bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from ZMYND8 Expression in Breast Cancer Cells Blocks T-Lymphocyte Surveillance to Promote Tumor Growth
Authors: Wang Yong , Luo Maowu , Chen Yan , Wang Yijie , Zhang Bo , Ren Zhenhua , Bao Lei , Wang Yanan , Wang Jennifer E. , Fu Yang-Xin , Luo Weibo , Wang Yingfei
Published: March 2024

Abstract
Emerging studies indicate that DNA damage in cancer cells triggers antitumor immunity, but its intrinsic regulatory mechanism in breast cancer cells remains poorly understood. Here, we show that ZMYND8 is upregulated and inhibits micronucleus formation and DNA damage in breast cancer cells. Loss of ZMYND8 triggered activation of the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase in micronuclei, leading to further activation of the downstream signaling effectors stimulator of IFN genes and NF-κB, but not TANK-binding kinase 1 and IFN regulatory factor 3, thereby inducing the expression of IFNβ and IFN-stimulated genes (ISG) in breast cancer cells in vitro and tumors in vivo. ZMYND8 knockout (KO) in breast cancer cells promoted infiltration of CD4+ and CD8+ T cells, leading to tumor inhibition in syngeneic mouse models, which was significantly attenuated by treatment of anti-CD4/CD8–depleting antibodies or anti-IFNAR1 antibody and in immunodeficient Rag1 KO mice. In human breast tumors, ZMYND8 was negatively correlated with ISGs, CD4, CD8A, CD8B, and the tumor-lymphocyte infiltration phenotype. Collectively, these findings demonstrate that maintenance of genome stability by ZMYND8 causes breast cancer cells to evade cytotoxic T-lymphocyte surveillance, which leads to tumor growth.
Significance:
These findings show that ZMYND8 is a new negative and intrinsic regulator of the innate immune response in breast tumor cells, and ZMYND8 may be a possible target for antitumor immunotherapy.
Data from Acute Kidney Injury Instigates Malignant Renal Cell Carcinoma via CXCR2 in Mice with Inactivated Trp53 and Pten in Proximal Tubular Kidney Epithelial Cells
Authors: Zhou Xunian , Xiao Fei , Sugimoto Hikaru , Li Bingrui , McAndrews Kathleen M. , Kalluri Raghu
Published: March 2024

Abstract
Renal cell carcinoma (RCC) is one of the most common urologic malignancies with the highest mortality rates worldwide. However, relevant mouse models that recapitulated the genetic alterations found in RCC have been lacking. In this study, we crossed Trp53 and Pten conditional knockout mice with Ggt1-Cre mice to generate a Ggt1-Cre; Trp53LoxP/LoxP; PtenLoxP/LoxP; YFPLoxP/LoxP (GPPY) mouse model, which resulted in the formation of dysplastic lesions involving kidney tubular epithelial cells (TEC), with only approximately 25% of mice developing RCC at an advanced age. Combining CRISPR/Cas9-mediated Vhl knockout in these mice increased the frequency of dysplasia, but failed to increase the incidence of RCC. Assessments of whether ischemic injury of TECs in the GPPY kidney without Vhl knockout influences the emergence of RCC revealed that advanced RCC predominantly emerged in the contralateral, noninjured kidney with 100% penetrance at a younger age, but rarely in the injured kidney due to severely damaged ischemic TEC. Injured TEC released CXCL1 into the microenvironment that traveled systemically to activate fibroblasts and recruit neutrophils to enable emergence of RCC in the contralateral kidney. Fibroblasts responded to CXCL1 via CXCR2 and recruited tumor-associated neutrophils, which in turn mediated tumor-promoting inflammation and angiogenesis. Treatment with anti-CXCR2 antibodies abolished the emergence of malignant RCC. Collectively, these results demonstrate a defining functional role of systemic inflammation and microenvironment in the emergence of malignant cancer from preestablished dysplastic precursor lesions.
Significance:
These results identify a role for CXCL1/CXCR2 and the tumor microenvironment in the development of RCC.
Data from Misannotated Multi-Nucleotide Variants in Public Cancer Genomics Datasets Lead to Inaccurate Mutation Calls with Significant Implications
Authors: Srinivasan Sujaya , Kalinava Natallia , Aldana Rafael , Li Zhipan , van Hagen Sjoerd , Rodenburg Sander Y.A. , Wind-Rotolo Megan , Qian Xiaozhong , Sasson Ariella S. , Tang Hao , Kirov Stefan
Published: March 2024

