bluuebunny/crossref_metadata_2025 huggingface dataset:
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 2024

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 Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis
Authors: Cheng Yang , Bai Fuxiang , Ren Xiaolei , Sun Renhui , Guo Xiaowei , Liu Wen , Wang Bo , Yang Yongheng , Zhang Xiaolu , Xu Yong , Li Chunyang , Yang Xiaoyun , Gao Lifen , Ma Chunhong , Li Xueen , Liang Xiaohong
Published: March 2024

Abstract
Macrophages perform key and distinct functions in maintaining tissue homeostasis by finely tuning their activation state. Within the tumor microenvironment, macrophages are reshaped to drive tumor progression. Here we report that tumor necrosis factor α-induced protein 8–like 1 (TIPE1) is highly expressed in macrophages and that depletion of TIPE1 impedes alternative activation of macrophages. TIPE1 enhanced activation of the PI3K/Akt pathway in macrophages by directly binding with and regulating the metabolism of phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). Accordingly, inhibition of the PI3K/Akt pathway significantly attenuated the effect of TIPE1 on macrophage alternative activation. Tumor-associated macrophages (TAM) in human liver cancer and melanoma tissues showed significantly upregulated TIPE1 expression that negatively correlated with patient survival. In vitro and in vivo, TIPE1 knockdown in macrophages retarded the growth and metastasis of liver cancer and melanoma. Furthermore, blockade or depletion of TGFβ signaling in macrophages abrogated the effects of TIPE1 on tumor cell growth and migration. Together, these results highlight that the phosphoinositide-related signaling pathway is involved in reprogramming TAMs to optimize the microenvironment for cancer progression.
Significance:
This work provides insight into the fine tuning of macrophage polarization and identifies a potential target for macrophage-based antitumor therapy.
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 2024

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 Alterations in the Global Proteome and Phosphoproteome in Third Generation EGFR TKI Resistance Reveal Drug Targets to Circumvent Resistance
Authors: Zhang Xu , Maity Tapan K. , Ross Karen E. , Qi Yue , Cultraro Constance M. , Bahta Meriam , Pitts Stephanie , Keswani Meghana , Gao Shaojian , Nguyen Khoa Dang P. , Cowart Julie , Kirkali Fatos , Wu Cathy , Guha Udayan
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer mortality worldwide. The treatment of patients with lung cancer harboring mutant EGFR with orally administered EGFR tyrosine kinase inhibitors (TKI) has been a paradigm shift. Osimertinib and rociletinib are third-generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard of care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here we characterized the proteome and phosphoproteome of a series of isogenic EGFR-mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs, comprising the most comprehensive proteomic dataset resource to date to investigate third generation EGFR TKI resistance in lung adenocarcinoma. Unbiased global quantitative mass spectrometry uncovered alterations in signaling pathways, revealed a proteomic signature of epithelial–mesenchymal transition, and identified kinases and phosphatases with altered expression and phosphorylation in TKI-resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition, resulting in subsequent inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Anticorrelation analyses of this phosphoproteomic dataset with published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures program predicted drugs with the potential to overcome EGFR TKI resistance. The PI3K/MTOR inhibitor dactolisib in combination with osimertinib overcame resistance both in vitro and in vivo. Taken together, this study reveals global proteomic alterations upon third generation EGFR TKI resistance and highlights potential novel approaches to overcome resistance.
Significance:
Global quantitative proteomics reveals changes in the proteome and phosphoproteome in lung cancer cells resistant to third generation EGFR TKIs, identifying the PI3K/mTOR inhibitor dactolisib as a potential approach to overcome resistance.
Data from Genetic Variants Associated with Therapy-Related Cardiomyopathy among Childhood Cancer Survivors of African Ancestry
Authors: Sapkota Yadav , Qin Na , Ehrhardt Matthew J. , Wang Zhaoming , Chen Yan , Wilson Carmen L. , Estepp Jeremie , Rai Parul , Hankins Jane S. , Burridge Paul W. , Jefferies John L. , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Armstrong Gregory T. , Mulrooney Daniel A. , Yasui Yutaka
Published: March 2024

Abstract
Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; n = 246) were compared with cardiotoxic-exposed survivors of European ancestry (n = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2–4 and grade 3–4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; P = 2.8 × 10−8) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; P = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2–4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2–4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry.
Significance:
Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors.

