bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Epstein–Barr Virus–Encoded Circular RNA CircBART2.2 Promotes Immune Escape of Nasopharyngeal Carcinoma by Regulating PD-L1
Authors: Ge Junshang , Wang Jie , Xiong Fang , Jiang Xianjie , Zhu Kunjie , Wang Yian , Mo Yongzhen , Gong Zhaojian , Zhang Shanshan , He Yi , Li Xiayu , Shi Lei , Guo Can , Wang Fuyan , Zhou Ming , Xiang Bo , Li Yong , Li Guiyuan , Xiong Wei , Zeng Zhaoyang
Published: March 2024

Abstract
Epstein–Barr virus (EBV) infection is an established cause of nasopharyngeal carcinoma (NPC) and is involved in a variety of malignant phenotypes, including tumor immune escape. EBV can encode a variety of circular RNAs (circRNA), however, little is known regarding the biological functions of these circRNAs in NPC. In this study, EBV-encoded circBART2.2 was found to be highly expressed in NPC where it upregulated PD-L1 expression and inhibited T-cell function in vitro and in vivo. circBART2.2 promoted transcription of PD-L1 by binding the helicase domain of RIG-I and activating transcription factors IRF3 and NF-κB, resulting in tumor immune escape. These results elucidate the biological function of circBART2.2, explain a novel mechanism of immune escape caused by EBV infection, and provide a new immunotherapy target for treating NPC.
Significance:
This work demonstrates that circBART2.2 binding to RIG-I is essential for the regulation of PD-L1 and subsequent immune escape in nasopharyngeal carcinoma.
Data from Circulating Small Extracellular Vesicles Activate TYRO3 to Drive Cancer Metastasis and Chemoresistance
Authors: Park Miso , Kim Ji Won , Kim Kyu Min , Kang Seungmin , Kim Wankyu , Kim Jin-Ki , Cho Youngnam , Lee Hyungjae , Baek Moon Chang , Bae Ju-Hyun , Lee Seung Hyun , Jeong Sung Baek , Lim Sung Chul , Jun Dae Won , Cho Sung Yun , Kim Yeonji , Choi Yong June , Kang Keon Wook
Published: March 2024

Abstract
Extracellular vesicles (EV) in the tumor microenvironment have emerged as crucial mediators that promote proliferation, metastasis, and chemoresistance. However, the role of circulating small EVs (csEV) in cancer progression remains poorly understood. In this study, we report that csEV facilitate cancer progression and determine its molecular mechanism. csEVs strongly promoted the migration of cancer cells via interaction with phosphatidylserine of csEVs. Among the three TAM receptors, TYRO3, AXL, and MerTK, TYRO3 mainly interacted with csEVs. csEV-mediated TYRO3 activation promoted migration and metastasis via the epithelial–mesenchymal transition and stimulation of RhoA in invasive cancer cells. Additionally, csEV–TYRO3 interaction induced YAP activation, which led to increased cell proliferation and chemoresistance. Combination treatment with gefitinib and KRCT-6j, a selective TYRO3 inhibitor, significantly reduced tumor volume in xenografts implanted with gefitinib-resistant non–small cell lung cancer cells. The results of this study show that TYRO3 activation by csEVs facilitates cancer cell migration and chemoresistance by activation of RhoA or YAP, indicating that the csEV/TYRO3 interaction may serve as a potential therapeutic target for aggressive cancers in the clinic.
Significance:
These findings demonstrate that circulating extracellular vesicles are a novel driver in migration and survival of aggressive cancer cells via TYRO3 activation.
Data from Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma
Authors: Lee Chang-Lung , Brock Kennedy D. , Hasapis Stephanie , Zhang Dadong , Sibley Alexander B. , Qin Xiaodi , Gresham Jeremy S. , Caraballo Isibel , Luo Lixia , Daniel Andrea R. , Hilton Matthew J. , Owzar Kouros , Kirsch David G.
Published: March 2024

