolism reprogramming. ChIRP-mass spectrometry and unique molecular identifier RNA immunoprecipitation and high-throughput sequencing (UMI RIP-seq) identified binding motifs of HOXC-AS3 with SIRT6. HOXC-AS3 selectively antagonized SIRT6-mediated H3K9ac deacetylation of glycolysis-related genes. Moreover, HOXC-AS3 binding to SIRT6 prevented contact inhibition of HIF1α, leading to reprogramming of metabolic pathways. In addition, HOXC-AS3, SP1, and miR-1224–5p formed a positive feedback loop to maintain cancer-promoting signals. Furthermore, administration of anti-HOXC-AS3-motif-RNAs effectively blocked the function of HOXC-AS3, ultimately suppressing breast cancer progression. These results reveal a critical role for HOXC-AS3 in regulating the metabolic reprogramming of breast cancer cells under metabolic stress. Use of an anti-HOXC-AS3-motif RNA mixture may be a promising strategy to suppress breast cancer progression.
Significance:
HOXC-AS3 is a low glucose–activated long noncoding RNA that triggers metabolic reprogramming in breast cancer cells to adapt to nutrient stress, identifying HOXC-AS3 as a potential therapeutic target for breast cancer treatment.
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 2024

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 FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance
Authors: Jing Weiqiang , Wang Ganyu , Cui Zhiwei , Xiong Gaozhong , Jiang Xin , Li Yue , Li Wushan , Han Bo , Chen Shouzhen , Shi Benkang
Published: March 2024

Abstract
Fibroblast growth factor receptor 3 (FGFR3) is frequently activated by mutation or overexpression, and it is a validated therapeutic target in urothelial carcinoma (UC) of the bladder. However, the role and detailed molecular mechanism of FGFR3 in the immune microenvironment of bladder cancer remain largely unknown. Here, we demonstrate that inhibition of FGFR3 in FGFR3-activated bladder cancer elevates PD-L1 protein levels by affecting its ubiquitination, thereby inhibiting the antitumor activity of CD8+ T cells. Tissue microarray analysis in human UC showed an inverse correlation between FGFR3 and PD-L1. Furthermore, NEDD4, an E3 ubiquitin ligase of the NEDD4 family of proteins, was phosphorylated by FGFR3 activation and served as a regulator of PD-L1 ubiquitination. Mechanistically, NEDD4 interacted with PD-L1 and catalyzed Lys48 (K48)-linked polyubiquitination of PD-L1. In mice bearing NEDD4 knockout bladder cancer, CD8+ T-cell infiltration and antitumor activity were significantly inhibited due to PD-L1 upregulation in bladder cancer cells. Furthermore, multiple FGFR3-activated tumor-bearing mouse models suggested that attenuated CD8+ T-cell–mediated antitumor efficacy following FGFR3-targeted therapy could be rescued by a combination with anti-PD-1 immunotherapy, which leads to effective tumor suppression. This study establishes a key molecular link between targeted therapy and immune surveillance and identifies NEDD4 as a crucial E3 ubiquitin ligase that targets PD-L1 for degradation in FGFR3-activated bladder cancer. These findings may potentially be exploited for combination therapies in UC of the bladder and possibly other malignancies with activated FGFR3.
Significance:
NEDD4 links two important molecules associated with targeted therapy and immune surveillance, providing mechanistic rationale and preclinical support for immuno-targeted combination therapy for FGFR3-activated bladder cancer.
Data from Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer
Authors: Wei Ruozheng , Zhou Yuning , Li Chang , Rychahou Piotr , Zhang Shulin , Titlow William B. , Bauman Greg , Wu Yuanyuan , Liu Jinpeng , Wang Chi , Weiss Heidi L. , Evers B. Mark , Wang Qingding
Published: March 2024

Abstract
The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression.
Significance:
This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival.

See related commentary by Montrose and Galluzzi, p. 1464