Abstract
Although next-generation sequencing is widely used in cancer to profile tumors and detect variants, most somatic variant callers used in these pipelines identify variants at the lowest possible granularity, single-nucleotide variants (SNV). As a result, multiple adjacent SNVs are called individually instead of as a multi-nucleotide variants (MNV). With this approach, the amino acid change from the individual SNV within a codon could be different from the amino acid change based on the MNV that results from combining SNV, leading to incorrect conclusions about the downstream effects of the variants. Here, we analyzed 10,383 variant call files (VCF) from the Cancer Genome Atlas (TCGA) and found 12,141 incorrectly annotated MNVs. Analysis of seven commonly mutated genes from 178 studies in cBioPortal revealed that MNVs were consistently missed in 20 of these studies, whereas they were correctly annotated in 15 more recent studies. At the BRAF V600 locus, the most common example of MNV, several public datasets reported separate BRAF V600E and BRAF V600M variants instead of a single merged V600K variant. VCFs from the TCGA Mutect2 caller were used to develop a solution to merge SNV to MNV. Our custom script used the phasing information from the SNV VCF and determined whether SNVs were at the same codon and needed to be merged into MNV before variant annotation. This study shows that institutions performing NGS sequencing for cancer genomics should incorporate the step of merging MNV as a best practice in their pipelines.
Significance:
Identification of incorrect mutation calls in TCGA, including clinically relevant BRAF V600 and KRAS G12, will influence research and potentially clinical decisions.
Data from CDK2-Mediated Upregulation of TNFα as a Mechanism of Selective Cytotoxicity in Acute Leukemia
Authors: Ding Husheng , Vincelette Nicole D. , McGehee Cordelia D. , Kohorst Mira A. , Koh Brian D. , Venkatachalam Annapoorna , Meng X. Wei , Schneider Paula A. , Flatten Karen S. , Peterson Kevin L. , Correia Cristina , Lee Sun-Hee , Patnaik Mrinal , Webster Jonathan A. , Ghiaur Gabriel , Smith B. Douglas , Karp Judith E. , Pratz Keith W. , Li Hu , Karnitz Larry M. , Kaufmann Scott H.
Published: March 2024

Abstract
Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acute myeloid leukemia (AML) and BCR/ABL–positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFα production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2–AP1–TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand–induced killing that can potentially be exploited for acute leukemia treatment.
Significance:
This study demonstrates that replication checkpoint inhibitors can kill AML cells through a pathway involving AP1-mediated TNF gene activation and subsequent TP53-independent, TNFα-induced apoptosis, which can potentially be exploited clinically.
Data from Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function
Authors: La Fleur Linnéa , Botling Johan , He Fei , Pelicano Catarina , Zhou Chikai , He Chenfei , Palano Giorgia , Mezheyeuski Artur , Micke Patrick , Ravetch Jeffrey V. , Karlsson Mikael C. I. , Sarhan Dhifaf
Published: March 2024

Abstract
The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non–small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAM) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of protumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased natural killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL37. MARCO-expressing TAMs blocked cytotoxic T-cell and NK-cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL10 production and diminished CD8 T-cell activities. Targeting MARCO or IL37 receptor (IL37R) by antibody or CRISPR knockout of IL37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and antitumoral capacity of NK cells and T cells and downmodulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK- and T-cell antitumor activities.
Significance:
This study defines tumor-derived IL37 and the macrophage scavenger receptor MARCO as potential therapeutic targets to remodel the immune-suppressive microenvironment in patients with lung cancer.
Data from KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer
Authors: Gao Lin , Zhang Wenbo , Zhang Jing , Liu Junmei , Sun Feifei , Liu Hui , Hu Jing , Wang Xin , Wang Xueli , Su Peng , Chen Shouzhen , Qu Sifeng , Shi Benkang , Xiong Xueting , Chen Weiwen , Dong Xuesen , Han Bo
Published: March 2024

Abstract
The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target.
Significance:
These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.
Data from LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway
Authors: Xu Fengyu , Huang Mengqi , Chen Qingyong , Niu Yi , Hu Yuhang , Hu Ping , Chen Ding , He Chi , Huang Kang , Zeng Zhu , Tang Jiang , Wang Fan , Zhao Yong , Wang Chunyou , Zhao Gang
Published: March 2024