See related commentary by Brown and Richard, p. 2272
Data from Activation of Notch and Myc Signaling via B-cell–Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia
Authors: Biran Anat , Yin Shanye , Kretzmer Helene , ten Hacken Elisa , Parvin Salma , Lucas Fabienne , Uduman Mohamed , Gutierrez Catherine , Dangle Nathan , Billington Leah , Regis Fara Faye , Rassenti Laura Z. , Mohammad Arman , Hoffmann Gabriela Brunsting , Stevenson Kristen , Zheng Mei , Witten Elizabeth , Fernandes Stacey M. , Tausch Eugen , Sun Clare , Stilgenbauer Stephan , Brown Jennifer R. , Kipps Thomas J. , Aster John C. , Gnirke Andreas , Neuberg Donna S. , Letai Anthony , Wang Lili , Carrasco Ruben D. , Meissner Alexander , Wu Catherine J.
Published: March 2024

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yields a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haploinsufficient tumor suppressor. B1a cells were confirmed as the cell of origin of disease in this model, and Dnmt3a depletion resulted in focal hypomethylation and activation of Notch and Myc signaling. Amplification of chromosome 15 containing the Myc gene was detected in all CLL mice tested, and infiltration of high-Myc–expressing CLL cells in the spleen was observed. Notably, hyperactivation of Notch and Myc signaling was exclusively observed in the Dnmt3a CLL mice, but not in three other CLL mouse models tested (Sf3b1-Atm, Ikzf3, and MDR), and Dnmt3a-depleted CLL were sensitive to pharmacologic inhibition of Notch signaling in vitro and in vivo. Consistent with these findings, human CLL samples with lower DNMT3A expression were more sensitive to Notch inhibition than those with higher DNMT3A expression. Altogether, these results suggest that Dnmt3a depletion induces CLL that is highly dependent on activation of Notch and Myc signaling.
Significance:
Loss of DNMT3A expression is a driving event in CLL and is associated with aggressive disease, activation of Notch and Myc signaling, and enhanced sensitivity to Notch inhibition.
Data from Hepatitis B–Induced IL8 Promotes Hepatocellular Carcinoma Venous Metastasis and Intrahepatic Treg Accumulation
Authors: Zhang Changlu , Gao Yanan , Du Chengzhi , Markowitz Geoffrey J. , Fu Jing , Zhang Zhenxing , Liu Chunliang , Qin Wenhao , Wang Hongyang , Wang Fan , Yang Pengyuan
Published: March 2024

Abstract
Hepatitis B–associated hepatocellular carcinoma (HCC) is often accompanied by severe vascular invasion and portal vein tumor thrombus, leading to a poor prognosis. However, the underlying mechanism of this disease remains obscure. In this study, we demonstrate that the hepatitis B virus (HBV)–encoded gene HBx induces high IL8 production through MEK–ERK signal activation, leading to enhanced endothelial permeability to facilitate tumor vascular invasion. In a vascular metastatic model using a tail vein injection in a transgenic mouse with selective expression of human CXCR1 in the endothelium, activation of the IL8–CXCR1 cascade by overexpression of IL8 in tumor cells dramatically enhanced liver metastasis. Mechanistically, IL8 selectively induced GARP-latent-TGFβ in liver sinusoidal endothelial cells and subsequently provoked preferential regulatory T-cell polarization to suppress antitumor immunity. Collectively, these findings reveal a hepatitis B–associated IL8–CXCR1 signaling axis that mediates vascular invasion and local microenvironmental immune escape of HCC to induce intrahepatic metastasis, which may serve as potential therapeutic targets for HBV-associated HCC.
Significance:
This study identifies a hepatitis B–induced IL8/CXCR1/TGFβ signaling cascade that suppresses antitumor immunity and enhances metastasis in hepatocellular carcinoma, providing new potential targets for therapeutic intervention.
Data from Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11
Authors: Wang Xinbo , Chen Yueqing , Wang Xudong , Tian Hongling , Wang Yanjin , Jin Jiali , Shan Zezhi , Liu Yu'e , Cai Zhenyu , Tong Xinyuan , Luan Yi , Tan Xiao , Luan Bing , Ge Xin , Ji Hongbin , Jiang Xuejun , Wang Ping
Published: March 2024