Abstract
Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-cell lymphoblastic leukemia/lymphoma. Here we aimed to identify key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/−, and KrasLA1 mice were not observed to harbor significantly higher numbers of nonsynonymous somatic mutations compared with thymic lymphomas from unirradiated p53−/− mice. However, distinct patterns of recurrent mutations arose in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Reporter mice for activation of Notch1 signaling revealed that total-body irradiation (TBI) enriched Notch1hi CD44+ thymocytes that could propagate in vivo after thymocyte transplantation. Mechanistically, genetic inhibition of Notch1 signaling in immature thymocytes prevented formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, these results demonstrate a critical role of activated Notch1 signaling in driving multistep carcinogenesis of thymic lymphoma following TBI in p53 WT mice.
Significance:
These findings reveal the mutational landscape and key drivers in murine radiation-induced thymic lymphoma, a classic animal model that has been used to study radiation carcinogenesis for over 70 years.
Data from Porphyromonas gingivalis Promotes Colorectal Carcinoma by Activating the Hematopoietic NLRP3 Inflammasome
Authors: Wang Xi , Jia Yiqun , Wen Liling , Mu Wenxin , Wu Xianrui , Liu Tao , Liu Xiangqi , Fang Juan , Luan Yizhao , Chen Ping , Gao Jinlong , Nguyen Ky-Anh , Cui Jun , Zeng Gucheng , Lan Ping , Chen Qianming , Cheng Bin , Wang Zhi
Published: March 2024

Abstract
Porphyromonas gingivalis (P. gingivalis) is a keystone periodontal pathogen associated with various digestive cancers. However, whether P. gingivalis can promote colorectal cancer and the underlying mechanism associated with such promotion remains unclear. In this study, we found that P. gingivalis was enriched in human feces and tissue samples from patients with colorectal cancer compared with those from patients with colorectal adenoma or healthy subjects. Cohort studies demonstrated that P. gingivalis infection was associated with poor prognosis in colorectal cancer. P. gingivalis increased tumor counts and tumor volume in the ApcMin/+ mouse model and increased tumor growth in orthotopic rectal and subcutaneous carcinoma models. Furthermore, orthotopic tumors from mice exposed to P. gingivalis exhibited tumor-infiltrating myeloid cell recruitment and a proinflammatory signature. P. gingivalis promoted colorectal cancer via NLRP3 inflammasome activation in vitro and in vivo. NLRP3 chimeric mice harboring orthotopic tumors showed that the effect of NLRP3 on P. gingivalis pathogenesis was mediated by hematopoietic sources. Collectively, these data suggest that P. gingivalis contributes to colorectal cancer neoplasia progression by activating the hematopoietic NLRP3 inflammasome.
Significance:
This study demonstrates that the periodontal pathogen P. gingivalis can promote colorectal tumorigenesis by recruiting myeloid cells and creating a proinflammatory tumor microenvironment.
Data from The BRCA1 Pseudogene Negatively Regulates Antitumor Responses through Inhibition of Innate Immune Defense Mechanisms
Authors: Han Yoo Jane , Zhang Jing , Lee Jung-Hyun , Mason Jennifer M. , Karginova Olga , Yoshimatsu Toshio F. , Hao Qinyu , Hurley Ian , Brunet Laia Paré , Prat Aleix , Prasanth Kannanganattu V. , Gack Michaela U. , Olopade Olufunmilayo I.
Published: March 2024

Abstract
Innate immune defense mechanisms play a pivotal role in antitumor responses. Recent evidence suggests that antiviral innate immunity is regulated not only by exogenous non–self-RNA but also by host-derived pseudogene RNAs. A growing body of evidence also indicates a biological role for pseudogenes as gene expression regulators or immune modulators. Here, we report an important role for BRCA1P1, the pseudogene of the BRCA1 tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. BRCA1P1 expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA-BRCA1P1 is increased in breast tumors compared with normal breast tissues. Depletion of BRCA1P1 induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, BRCA1P1-deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of BRCA1P1 increases host innate immune responses and restricts virus replication. In converse, overexpression of BRCA1P1 reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA-BRCA1P1 is localized in the nucleus, binds to the NF-κB subunit RelA, and negatively regulates antiviral gene expression. Finally, in a xenograft mouse model of breast cancer, depletion of BRCA1P1 stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for BRCA1P1 in innate immune defense mechanisms and antitumor responses. This mechanism of antiviral immunity regulated by a host-derived pseudogene RNA may guide the development of novel therapies targeting immune responses in breast cancer.
Significance:
This study identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and antitumor responses through regulation of antiviral gene expression.
Data from Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition
Authors: Butler Lisa M. , Mah Chui Yan , Machiels Jelle , Vincent Andrew D. , Irani Swati , Mutuku Shadrack M. , Spotbeen Xander , Bagadi Muralidhararao , Waltregny David , Moldovan Max , Dehairs Jonas , Vanderhoydonc Frank , Bloch Katarzyna , Das Rajdeep , Stahl Jurgen , Kench James G. , Gevaert Thomas , Derua Rita , Waelkens Etienne , Nassar Zeyad D. , Selth Luke A. , Trim Paul J. , Snel Marten F. , Lynn David J. , Tilley Wayne D. , Horvath Lisa G. , Centenera Margaret M. , Swinnen Johannes V.
Published: March 2024