Abstract
Gemcitabine (GEM) resistance is a major challenge for chemotherapy of pancreatic cancer. Previous studies have reported on the role of long noncoding RNA (lncRNA) in tumorigenesis of pancreatic cancer, however, the involvement of lncRNA in the development of GEM resistance of pancreatic cancer remains unclear. In the present study, we demonstrated that the antisense RNA1 of HIF1α (HIF1A-AS1) was significantly elevated in the GEM-resistant pancreatic cancer cells. Gain- and lost-of-function experiments validated that HIF1A-AS1 promoted GEM resistance of pancreatic cancer cells both in vitro and vivo. We further revealed that HIF1A-AS1 upregulated HIF1α expression and thus promoted glycolysis to enhance GEM resistance of pancreatic cancer cells. Mechanistically, HIF1A-AS1 facilitated the interaction between serine/threonine kinase AKT and Y-box–binding protein 1 (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIF1α mRNA that consequently promoted translation of HIF1α. Furthermore, HIF1α promoted HIF1A-AS1 transcription by directly binding to the HIF1α response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF1α were upregulated in pancreatic cancer tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF1α that contributes to GEM resistance of pancreatic cancer and indicate that HIF1A-AS1 might serve as a novel therapeutic target for GEM resistance of pancreatic cancer.
Significance:
These findings show that a reciprocal feedback of HIF1A-AS1 and HIF1α promotes gemcitabine resistance of pancreatic cancer, which provides an applicable therapeutic target.
Data from Nicotine-Induced ILF2 Facilitates Nuclear mRNA Export of Pluripotency Factors to Promote Stemness and Chemoresistance in Human Esophageal Cancer
Authors: Li Yue , Wang Meng , Yang Muwen , Xiao Yunyun , Jian Yunting , Shi Dongni , Chen Xiangfu , Ouyang Ying , Kong Lingzhi , Huang Xinjian , Bai Jiewen , Hu Yameng , Lin Chuyong , Song Libing
Published: March 2024

Abstract
Balancing mRNA nuclear export kinetics with its nuclear decay is critical for mRNA homeostasis control. How this equilibrium is aberrantly disrupted in esophageal cancer to acquire cancer stem cell properties remains unclear. Here we find that the RNA-binding protein interleukin enhancer binding factor 2 (ILF2) is robustly upregulated by nicotine, a major chemical component of tobacco smoke, via activation of JAK2/STAT3 signaling and significantly correlates with poor prognosis in heavy-smoking patients with esophageal cancer. ILF2 bound the THO complex protein THOC4 as a regulatory cofactor to induce selective interactions with pluripotency transcription factor mRNAs to promote their assembly into export-competent messenger ribonucleoprotein complexes. ILF2 facilitated nuclear mRNA export and inhibited hMTR4-mediated exosomal degradation to promote stabilization and expression of SOX2, NANOG, and SALL4, resulting in enhanced stemness and tumor-initiating capacity of esophageal cancer cells. Importantly, inducible depletion of ILF2 significantly increased the therapeutic efficiency of cisplatin and abrogated nicotine-induced chemoresistance in vitro and in vivo. These findings reveal a novel role of ILF2 in nuclear mRNA export and maintenance of cancer stem cells and open new avenues to overcome smoking-mediated chemoresistance in esophageal cancer.
Significance:
This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer.
Data from Long Noncoding RNA VESTAR Regulates Lymphangiogenesis and Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma by Enhancing VEGFC mRNA Stability
Authors: Wang Yali , Zhang Weimin , Liu Wenzhong , Huang Lijie , Wang Yan , Li Dan , Wang Guangchao , Zhao Zitong , Chi Xinming , Xue Yu , Song Yongmei , Liu Xuefeng , Zhan Qimin
Published: March 2024