Abstract
Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment.
Significance:
This study uncovers a SOX2–SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.
Data from Loss of FBXW7 Correlates with Increased IDH1 Expression in Glioma and Enhances IDH1-Mutant Cancer Cell Sensitivity to Radiation
Authors: Yang Zhuo , Hu Nan , Wang Weiwei , Hu Weihua , Zhou Shaolong , Shi Jianxiang , Li Minghe , Jing Zhou , Chen Chao , Zhang Xuyang , Yang Ruyi , Fu Xudong , Wang Xinjun
Published: March 2024

Abstract
F-box and WD repeat domain containing 7 (FBXW7) is a substrate receptor of the ubiquitin ligase SKP1-Cullin1-F-box complex and a potent tumor suppressor that prevents unregulated cell growth and tumorigenesis. However, little is known about FBXW7-mediated control of cell metabolism and related functions in cancer therapy. Here, we report that FBXW7 expression inversely correlates with the expression levels of the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in patients with glioma and public glioma datasets. Deletion of FBXW7 significantly increased both wild-type (WT) and mutant IDH1 expression, which was mediated by blocking degradation of sterol regulatory element binding protein 1 (SREBP1). The upregulation of neomorphic mutant IDH1 by FBXW7 deletion stimulated production of the oncometabolite 2-hydroxyglutarate at the expense of increasing pentose phosphate pathway activity and NADPH consumption, limiting the buffering ability against radiation-induced oxidative stress. In addition, FBXW7 knockout and IDH1 mutations induced nonhomologous end joining and homologous recombination defects, respectively. In vitro and in vivo, loss of FBXW7 dramatically enhanced the efficacy of radiation treatment in IDH1-mutant cancer cells. Taken together, this work identifies FBXW7 deficiency as a potential biomarker representing both DNA repair and metabolic vulnerabilities that sensitizes IDH1-mutant cancers to radiotherapy.
Significance:
Deficiency of FBXW7 causes defects in DNA repair and disrupts NADPH homeostasis in IDH1-mutant glioma cells, conferring high sensitivity to radiotherapy.
Data from Patterns of Carbon-Bound Exogenous Compounds in Patients with Lung Cancer and Association with Disease Pathophysiology
Authors: Kunzke Thomas , Prade Verena M. , Buck Achim , Sun Na , Feuchtinger Annette , Matzka Marco , Fernandez Isis E. , Wuyts Wim , Ackermann Maximilian , Jonigk Danny , Aichler Michaela , Schmid Ralph A. , Eickelberg Oliver , Berezowska Sabina , Walch Axel
Published: March 2024

Abstract
Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 patients with lung cancer in highly variable and unique patterns. The characteristic nature of carbon-bound exogenous compounds had a strong association with patient outcome, tumor progression, the tumor immune microenvironment, programmed death-ligand 1 (PD-L1) expression, and DNA damage. Spatial correlation network analyses revealed substantial differences in the metabolome of tumor cells compared with tumor stroma depending on carbon-bound exogenous compounds. Overall, the bioactive pool of exogenous compounds is associated with several changes in lung cancer pathophysiology and correlates with patient outcome. Given the high prevalence of anthracosis in the lungs of adult humans, future work should investigate the role of carbon-bound exogenous compounds in lung carcinogenesis and lung cancer therapy.
Significance:
This study identifies a bioactive pool of carbon-bound exogenous compounds in patient tissues associated with several tumor biological features, contributing to an improved understanding of drivers of lung cancer pathophysiology.
Data from N6-Methyladenosine Regulates mRNA Stability and Translation Efficiency of KRT7 to Promote Breast Cancer Lung Metastasis
Authors: Chen Feng , Chen Zhuojia , Guan Tao , Zhou Yan , Ge Lichen , Zhang Haisheng , Wu Yingmin , Jiang Guan-Min , He Weiling , Li Jiexin , Wang Hongsheng
Published: March 2024