Abstract
Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the “lipidome” in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting.
Significance:
This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.
Data from Single-Cell RNA Sequencing Reveals the Cellular Origin and Evolution of Breast Cancer in BRCA1 Mutation Carriers
Authors: Hu Li , Su Liming , Cheng Hainan , Mo Chunling , Ouyang Tao , Li Jinfeng , Wang Tianfeng , Fan Zhaoqing , Fan Tie , Lin Benyao , Zhang Jianguang , Xie Yuntao
Published: March 2024

Abstract
The cell of origin and the development of breast cancer are not fully elucidated in BRCA1 mutation carriers, especially for estrogen receptor (ER)–positive breast cancers. Here, we performed single-cell RNA sequencing (RNA-seq) on 82,122 cells isolated from the breast cancer tissues and adjacent or prophylactic normal breast tissues from four BRCA1 mutation carriers and three noncarriers. Whole-exome sequencing was performed on breast tumors from the four BRCA1 mutation carriers; for validation, bulk RNA-seq was performed on adjacent normal breast tissues from eight additional BRCA1 mutation carriers and 14 noncarriers. Correlation analyses suggested that breast cancers in BRCA1 mutation carriers might originate from luminal cells. The aberrant luminal progenitor cells with impaired differentiation were significantly increased in normal breast tissues in BRCA1 mutation carriers compared with noncarriers. These observations were further validated by the bulk RNA-seq data from additional BRCA1 mutation carriers. These data suggest that the cell of origin of basal-like breast tumors (ERneg) in BRCA1 mutation carriers might be luminal progenitor cells. The expression of TP53 and BRCA1 was decreased in luminal progenitor cells from normal breast tissue in BRCA1 mutation carriers, which might trigger the basal/mesenchymal transition of luminal progenitors and might result in basal-like tumor development. Furthermore, ERhigh luminal tumors might originate from mature luminal cells. Our study provides in-depth evidence regarding the cells of origin of different breast cancer subtypes in BRCA1 mutation carriers.
Significance:
Single-cell RNA-seq data indicate that basal-like breast cancer (ERneg) might originate from luminal progenitors, and ERhigh luminal breast cancer might originate from mature luminal cells in BRCA1 mutation carriers.
Data from HDAC5 Loss Impairs RB Repression of Pro-Oncogenic Genes and Confers CDK4/6 Inhibitor Resistance in Cancer
Authors: Zhou Yingke , Jin Xin , Ma Jian , Ding Donglin , Huang Zhenlin , Sheng Haoyue , Yan Yuqian , Pan Yunqian , Wei Ting , Wang Liguo , Wu Heshui , Huang Haojie
Published: March 2024

Abstract
The tumor-suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in histone deacetylase (HDAC) proteins such as HDAC1. Here, we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorylation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell-cycle–related pro-oncogenic genes. HDAC5 loss also conferred resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells in vitro and prostate tumors in vivo, but this effect was overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and define a new mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells.
Significance:
This study defines a previously uncharacterized role of HDAC5 in tumor suppression and provides a viable strategy to overcome CDK4/6 inhibitor resistance in HDAC5-deficent cancer.
Data from SHP2-Mediated Inhibition of DNA Repair Contributes to cGAS–STING Activation and Chemotherapeutic Sensitivity in Colon Cancer
Authors: Wei Bin , Xu Lingyan , Guo Wenjie , Wang Yuanyuan , Wu Jingjing , Li Xiaofei , Cai Xiaomin , Hu Jinbo , Wang Meijing , Xu Qiang , Liu Wen , Gu Yanhong
Published: March 2024