Abstract
Lymph node metastasis is one of the most malignant clinical features in patients with esophageal squamous cell carcinoma (ESCC). Understanding the mechanism of lymph node metastasis will provide treatment strategies for patients with ESCC. Long noncoding RNAs (lncRNA) play a critical role in the development and progression of human cancers. However, the role and mechanism of lncRNAs in lymph node metastasis remain largely unknown. Here we show that VEGFC mRNA stability–associated long noncoding RNA (VESTAR) is involved in lymph node metastasis of ESCC. VESTAR was overexpressed in ESCC tissues and was predictive of poor prognosis in patients with ESCC. In ESCC, NXF1 and SRSF3 facilitated nuclear export of VESTAR to the cytoplasm, which was associated with lymph node metastasis. Depletion of VESTAR inhibited ESCC-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, VESTAR directly bound and stabilized VEGFC mRNA. VESTAR also interacted with HuR, a positive regulator of VEGFC mRNA stability, and increased HuR binding to VEGFC mRNA. Our study reveals a novel lncRNA-guided mechanism of lymph node metastasis in ESCC and may provide a potential target for treatment of ESCC lymphatic metastasis.
Significance:
These findings illustrate the lncRNA-guided regulation of VEGFC mRNA stability via direct RNA–RNA interactions, highlighting a therapeutic target for patients with ESCC with lymphatic metastasis.
Data from FSTL1 Secreted by Activated Fibroblasts Promotes Hepatocellular Carcinoma Metastasis and Stemness
Authors: Loh Jia-Jian , Li Tsz-Wai , Zhou Lei , Wong Tin-Lok , Liu Xue , Ma Victor W.S. , Lo Chung-Mau , Man Kwan , Lee Terence K. , Ning Wen , Tong Man , Ma Stephanie
Published: March 2024

Abstract
The tumor microenvironment plays a critical role in maintaining the immature phenotype of tumor-initiating cells (TIC) to promote cancer. Hepatocellular carcinoma (HCC) is a unique disease in that it develops in the setting of fibrosis and cirrhosis. This pathologic state commonly shows an enrichment of stromal myofibroblasts, which constitute the bulk of the tumor microenvironment and contribute to disease progression. Follistatin-like 1 (FSTL1) has been widely reported as a proinflammatory mediator in different fibrosis-related and inflammatory diseases. Here we show FSTL1 expression to be closely correlated with activated fibroblasts and to be elevated in regenerative, fibrotic, and disease liver states in various mouse models. Consistently, FSTL1 lineage cells gave rise to myofibroblasts in a CCL4-induced hepatic fibrosis mouse model. Clinically, high FSTL1 in fibroblast activation protein–positive (FAP+) fibroblasts were significantly correlated with more advanced tumors in patients with HCC. Although FSTL1 was expressed in primary fibroblasts derived from patients with HCC, it was barely detectable in HCC cell lines. Functional investigations revealed that treatment of HCC cells and patient-derived 3D organoids with recombinant FSTL1 or with conditioned medium collected from hepatic stellate cells or from cells overexpressing FSTL1 could promote HCC growth and metastasis. FSTL1 bound to TLR4 receptor, resulting in activation of AKT/mTOR/4EBP1 signaling. In a preclinical mouse model, blockade of FSTL1 mitigated HCC malignancy and metastasis, sensitized HCC tumors to sorafenib, prolonged survival, and eradicated the TIC subset. Collectively, these data suggest that FSTL1 may serve as an important novel diagnostic/prognostic biomarker and therapeutic target in HCC.
Significance:
This study shows that FSTL1 secreted by activated fibroblasts in the liver microenvironment augments hepatocellular carcinoma malignancy, providing a potential new strategy to improve treatment of this aggressive disease.
Data from Valosin-Containing Protein Stabilizes Mutant p53 to Promote Pancreatic Cancer Growth
Authors: Wang Jieqiong , Chen Yajie , Huang Canhua , Hao Qian , Zeng Shelya X. , Omari Sara , Zhang Yu , Zhou Xiang , Lu Hua
Published: March 2024

Abstract
Approximately 80% of human pancreatic ductal adenocarcinomas (PDAC) harbor TP53 mutations, among which, R273H is the most frequent. Although p53-R273H is known to possess gain-of-function properties, how it is regulated in PDAC has not been extensively explored. Here we identify valosin-containing protein (VCP) as a regulator of p53-R273H by conducting immunoprecipitation-tandem mass spectrometry analysis. VCP bound p53-R273H at its DNA binding domain. Ectopic or endogenous VCP stabilized p53-R273H by binding to MDM2 and disrupting its association with mutant p53. Inhibition of VCP either by genetic depletion or the pharmacologic inhibitor CB-5083 increased ubiquitination and degradation of p53-R273H, leading to cell death. Consistently, ablation of VCP markedly retarded growth of cultured PDAC cells and xenograft PDAC tumors. Together, these results unveil VCP as a novel partner of p53-R273H in promoting PDAC growth and as a potential target for developing anti-PDAC therapy.
Significance:
These findings identify valosin-containing protein (VCP) as a novel regulator of p53-R273H stability and suggest VCP as a potential target for development of pancreatic cancer therapy.
Data from An Oncolytic Virus Expressing IL15/IL15Rα Combined with Off-the-Shelf EGFR-CAR NK Cells Targets Glioblastoma
Authors: Ma Rui , Lu Ting , Li Zhenlong , Teng Kun-Yu , Mansour Anthony G. , Yu Melissa , Tian Lei , Xu Bo , Ma Shoubao , Zhang Jianying , Barr Tasha , Peng Yong , Caligiuri Michael A. , Yu Jianhua
Published: March 2024