Abstract
The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them as BCLMF3 cells. In these cells, mRNA N6-methyladenosine (m6A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m6A-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m6A promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7.
Significance:
This study suggests that N6-methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.
Data from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity
Authors: Grisaru-Tal Sharon , Dulberg Shai , Beck Lir , Zhang Chunyan , Itan Michal , Hediyeh-zadeh Soroor , Caldwell Julie , Rozenberg Perri , Dolitzky Avishay , Avlas Shmuel , Hazut Inbal , Gordon Yaara , Shani Ophir , Tsuriel Shlomo , Gerlic Motti , Erez Neta , Jacquelot Nicolas , Belz Gabrielle T. , Rothenberg Marc E. , Davis Melissa J. , Yu Hua , Geiger Tamar , Madi Asaf , Munitz Ariel
Published: March 2024

Abstract
The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein–coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ–activated eosinophils facilitated CD4+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics.
Significance:
These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.
Data from AMPK–mTOR–Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells
Authors: You Bo , Xia Tian , Gu Miao , Zhang Zhenxin , Zhang Qicheng , Shen Jianhong , Fan Yue , Yao Hui , Pan Si , Lu Yingna , Cheng Tianyi , Yang Zhiyuan , He Xin , Zhang Hao , Shi Muqi , Liu Dong , You Yiwen
Published: March 2024

Abstract
Dormant cancer cells that survive anticancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction. Moreover, pharmacologic or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in patients with NPC. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer.
Significance:
Pretreatment with an autophagy inhibitor before chemotherapy could prevent formation of therapy-induced dormant polyploid giant cancer cells, thereby reducing recurrence and metastasis of nasopharyngeal carcinoma.
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 2024

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 RNA Helicase DHX37 Facilitates Liver Cancer Progression by Cooperating with PLRG1 to Drive Superenhancer-Mediated Transcription of Cyclin D1
Authors: Liu Zhen , Ye Youqiong , Liu Yizhe , Liu Yanfang , Chen Huifang , Shen Mengting , Wang Zhen , Huang Shenglin , Han Leng , Chen Zhiao , He Xianghuo
Published: March 2024

Abstract
RNA helicases are dysregulated in tumors. Here, we identified DHX37 as one of the top RNA helicase genes with upregulated expression in hepatocellular carcinoma (HCC). DHX37 promoted proliferation of liver cancer cells in vitro and in vivo. Epigenomic profiling of DHX37-knockdown and control HCC cells revealed that DHX37 is associated with superenhancer activity. Mechanistically, DHX37 interacted with pleiotropic regulator 1 (PLRG1) to transcriptionally activate cyclin D1 (CCND1) expression via co-occupation of its promoter and superenhancer elements. DHX37 and PLRG1 promoted liver cancer cell proliferation and contributed to the poor prognosis of patients with HCC. Importantly, CCND1 inhibitors were effective as antiproliferative agents for liver cancer. These results together demonstrate a cooperative mechanistic interaction between DHX37 and PLRG1 that regulates CCND1 expression and promotes liver cancer progression, advancing our understanding of the epigenetic and transcriptional dysregulations mediated by RNA helicases and superenhancers in HCC.
Significance:
This work characterizes a novel mechanism of superenhancer-driven cyclin D1 upregulation by DHX37 and PLRG1, implicating this pathway as a potential therapeutic target in hepatocellular carcinoma.
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 2024