Abstract
As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase–stimulator of IFN genes (STING) pathway plays an important role in antitumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell–intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated PARP1 after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon cancer models, in part via STING pathway-mediated antitumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon cancer.
Significance:
Dephosphorylation of PARP1 by SHP2 simultaneously suppresses DNA repair and enhances STING pathway-mediated antitumor immunity, highlighting SHP2 activation as a potential therapeutic approach in colon cancer.
Data from Mesenchymal Stem Cell–Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region
Authors: Sandiford Oleta A. , Donnelly Robert J. , El-Far Markos H. , Burgmeyer Lisa M. , Sinha Garima , Pamarthi Sri Harika , Sherman Lauren S. , Ferrer Alejandra I. , DeVore Dariana E. , Patel Shyam A. , Naaldijk Yahaira , Alonso Sara , Barak Pradeep , Bryan Margarette , Ponzio Nicholas M. , Narayanan Ramaswamy , Etchegaray Jean-Pierre , Kumar Rakesh , Rameshwar Pranela
Published: March 2024

Abstract
In the bone marrow (BM), breast cancer cells (BCC) can survive in dormancy for decades as cancer stem cells (CSC), resurging as tertiary metastasis. The endosteal region where BCCs exist as CSCs poses a challenge to target them, mostly due to the coexistence of endogenous hematopoietic stem cells. This study addresses the early period of dormancy when BCCs enter BM at the perivascular region to begin the transition into CSCs, which we propose as the final step in dormancy. A two-step process comprises the Wnt-β-catenin pathway mediating BCC dedifferentiation into CSCs at the BM perivascular niche. At this site, BCCs responded to two types of mesenchymal stem cell (MSC)–released extracellular vesicles (EV) that may include exosomes. Early released EVs began the transition into cycling quiescence, DNA repair, and reorganization into distinct BCC subsets. After contact with breast cancer, the content of EVs changed (primed) to complete dedifferentiation into a more homogeneous population with CSC properties. BCC progenitors (Oct4alo), which are distant from CSCs in a hierarchical stratification, were sensitive to MSC EVs. Despite CSC function, Oct4alo BCCs expressed multipotent pathways similar to CSCs. Oct4alo BCCs dedifferentiated and colocalized with MSCs (murine and human BM) in vivo. Overall, these findings elucidate a mechanism of early dormancy at the BM perivascular region and provide evidence of epigenome reorganization as a potential new therapy for breast cancer.
Significance:
These findings describe how the initial process of dormancy and dedifferentiation of breast cancer cells at the bone marrow perivascular niche requires mesenchymal stem cell–derived exosomes, indicating a potential target for therapeutic intervention.
Data from M6A Demethylase ALKBH5 Regulates PD-L1 Expression and Tumor Immunoenvironment in Intrahepatic Cholangiocarcinoma
Authors: Qiu Xinyao , Yang Shuai , Wang Shan , Wu Jianmin , Zheng Bo , Wang Kaiting , Shen Siyun , Jeong Seogsong , Li Zhixuan , Zhu Yanjing , Wu Tong , Wu Xuan , Wu Rui , Liu Weiwei , Wang Hong-Yang , Chen Lei
Published: March 2024