Abstract
IL15 is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses (OV) specifically lyse tumors and activate immune responses. Systemic administration of IL15 or its complex with the IL15Rα and chimeric antigen receptor (CAR) natural killer (NK) cells are currently being tested in the clinic. Here, we generated a herpes simplex 1–based OV-expressing human IL15/IL15Rα sushi domain fusion protein (named OV-IL15C), as well as off-the-shelf EGFR-CAR NK cells, and studied their monotherapy and combination efficacy in vitro and in multiple glioblastoma (GBM) mouse models. In vitro, soluble IL15/IL15Rα complex was secreted from OV-IL15C–infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD8+ T cells. Frozen, readily available off-the-shelf EGFR-CAR NK cells showed enhanced killing of tumor cells compared with empty vector–transduced NK cells. In vivo, OV-IL15C significantly inhibited tumor growth and prolonged survival of GBM-bearing mice in the presence of CD8+ T cells compared with parental OV. OV-IL15C plus EGFR-CAR NK cells synergistically suppressed tumor growth and significantly improved survival compared with either monotherapy, correlating with increased intracranial infiltration and activation of NK and CD8+ T cells and elevated persistence of CAR NK cells in an immunocompetent model. Collectively, OV-IL15C and off-the-shelf EGFR-CAR NK cells represent promising therapeutic strategies for GBM treatment to improve the clinical management of this devastating disease.
Significance:
The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma.
Data from mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma
Authors: Zhang Shanshan , Zhou Yu-Feng , Cao Jian , Burley Stephen K. , Wang Hui-Yun , Zheng X.F. Steven
Published: March 2024

Abstract
The SWI/SNF chromatin remodeling complexes control accessibility of chromatin to transcriptional and coregulatory machineries. Chromatin remodeling plays important roles in normal physiology and diseases, particularly cancer. The ARID1A-containing SWI/SNF complex is commonly mutated and thought to be a key tumor suppressor in hepatocellular carcinoma (HCC), but its regulation in response to oncogenic signals remains poorly understood. mTOR is a conserved central controller of cell growth and an oncogenic driver of HCC. Remarkably, cancer mutations in mTOR and SWI/SNF complex are mutually exclusive in human HCC tumors, suggesting that they share a common oncogenic function. Here, we report that mTOR complex 1 (mTORC1) interact with ARID1A and regulates ubiquitination and proteasomal degradation of ARID1A protein. The mTORC1–ARID1A axis promoted oncogenic chromatin remodeling and YAP-dependent transcription, thereby enhancing liver cancer cell growth in vitro and tumor development in vivo. Conversely, excessive ARID1A expression counteracted AKT-driven liver tumorigenesis in vivo. Moreover, dysregulation of this axis conferred resistance to mTOR-targeted therapies. These findings demonstrate that the ARID1A–SWI/SNF complex is a regulatory target for oncogenic mTOR signaling, which is important for mTORC1-driven hepatocarcinogenesis, with implications for therapeutic interventions in HCC.
Significance:
mTOR promotes oncogenic chromatin remodeling by controlling ARID1A degradation, which is important for liver tumorigenesis and response to mTOR- and YAP-targeted therapies in hepatocellular carcinoma.