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 EIF4A3-Induced circARHGAP29 Promotes Aerobic Glycolysis in Docetaxel-Resistant Prostate Cancer through IGF2BP2/c-Myc/LDHA Signaling
Authors: Jiang Xingkang , Guo Shanqi , Wang Shuo , Zhang Yangyi , Chen Haojie , Wang Yong , Liu Ranlu , Niu Yuanjie , Xu Yong
Published: March 2024

Abstract
Docetaxel-based chemotherapy is a standard-of-care treatment for metastatic prostate cancer, and chemoresistance remains a major challenge in clinical practice. Recent studies have demonstrated that circular RNAs (circRNA) play critical roles in the development and progression of prostate cancer. However, the biological roles and potential functions of circRNAs in mediating docetaxel-resistant prostate cancer have yet to be well elucidated. In this study, we analyzed the expression profiles of circRNAs in docetaxel-resistant and -sensitive prostate cancer cells through RNA sequencing and found that expression of circARHGAP29 was significantly upregulated in docetaxel-resistant cell lines and clinical samples. Ectopic expression of circARHGAP29 triggered docetaxel resistance and aerobic glycolysis in prostate cancer cells, which was reduced by silencing circARHGAP29. Moreover, eukaryotic initiation factor 4A3, which bound the back-spliced junction site and the downstream flanking sequence of circARHGAP29, induced cyclization and cytoplasmic export of circARHGAP29. circARHGAP29 increased the stability of lactate dehydrogenase A (LDHA) mRNA by strengthening its interaction with insulin-like growth factor 2 mRNA-binding protein 2, leading to enhanced glycolytic metabolism. In addition, circARHGAP29 interacted with and stabilized c-Myc mRNA and protein, which further increased LDHA expression by facilitating its transcription. These findings reveal the crucial function of circARHGAP29 in prostate cancer glycolysis by increasing and stabilizing LDHA mRNA, providing a promising therapeutic target in docetaxel-resistant prostate cancer.
Significance:
Upregulation of a novel circRNA, circARHGAP29, promotes docetaxel resistance and glycolytic metabolism, suggesting it could be a prognostic biomarker and therapeutic target in chemoresistant prostate cancer.
Data from TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling
Authors: Zhang Xinchao , Li Shuyan , He Jing , Jin Yunjie , Zhang Ruonan , Dong Wenjing , Lin Mingen , Yang Yajing , Tian Tongguan , Zhou Yuefan , Xu Yixin , Lei Qun-Ying , Zhang Jing , Zhang Qing , Xu Yanping , Lv Lei
Published: March 2024

Abstract
Inactivating mutations of von Hippel–Lindau (VHL) are highly prevalent in clear cell renal cell carcinoma (ccRCC). Improved understanding of the vulnerabilities of VHL-deficient ccRCC could lead to improved treatment strategies. The activity of DNA dioxygenase ten-eleven translocation (TET)2 is significantly reduced in multiple cancers by different mechanisms, but its role in ccRCC progression remains unclear. Here, we report that increased expression of TET2, but not TET1 and TET3, is negatively associated with tumor metastasis and advanced tumor stage and is positively associated with good prognosis uniquely in ccRCC among all 33 types of cancer in The Cancer Genome Atlas datasets. TET2 restrained glycolysis and pentose phosphate pathway metabolism in a VHL deficiency–dependent manner, thereby suppressing ccRCC progression. Notably, TET2 and VHL mutations tended to cooccur in ccRCC, providing genetic evidence that they cooperate to inhibit the progression of ccRCC. Mechanistically, TET2 was recruited by transcription factor HNF4α to activate FBP1 expression, which antagonized the function of hypoxia-inducible factor-1/2α (HIF1/2α) in metabolic reprogramming to impede ccRCC growth. Stimulating the TET2-FBP1 axis with vitamin C repressed the growth of VHL-deficient ccRCC with wild-type TET2 and increased the sensitivity to glycolysis inhibitors. Moreover, combined expression levels of the HNF4α–TET2-FBP1 axis served as a biomarker of prognosis in patients with ccRCC. This study reveals a unique function of TET2 in the suppression of tumor metabolism and HIF signaling, and it also provides therapeutic targets, potential drugs, and prognostic markers for the management of ccRCC.
Significance:
The identification of TET2-mediated inhibition of HIF signaling and tumor metabolic reprogramming provides insights for new therapeutic strategies for VHL-deficient ccRCC.
Data from Genetic, Pharmacogenomic, and Immune Landscapes of Enhancer RNAs Across Human Cancers
Authors: Zhang Zhao , Luo Mei , Li Qiang , Liu Yuan , Lussier Charles , Zhang Jian , Ye Youqiong , Guo An-Yuan , Han Leng
Published: March 2024