Abstract
N6-methyladenosine (m6A) has been reported as an important mechanism of posttranscriptional regulation. Programmed death-ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. Here we report ALKBH5 as an important m6A demethylase that orchestrates PD-L1 expression in intrahepatic cholangiocarcinoma (ICC). Regulation of PD-L1 expression by ALKBH5 was confirmed in human ICC cell lines. Sequencing of the m6A methylome identified PD-L1 mRNA as a direct target of m6A modification whose levels were regulated by ALKBH5. Furthermore, ALKBH5 and PD-L1 mRNA were shown to interact. ALKBH5 deficiency enriched m6A modification in the 3′UTR region of PD-L1 mRNA, thereby promoting its degradation in a YTHDF2-dependent manner. In vitro and in vivo, tumor-intrinsic ALKBH5 inhibited the expansion and cytotoxicity of T cells by sustaining tumor cell PD-L1 expression. The ALKBH5-PD-L1–regulating axis was further confirmed in human ICC specimens. Single-cell mass cytometry analysis unveiled a complex role of ALKBH5 in the tumor immune microenvironment by promoting the expression of PD-L1 on monocytes/macrophages and decreasing the infiltration of myeloid-derived suppressor-like cells. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with strong nuclear expression patterns of ALKBH5 are more sensitive to anti-PD1 immunotherapy. Collectively, these results describe a new regulatory mechanism of PD-L1 by mRNA epigenetic modification by ALKBH5 and the potential role of ALKBH5 in immunotherapy response, which might provide insights for cancer immunotherapies.
Significance:
This study identifies PD-L1 mRNA as a target of ALKBH5 and reveals a role for ALKBH5 in regulating the tumor immune microenvironment and immunotherapy efficacy.
Data from A Wnt-Independent LGR4–EGFR Signaling Axis in Cancer Metastasis
Authors: Yue Fei , Jiang Weiyu , Ku Amy T. , Young Adelaide I.J. , Zhang Weijie , Souto Eric P. , Gao Yankun , Yu Zihan , Wang Yi , Creighton Chad J. , Nagi Chandandeep , Wang Tao , Hilsenbeck Susan G. , Feng Xin-Hua , Huang Shixia , Coarfa Cristian , Zhang Xiang H.-F. , Liu Qingyun , Lin Xia , Li Yi
Published: March 2024

Abstract
Leucine-rich repeat-containing G protein–coupled receptors 4, 5, and 6 (LGR4/5/6) play critical roles in development and cancer. The widely accepted mechanism is that these proteins, together with their R-spondin ligands, stabilize Wnt receptors, thus potentiating Wnt signaling. Here we show that LGR4 enhanced breast cancer cell metastasis even when Wnt signaling was deactivated pharmacologically or genetically. Furthermore, LGR4 mutants that cannot potentiate Wnt signaling nevertheless promoted breast cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Multiomic screening identified EGFR as a crucial mediator of LGR4 activity in cancer progression. Mechanistically, LGR4 interacted with EGFR and blocked EGFR ubiquitination and degradation, resulting in persistent EGFR activation. Together, these data uncover a Wnt-independent LGR4–EGFR signaling axis with broad implications for cancer progression and targeted therapy.
Significance:
This work demonstrates a Wnt-independent mechanism by which LGR4 promotes cancer metastasis.

See related commentary by Stevens and Williams, p. 4397
Data from Mesothelin-Specific CAR T Cells Target Ovarian Cancer
Authors: Schoutrop Esther , El-Serafi Ibrahim , Poiret Thomas , Zhao Ying , Gultekin Okan , He Rui , Moyano-Galceran Lidia , Carlson Joseph W. , Lehti Kaisa , Hassan Moustapha , Magalhaes Isabelle , Mattsson Jonas
Published: March 2024

Abstract
New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4–1BB (MBBz) CAR T cells induced long-term remission in some SKOV3–bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG3 in an antigen-dependent manner while MSLN+ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating that coinhibitory pathways impede CAR T-cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z- and MBBz-treated mice characterized by elevated T-cell secreted factors that had increased survival, higher CD8+ T-cell tumor infiltration, less exhausted CAR T-cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer.
Significance:
These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.
Data from PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer
Authors: Yu Tian-Jian , Liu Ying-Ying , Li Xiao-Guang , Lian Bi , Lu Xun-Xi , Jin Xi , Shao Zhi-Ming , Hu Xin , Di Gen-Hong , Jiang Yi-Zhou
Published: March 2024

Abstract
Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC.
Significance:
A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.
Data from Platelet TLR4-ERK5 Axis Facilitates NET-Mediated Capturing of Circulating Tumor Cells and Distant Metastasis after Surgical Stress
Authors: Ren Jinghua , He Jiayi , Zhang Hongji , Xia Yujia , Hu Zhiwei , Loughran Patricia , Billiar Timothy , Huang Hai , Tsung Allan
Published: March 2024