See related commentary by Pease and Fernandez-Zapico, p. 5608
Data from Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis
Authors: Zhu Mingrui , Huang Yi , Bender Matthew E. , Girard Luc , Kollipara Rahul , Eglenen-Polat Buse , Naito Yujiro , Savage Trisha K. , Huffman Kenneth E. , Koyama Shohei , Kumanogoh Atsushi , Minna John D. , Johnson Jane E. , Akbay Esra A.
Published: March 2024

Abstract
Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with SCLC. This may reflect defects in immune surveillance. Here we illustrate that evading natural killer (NK) surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK-cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. Chromatin immunoprecipitation sequencing showed NKG2DL loci in SCLC are inaccessible compared with NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell–dependent manner. Likewise, histone deacetylase inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma.
Significance:
This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.
Data from Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling
Authors: Kong Cheng , Yan Xuebing , Zhu Yefei , Zhu Huiyuan , Luo Ying , Liu Peipei , Ferrandon Sylvain , Kalady Matthew F. , Gao Renyuan , He Jide , Yin Fang , Qu Xiao , Zheng Jiayi , Gao Yaohui , Wei Qing , Ma Yanlei , Liu Jun-Yan , Qin Huanlong
Published: March 2024

Abstract
Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial–mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer.
Significance:
This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13–EpOME axis in Fn-infected patients.
Data from Spatiotemporal Heterogeneity across Metastases and Organ-Specific Response Informs Drug Efficacy and Patient Survival in Colorectal Cancer
Authors: Zhou Jiawei , Li Quefeng , Cao Yanguang
Published: March 2024

Abstract
The sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it fails to address response heterogeneity across metastases. This study argues that spatiotemporal heterogeneity across metastases and organ-specific response is informative for drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients from five phase III clinical trials. Initially, a metric Gower distance was applied to quantify response heterogeneity across metastases. Next, the spatiotemporal response heterogeneity across anatomic sites, therapies, and KRAS mutation status was assessed and examined for its association with drug efficacy and long-term patient survival. The response of metastatic lesions broadly differed across anatomic sites and therapies. About 60% of patients had at least one lesion respond contrarily from total tumor size. High interlesion heterogeneity was associated with shorter progression-free survival and overall survival. Targeted therapies (bevacizumab or panitumumab) combined with standard chemotherapy reduced interlesion heterogeneity and elicited more favorable effects from liver lesions (P < 0.001) than chemotherapy alone. Moreover, the favorable responses in liver metastases (> 30% shrinkage) were associated with extended patient overall survival (P < 0.001), in contrast to lesions in the lungs and lymph nodes. Altogether, the spatiotemporal response heterogeneity across metastases informed drug efficacy and patient survival, which could improve the current methods for treatment evaluation and patient prognosis.
Significance:
These findings support the modification of RECIST criteria to include individual lesion response to improve assessments of drug efficacy.
Data from MTAP Deficiency–Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting De Novo Purine Synthesis and Glycolysis in Pancreatic Cancer
Authors: Hu Qiangsheng , Qin Yi , Ji Shunrong , Shi Xiuhui , Dai Weixing , Fan Guixiong , Li Shuo , Xu Wenyan , Liu Wensheng , Liu Mengqi , Zhang Zheng , Ye Zeng , Zhou Zhijun , Yang Jingxuan , Zhuo Qifeng , Yu Xianjun , Li Min , Xu Xiaowu
Published: March 2024

Abstract
Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion–mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.
Significance:
This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.
Data from AMBRA1 Promotes TGFβ Signaling via Nonproteolytic Polyubiquitylation of Smad4
Authors: Liu Jinquan , Yuan Bo , Cao Jin , Luo Hongjie , Gu Shuchen , Zhang Mengdi , Ding Ran , Zhang Long , Zhou Fangfang , Hung Mien-Chie , Xu Pinglong , Lin Xia , Jin Jianping , Feng Xin-Hua
Published: March 2024

Abstract
Transforming growth factor β (TGFβ) is prometastatic in advanced cancers and its biological activities are mainly mediated by the Smad family of proteins. Smad4 is the central signal transducer and transcription factor in the TGFβ pathway, yet the underlying mechanisms that govern transcriptional activities of Smad4 are not fully understood. Here, we show that AMBRA1, a member of the DDB1 and CUL4-associated factor (DCAF) family of proteins, serves as the substrate receptor for Smad4 in the CUL4-RING (CRL4) ubiquitin ligase complex. The CRL4-AMBRA1 ubiquitin ligase mediates nonproteolytic polyubiquitylation of Smad4 to enhance its transcriptional functions. Consequently, AMBRA1 potentiated TGFβ signaling and critically promoted TGFβ-induced epithelial-to-mesenchymal transition, migration, and invasion of breast cancer cells. Mouse models of breast cancer demonstrated that AMBRA1 promotes metastasis. Collectively, these results show that CRL4-AMBRA1 facilitates TGFβ-driven metastasis by increasing Smad4 polyubiquitylation, suggesting AMBRA1 may serve as a new therapeutic target in metastatic breast cancer.
Significance:
This study identifies AMBRA1 as a novel regulator of TGFβ signaling and breast cancer metastasis, supporting further exploration of AMBRA1 as a target for cancer therapy.
Data from USP48 Is Upregulated by Mettl14 to Attenuate Hepatocellular Carcinoma via Regulating SIRT6 Stabilization
Authors: Du Lutao , Li Yang , Kang Min , Feng Maoxiao , Ren Yidan , Dai Hongliang , Wang Yumin , Wang Yunshan , Tang Bo
Published: March 2024