Abstract
Enhancer RNAs (eRNA) regulate gene expression and play critical roles in cancer. Using large-scale omics data from The Cancer Genome Atlas (TCGA), we systematically investigated the impact of genetic variants on eRNA expression and identified approximately 1 million eRNA quantitative trait loci (eRNA-QTL) as cis- and trans-acting. Over 16,000 eRNA-QTLs were associated with patient overall survival. Assessing the impact of eRNAs on more than 1,000 imputed anticancer drug responses across approximately 10,000 patients with cancer revealed more than 7 million significant associations. Furthermore, approximately 240,000 significant associations were identified between eRNA expression and immune cell abundance deconvoluted by TIMER, CIBERSORT, ImmuCellAI, and ImmuneCellGSVA. Finally, a user-friendly data portal was generated: Genetic, Pharmacogenomic, and Immune Landscapes of eRNAs (GPIeR; https://hanlab.tamhsc.edu/GPIeR/). GPIeR is a large-scale multidimensional data portal that can be used to explore eRNA-associated genetic variants, drug responses, and immune infiltration, with the purpose of facilitating functional and clinical investigations of eRNAs in cancer.
Significance:
This study provides insights into the impact of the enhancer RNA (eRNA) landscape on patient outcome, the immune microenvironment, and drug response across cancers and develops a multidimensional data portal to facilitate eRNA research.
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 2024

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 And-1 Coordinates with the FANCM Complex to Regulate Fanconi Anemia Signaling and Cisplatin Resistance
Authors: Zhang Yi , Li Jing , Zhou Yuan , Li Zhuqing , Peng Changmin , Pei Huadong , Zhu Wenge
Published: March 2024

Abstract
The Fanconi anemia (FA) pathway is essential for repairing DNA interstrand crosslinks (ICL). ICLs induce stalled DNA replication forks and trigger activation of the FA pathway by promoting recruitment of the FANCM/FAAP24/MHF complex to ICL sites. Given that stalled replication forks are proximal to ICL sites, fork-associated proteins may coordinate with FA factors to rapidly sense ICLs for activation of FA signaling. Here we report that And-1, a replisome protein, is critical for activation of the FA pathway by sensing ICL-stalled forks and recruiting the FANCM/FAAP24 complex to ICLs. In response to ICLs, And-1 rapidly accumulated at ICL-stalled forks in a manner dependent on ataxia telangiectasia and Rad3-related protein–induced phosphorylation at T826. And-1 phosphorylation triggered an intramolecular change that promoted the interaction of And-1 with FANCM/FAAP24, resulting in recruitment of the FANCM/FAAP24 complex to ICLs. Furthermore, p-T826 And-1 was elevated in cisplatin-resistant ovarian cancer cells, and activated And-1 contributed to cisplatin resistance. Collectively, these studies elucidate a mechanism by which And-1 regulates FA signaling and identify And-1 as a potential target for developing therapeutic approaches to treat platinum-resistant ovarian cancer.
Significance:
This work shows that phosphorylation of And-1 by ATR activates Fanconi anemia signaling at interstrand crosslink–stalled replication forks by recruiting the FANCM/FAAP24 complex, revealing And-1 as a potential therapeutic target in cancer.
Data from CHD1 Promotes Sensitivity to Aurora Kinase Inhibitors by Suppressing Interaction of AURKA with Its Coactivator TPX2
Authors: Li Haoyan , Wang Yin , Lin Kevin , Venkadakrishnan Varadha Balaji , Bakht Martin , Shi Wei , Meng Chenling , Zhang Jie , Tremble Kaitlyn , Liang Xin , Song Jian H. , Feng Xu , Van Vivien , Deng Pingna , Burks Jared K. , Aparicio Ana , Keyomarsi Khandan , Chen Junjie , Lu Yue , Beltran Himisha , Zhao Di
Published: March 2024