Abstract
Surgical removal of malignant tumors is a mainstay in controlling most solid cancers. However, surgical insult also increases the risk of tumor recurrence and metastasis. Tissue trauma activates the innate immune system locally and systemically, mounting an inflammatory response. Platelets and neutrophils are two crucial players in the early innate immune response that heals tissues, but their actions may also contribute to cancer cell dissemination and distant metastasis. Here we report that surgical stress–activated platelets enhance the formation of platelet-tumor cell aggregates, facilitating their entrapment by neutrophil extracellular traps (NET) and subsequent distant metastasis. A murine hepatic ischemia/reperfusion (I/R) injury model of localized surgical stress showed that I/R promotes capturing of aggregated circulating tumor cells (CTC) by NETs and eventual metastasis to the lungs, which are abrogated when platelets are depleted. Hepatic I/R also increased deposition of NETs within the lung microvasculature, but depletion of platelets had no effect. TLR4 was essential for platelet activation and platelet-tumor cell aggregate formation in an ERK5-GPIIb/IIIa integrin-dependent manner. Such aggregation facilitated NET-mediated capture of CTCs in vitro under static and dynamic conditions. Blocking platelet activation or knocking out TLR4 protected mice from hepatic I/R-induced metastasis with no CTC entrapment by NETs. These results uncover a novel mechanism where platelets and neutrophils contribute to metastasis in the setting of acute inflammation. Targeted disruption of the interaction between platelets and NETs holds therapeutic promise to prevent postoperative distant metastasis.
Significance:
Targeting platelet activation via TLR4/ERK5/integrin GPIIb/IIIa signaling shows potential for preventing NET-driven distant metastasis in patients post-resection.
Data from Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate Cancer
Authors: Kumar Rajendra , Mendonca Janet , Owoyemi Olutosin , Boyapati Kavya , Thomas Naiju , Kanacharoen Suthicha , Coffey Max , Topiwala Deven , Gomes Carolina , Ozbek Busra , Jones Tracy , Rosen Marc , Dong Liang , Wiens Sadie , Brennen W. Nathaniel , Isaacs John T. , De Marzo Angelo M. , Markowski Mark C. , Antonarakis Emmanuel S. , Qian David Z. , Pienta Kenneth J. , Pardoll Drew M. , Carducci Michael A. , Denmeade Samuel R. , Kachhap Sushant K.
Published: March 2024

Abstract
The discovery that androgens play an important role in the progression of prostate cancer led to the development of androgen deprivation therapy (ADT) as a first line of treatment. However, paradoxical growth inhibition has been observed in a subset of prostate cancer upon administration of supraphysiologic levels of testosterone (SupraT), both experimentally and clinically. Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive prostate cancer cells. This was initiated by the induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activated nucleic acid sensors converge on NFκB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT resulted in increased migration of cytotoxic immune cells to tumor beds in xenograft models and patient tumors. Collectively, these findings indicate that SupraT may inhibit a subset of prostate cancer by activating nucleic acid sensors and downstream immune signaling.
Significance:
This study demonstrates that supraphysiologic testosterone induces two parallel autophagy-mediated processes, ferritinophagy and nucleophagy, which then activate nucleic acid sensors to drive immune signaling pathways in prostate cancer.
Data from Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization
Authors: Kumagai Ken , Shimizu Takahiro , Takai Atsushi , Kakiuchi Nobuyuki , Takeuchi Yasuhide , Hirano Tomonori , Takeda Haruhiko , Mizuguchi Aya , Teramura Mari , Ito Takahiko , Iguchi Eriko , Nikaido Mitsuhiro , Eso Yuji , Takahashi Ken , Ueda Yoshihide , Miyamoto Shin'ichi , Obama Kazutaka , Ogawa Seishi , Marusawa Hiroyuki , Seno Hiroshi
Published: March 2024

Abstract
Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; 19 single glands in the noninflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole-exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. In addition, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and The Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired CN aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable with those of IGC, contributing to field cancerization.
Significance:
This study contributes to our understanding of gastric intestinal metaplasia as a risk factor for gastric adenocarcinoma via their multifocal expansion and acquisition of CNAs and somatic mutations.
Data from Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis
Authors: Wei Yi-ting , Wang Xu-ru , Yan Chunguang , Huang Fang , Zhang Yunpeng , Liu Xueming , Wen Zhi-fa , Sun Xiao-tong , Zhang Yue , Chen Yong-qiang , Gao Rong , Pan Ning , Wang Li-xin
Published: March 2024