Abstract
Exploiting cancer metabolism for the clinical benefit of patients with hepatocellular carcinoma (HCC) is a topic under active investigation. Ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family, is involved in tumor growth, inflammation, and genome stability. However, the role of USP48 in HCC tumorigenesis remains unknown. In this study, we report that expression of USP48 is downregulated in diethylnitrosamine-induced liver tumorigenesis in mice as well as in human HCC. USP48 physically bound and stabilized SIRT6 by K48-linked deubiquitination at the K33 and K128 sites of SIRT6, which impeded metabolic reprogramming to hamper HCC tumorigenesis. Moreover, methyltransferase-like 14 (Mettl14)–induced m6A modification participated in the regulation of USP48 in HCC by maintaining USP48 mRNA stability. Our work uncovers the tumor-suppressive function of the Mettl14–USP48–SIRT6 axis via modulation of glycolysis, providing new insights into the critical roles of metabolic activities in HCC and identifying an attractive target for future treatment studies.
Significance:
These findings demonstrate that USP48 is regulated by Mettl14-induced m6A modification and stabilizes SIRT6 to attenuate HCC glycolysis and malignancy.
Data from ATR/ATM-Mediated Phosphorylation of BRCA1 T1394 Promotes Homologous Recombinational Repair and G2–M Checkpoint Maintenance
Authors: Foo Tzeh K. , Vincelli Gabriele , Huselid Eric , Her Joonyoung , Zheng Haiyan , Simhadri Srilatha , Wang Meiling , Huo Yanying , Li Tao , Yu Xiaochun , Li Hong , Zhao Weixing , Bunting Samuel F. , Xia Bing
Published: March 2024

Abstract
BRCA1 maintains genome integrity and suppresses tumorigenesis by promoting homologous recombination (HR)–mediated repair of DNA double-strand breaks (DSB) and DNA damage-induced cell-cycle checkpoints. Phosphorylation of BRCA1 by ATM, ATR, CHK2, CDK, and PLK1 kinases has been reported to regulate its functions. Here we show that ATR and ATM-mediated phosphorylation of BRCA1 on T1394, a highly conserved but functionally uncharacterized site, is a key modification for its function in the DNA damage response (DDR). Following DNA damage, T1394 phosphorylation ensured faithful repair of DSBs by promoting HR and preventing single-strand annealing, a deletion-generating repair process. BRCA1 T1394 phosphorylation further safeguarded chromosomal integrity by maintaining the G2–M checkpoint. Moreover, multiple patient-derived BRCA1 variants of unknown significance were shown to affect T1394 phosphorylation. These results establish an important regulatory mechanism of BRCA1 function in the DDR and may have implications in the development or prognosis of BRCA1-associated cancers.
Significance:
This study identifies a BRCA1 phosphorylation event critical for its DNA repair function and reveals the functional defects of several BRCA1 variants of unknown significance.
Data from Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma
Authors: Anderson Nicole M. , Qin Xiaodan , Finan Jennifer M. , Lam Andrew , Athoe Jacob , Missiaen Rindert , Skuli Nicolas , Kennedy Annie , Saini Amandeep S. , Tao Ting , Zhu Shizhen , Nissim Itzhak , Look A. Thomas , Qing Guoliang , Simon M. Celeste , Feng Hui
Published: March 2024

Abstract
High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma.
Significance:
These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.
Data from Targeting c-Myc to Overcome Acquired Resistance of EGFR Mutant NSCLC Cells to the Third-Generation EGFR Tyrosine Kinase Inhibitor, Osimertinib
Authors: Zhu Lei , Chen Zhen , Zang Hongjing , Fan Songqing , Gu Jiajia , Zhang Guojing , Sun Kevin D.-Y. , Wang Qiming , He Yong , Owonikoko Taofeek K. , Ramalingam Suresh S. , Sun Shi-Yong
Published: March 2024