Abstract
Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the coactivator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies.
Significance:
CHD1 plays a critical role in controlling AURKA activation and promoting Aurora kinase inhibitor sensitivity, providing a potential clinical biomarker to guide cancer treatment.
Data from GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors
Authors: Li Yunzheng , Li Binghua , Xu Yanchao , Qian Liyuan , Xu Tiancheng , Meng Gang , Li Huan , Wang Ye , Zhang Laizhu , Jiang Xiang , Liu Qi , Xie Yuanyuan , Cheng Chunxiao , Sun Beicheng , Yu Decai
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is one of the primary liver malignancies with a poor prognosis. Glutamic-oxaloacetic transaminase 2 (GOT2) is a highly tissue-specific gene in the liver, but the roles GOT2 plays in the progression of HCC remain unclear. Here, we report that GOT2 is downregulated in HCC tumor tissues and that low expression of GOT2 is associated with advanced progression and poor prognosis. In HCC cells, knockdown of GOT2 promoted proliferation, migration, and invasion. In mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, silencing of GOT2 enhanced glutaminolysis, nucleotide synthesis, and glutathione synthesis by reprogramming glutamine metabolism to support the cellular antioxidant system, which activated the PI3K/AKT/mTOR pathway to contribute to HCC progression. Furthermore, HCC with low expression of GOT2 was highly dependent on glutamine metabolism and sensitive to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, GOT2 is involved in glutamine metabolic reprogramming to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.
Significance:
Altered glutamine metabolism induced by GOT2 loss supports HCC growth and metastasis but confers a targetable vulnerability to glutaminase inhibitors.
Data from Quantification of Neoantigen-Mediated Immunoediting in Cancer Evolution
Authors: Wu Tao , Wang Guangshuai , Wang Xuan , Wang Shixiang , Zhao Xiangyu , Wu Chenxu , Ning Wei , Tao Ziyu , Chen Fuxiang , Liu Xue-Song
Published: March 2024

Abstract
Immunoediting includes three temporally distinct stages, termed elimination, equilibrium, and escape, and has been proposed to explain the interactions between cancer cells and the immune system during the evolution of cancer. However, the status of immunoediting in cancer remains unclear, and the existence of neoantigen depletion in untreated cancer has been debated. Here we developed a distribution pattern-based method for quantifying neoantigen-mediated negative selection in cancer evolution. The method can provide a robust and reliable quantification for immunoediting signal in individual patients with cancer. Moreover, this method demonstrated the prevalence of immunoediting in the immunotherapy-naive cancer genome. The elimination and escape stages of immunoediting can be quantified separately, where tumor types with strong immunoediting-elimination exhibit a weak immunoediting-escape signal, and vice versa. The quantified immunoediting-elimination signal was predictive of clinical response to cancer immunotherapy. Collectively, immunoediting quantification provides an evolutionary perspective for evaluating the antigenicity of neoantigens and reveals a potential biomarker for precision immunotherapy in cancer.
Significance:
Quantification of neoantigen-mediated negative selection in cancer progression reveals distinct features of cancer immunoediting and can serve as a potential biomarker to predict immunotherapy response.
Data from DLGAP1-AS2–Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma
Authors: Nan Yabing , Luo Qingyu , Wu Xiaowei , Liu Shi , Zhao Pengfei , Chang Wan , Zhou Aiping , Liu Zhihua
Published: March 2024

Abstract
Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most patients with SCC experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and to explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein–coupled receptors formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2–targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.
Significance:
This study identifies D-AS2 as a targetable lipid-related long noncoding RNA that increases phospholipase D activity to promote YAP signaling, triggering chemoresistance in SCC.