Abstract
The immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5′-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer.
Significance:
Thymosin α-1 improves the curative effect of chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis.
Data from JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA
Authors: Ni Zegui , Sun Pengli , Zheng Jin , Wu Mingqing , Yang Congcong , Cheng Maosheng , Yin Mingwei , Cui Chengying , Wang Guangxian , Yuan Lin , Gao Qian , Li Yang
Published: March 2024

Abstract
The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3′-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer.
Significance:
The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.
Data from EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody–Drug Conjugate HER3–DXd
Authors: Haikala Heidi M. , Lopez Timothy , Köhler Jens , Eser Pinar O. , Xu Man , Zeng Qing , Teceno Tyler J. , Ngo Kenneth , Zhao Yutong , Ivanova Elena V. , Bertram Arrien A. , Leeper Brittaney A. , Chambers Emily S. , Adeni Anika E. , Taus Luke J. , Kuraguchi Mari , Kirschmeier Paul T. , Yu Channing , Shiose Yoshinobu , Kamai Yasuki , Qiu Yang , Paweletz Cloud P. , Gokhale Prafulla C. , Jänne Pasi A.
Published: March 2024

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-mutant non–small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in EGFR-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3–DXd is an antibody–drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3–DXd across a series of EGFR inhibitor–resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3–DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3–DXd. The combination of osimertinib and HER3–DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients.
Significance:
EGFR inhibition leads to increased HER3 membrane expression and promotes HER3–DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3–DXd combination in EGFR-mutant lung cancer.

See related commentary by Lim et al., p. 18
Data from LncRNA Uc003xsl.1-Mediated Activation of the NFκB/IL8 Axis Promotes Progression of Triple-Negative Breast Cancer
Authors: Xu Ying , Ren Wei , Li Qingjian , Duan Chaohui , Lin Xiaorong , Bi Zhuofei , You Kaiyun , Hu Qian , Xie Ning , Yu Yunfang , Xu Xiaoding , Hu Hai , Yao Herui
Published: March 2024

Abstract
Aberrant activation of NFκB orchestrates a critical role in tumor carcinogenesis; however, the regulatory mechanisms underlying this activation are not fully understood. Here we report that a novel long noncoding RNA (lncRNA) Uc003xsl.1 is highly expressed in triple-negative breast cancer (TNBC) and correlates with poor outcomes in patients with TNBC. Uc003xsl.1 directly bound nuclear transcriptional factor NFκB-repressing factor (NKRF), subsequently preventing NKRF from binding to a specific negative regulatory element in the promoter of the NFκB-responsive gene IL8 and abolishing the negative regulation of NKRF on NFκB-mediated transcription of IL8. Activation of the NFκB/IL8 axis promoted the progression of TNBC. Trop2-based antibody–drug conjugates have been applied in clinical trials in TNBC. In this study, a Trop2-targeting, redox-responsive nanoparticle was developed to systematically deliver Uc003xsl.1 siRNA to TNBC cells in vivo, which reduced Uc003xsl.1 expression and suppressed TNBC tumor growth and metastasis. Therefore, targeting Uc003xsl.1 to suppress the NFκB/IL8 axis represents a promising therapeutic strategy for TNBC treatment.
Significance:
These findings identify an epigenetic-driven NFκB/IL8 cascade initiated by a lncRNA, whose aberrant activation contributes to tumor metastasis and poor survival in patients with triple-negative breast cancer.
Data from Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis
Authors: Sendi Hossein , Yazdimamaghani Mostafa , Hu Mengying , Sultanpuram Nikhila , Wang Jie , Moody Amber S. , McCabe Ellie , Zhang Jiajie , Graboski Amanda , Li Liantao , Rojas Juan D. , Dayton Paul A. , Huang Leaf , Wang Andrew Z.
Published: March 2024