Abstract
Osimertinib (AZD9291 or TAGRISSO) is a promising and approved third-generation EGFR tyrosine kinase inhibitor (TKI) for treating patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A fuller understanding of the mechanism of action of osimertinib and its linkage to acquired resistance will enable the development of more efficacious therapeutic strategies. Consequently, we have identified a novel connection between osimertinib or other EGFR-TKIs and c-Myc. Osimertinib rapidly and sustainably decreased c-Myc levels primarily via enhancing protein degradation in EGFR-mutant (EGFRm) NSCLC cell lines and xenograft tumors. c-Myc levels were substantially elevated in different EGFRm NSCLC cell lines with acquired resistance to osimertinib in comparison with their corresponding parental cell lines and could not be reduced any further by osimertinib. Consistently, c-Myc levels were elevated in the majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment compared with their corresponding untreated baseline c-Myc levels. Suppression of c-Myc through knockdown or pharmacologic targeting with BET inhibitors restored the response of resistant cell lines to osimertinib. These findings indicate that c-Myc modulation mediates the therapeutic efficacy of osimertinib and the development of osimertinib acquired resistance. Furthermore, they establish c-Myc as a potential therapeutic target and warrant clinical testing of BET inhibition as a potential strategy to overcome acquired resistance to osimertinib or other EGFR inhibitors.
Significance:
This study demonstrates a critical role of c-Myc modulation in mediating therapeutic efficacy of osimertinib including osimertinib acquired resistance and suggests targeting c-Myc as a potential strategy to overcome osimertinib acquired resistance.
Data from Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer
Authors: Musolf Anthony M. , Simpson Claire L. , Moiz Bilal A. , Pikielny Claudio W. , Middlebrooks Candace D. , Mandal Diptasri , de Andrade Mariza , Cole Michael D. , Gaba Colette , Yang Ping , You Ming , Li Yafang , Kupert Elena Y. , Anderson Marshall W. , Schwartz Ann G. , Pinney Susan M. , Amos Christopher I. , Bailey-Wilson Joan E.
Published: March 2024

Abstract
Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work.
Significance:
This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.
Data from Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-Deficient Non–Small Cell Lung Cancer
Authors: Li Rui , Salehi-Rad Ramin , Crosson William , Momcilovic Milica , Lim Raymond J. , Ong Stephanie L. , Huang Zi Ling , Zhang Tianhao , Abascal Jensen , Dumitras Camelia , Jing Zhe , Park Stacy J. , Krysan Kostyantyn , Shackelford David B. , Tran Linh M. , Liu Bin , Dubinett Steven M.
Published: March 2024

Abstract
LKB1 inactivating mutations are commonly observed in patients with KRAS-mutant non–small cell lung cancer (NSCLC). Although treatment of NSCLC with immune checkpoint inhibitors (ICI) has resulted in improved overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations drive primary resistance to ICIs in NSCLC. Effective therapeutic options that overcome ICI resistance in LKB1-mutant NSCLC are limited. Here, we report that loss of LKB1 results in increased secretion of the C–X–C motif (CXC) chemokines with an NH2-terminal Glu-Leu-Arg (ELR) motif in premalignant and cancerous cells, as well as in genetically engineered murine models (GEMM) of NSCLC. Heightened levels of ELR+ CXC chemokines in LKB1-deficient murine models of NSCLC positively correlated with increased abundance of granulocytic myeloid-derived suppressor cells (G-MDSC) locally within the tumor microenvironment and systemically in peripheral blood and spleen. Depletion of G-MDSCs with antibody or functional inhibition via all-trans-retinoic acid (ATRA) led to enhanced antitumor T-cell responses and sensitized LKB1-deficent murine tumors to PD-1 blockade. Combination therapy with anti–PD-1 and ATRA improved local and systemic T-cell proliferation and generated tumor-specific immunity. Our findings implicate ELR+ CXC chemokine-mediated enrichment of G-MDSCs as a potential mediator of immunosuppression in LKB1-deficient NSCLC and provide a rationale for using ATRA in combination with anti–PD-1 therapy in patients with LKB1-deficient NSCLC refractory to ICIs.
Significance:
These findings show that accumulation of myeloid-derived suppressor cells in LKB1-deficient non–small cell lung cancer can be overcome via treatment with all-trans-retinoic acid, sensitizing tumors to immunotherapy.