Abstract
Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA.
Significance:
Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.
Data from Genome-Wide Association Analyses Identify CATSPERE as a Mediator of Colorectal Cancer Susceptibility and Progression
Authors: Meng Yixuan , Du Mulong , Gu Dongying , Li Chen , Li Shuwei , Zhang Qiuyi , Ben Shuai , Zhu Qiuyuan , Xin Junyi , Zhang Zhengdong , Hu Zhibin , Shen Hongbing , Jiang Kewei , Wang Meilin
Published: March 2024

Abstract
Genome-wide association studies (GWAS) have revealed numerous genetic loci associated with colorectal cancer risk, but the mechanisms underlying these loci have not been comprehensively elucidated. In this study, we performed a GWAS meta-analysis with a two-stage replication strategy by combining eight colorectal cancer cohorts encompassing 7,186 cases and 8,512 controls in Chinese populations, accompanied by an evaluation encompassing 29,832 cases and 406,694 controls in European populations. The genetic variant rs505706 A>G, located at chr1q44 in the upstream region of catsper channel auxiliary subunit epsilon (CATSPERE), was associated with colorectal cancer risk and exhibited genome-wide significance (OR, 0.73; 95% confidence interval, 0.67–0.80; P = 9.75 × 10–12). Cell line and animal models were applied to assess the biological function of the genetic risk variant and the corresponding susceptibility gene. Genetically, the G allele of rs505706 resulted in long-range regulatory effects, reducing the binding affinity of POU2F1 for the CATSPERE promoter and thus abolishing the inhibitory effect of POU2F1 on CATSPERE transcription. Phenotypically, CATSPERE upregulation attenuated tumor growth in both colorectal cancer cells and xenograft models. Mechanistically, CATSPERE promoted calcium ion influx and apoptotic pathway activity. In zebrafish models, CATSPERE exerted pleiotropic effects, enhancing the progression of colorectal cancer. Collectively, these findings highlight a colorectal cancer susceptibility locus that acts to remotely modulate the activity of CATSPERE, a gene that mediates multiple functions involved in colorectal tumorigenesis and progression.
Significance:
A GWAS meta-analysis identifies a novel susceptibility locus harboring a genetic risk variant that mediates pleiotropic biological effects in colorectal tumorigenesis and progression.
Data from The Roles of RNA Helicases in DNA Damage Repair and Tumorigenesis Reveal Precision Therapeutic Strategies
Authors: Xie Jinru , Wen Ming , Zhang Jiao , Wang Zheng , Wang Meng , Qiu Yanfang , Zhao Wenchao , Zhu Fang , Yao Mianfeng , Rong Zhuoxian , Hu Wenfeng , Pei Qian , Sun Xiaoxiang , Li Jinchen , Mao Zhiyong , Sun Lun-Quan , Tan Rong
Published: March 2024

Abstract
DEAD-box RNA helicases belong to a large group of RNA-processing factors and play vital roles unwinding RNA helices and in ribosomal RNA biogenesis. Emerging evidence indicates that RNA helicases are associated with genome stability, yet the mechanisms behind this association remain poorly understood. In this study, we performed a comprehensive analysis of RNA helicases using multiplatform proteogenomic databases. More than 50% (28/49) of detected RNA helicases were highly expressed in multiple tumor tissues, and more than 60% (17/28) of tumor-associated members were directly involved in DNA damage repair (DDR). Analysis of repair dynamics revealed that these RNA helicases are engaged in an extensively broad range of DDR pathways. Among these factors is DDX21, which was prominently upregulated in colorectal cancer. The high expression of DDX21 gave rise to frequent chromosome exchange and increased genome fragmentation. Mechanistically, aberrantly high expression of DDX21 triggered inappropriate repair processes by delaying homologous recombination repair and increasing replication stress, leading to genome instability and tumorigenesis. Treatment with distinct chemotherapeutic drugs caused higher lethality to cancer cells with genome fragility induced by DDX21, providing a perspective for treatment of tumors with high DDX21 expression. This study revealed the role of RNA helicases in DNA damage and their associations with cancer, which could expand therapeutic strategies and improve precision treatments for cancer patients with high expression of RNA helicases.
Significance:
The involvement of the majority of tumor-associated RNA helicases in the DNA damage repair process suggests a new mechanism of tumorigenesis and offers potential alternative therapeutic strategies for cancer.