bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from BET Inhibitors Potentiate Chemotherapy and Killing of SPOP-Mutant Colon Cancer Cells via Induction of DR5
Authors: Tan Xiao , Tong Jingshan , Wang Yi-Jun , Fletcher Rochelle , Schoen Robert E. , Yu Jian , Shen Liangfang , Zhang Lin
Published: March 2023

Abstract
Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.

Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.
Data from Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma
Authors: Sato Takashi , Yoo Seungyeul , Kong Ranran , Sinha Abhilasha , Chandramani-Shivalingappa Prashanth , Patel Ayushi , Fridrikh Maya , Nagano Osamu , Masuko Takashi , Beasley Mary Beth , Powell Charles A. , Zhu Jun , Watanabe Hideo
Published: March 2023

Abstract
Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its nonstratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed “neural” subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein–protein interaction and genomic cooccupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the “neural” LUSC. Forced expression of p63 downregulated Brn2 in the “neural” LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK–ERK pathways, suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted.
Significance:
Epigenomic profiling reveals a novel subtype of lung squamous cell carcinoma with neural differentiation.
Data from Isoflavone ME-344 Disrupts Redox Homeostasis and Mitochondrial Function by Targeting Heme Oxygenase 1
Authors: Zhang Leilei , Zhang Jie , Ye Zhiwei , Manevich Yefim , Ball Lauren E. , Bethard Jennifer R. , Jiang Yu-Lin , Broome Ann-Marie , Dalton Annamarie C. , Wang Gavin Y. , Townsend Danyelle M. , Tew Kenneth D.
Published: March 2023

Abstract
ME-344 is a second-generation isoflavone with unusual cytotoxic properties that is in clinical testing in cancer. To identify targets that contribute to its anticancer activity and therapeutic index, we used lung cancer cell lines that are naturally sensitive or resistant to ME-344. Drug-induced apoptosis was linked with enhanced levels of reactive oxygen species and this initiated a nuclear erythroid factor 2-like 2 signaling response, downstream of which, heme oxygenase 1 (HO-1) was also found to be time-dependently inhibited by ME-344. ME-344 specifically bound to, and altered, HO-1 structure and increased HO-1 translocation from the rough endoplasmic reticulum to mitochondria, but only in drug-sensitive cells. These effects did not occur in either drug-resistant or primary lung fibroblasts with lower HO-1 basal levels. HO-1 was confirmed as a drug target by using surface plasmon resonance technology and through interaction with a clickable ME-344 compound (M2F) and subsequent proteomic analyses, showing direct binding of ME-344 with HO-1. Proteomic analysis showed that clusters of mitochondrial proteins, including voltage-dependent anion-selective channels, were also impacted by ME-344. Human lung cancer biopsies expressed higher levels of Nrf2 and HO-1 compared with normal tissues. Overall, our data show that ME-344 inhibits HO-1 and impacts its mitochondrial translocation. Other mitochondrial proteins are also affected, resulting in interference in tumor cell redox homeostasis and mitochondrial function. These factors contribute to a beneficial therapeutic index and support continued clinical development of ME-344.
Significance:
A novel cytotoxic isoflavone is shown to inhibit heme oxygenase, a desirable yet elusive target that disrupts redox homeostasis causing cell death.
Data from A PolH Transcript with a Short 3′UTR Enhances PolH Expression and Mediates Cisplatin Resistance
Authors: Zhang Jin , Sun Wenqiang , Ren Cong , Kong Xiangmudong , Yan Wensheng , Chen Xinbin
Published: March 2023

Abstract
Platinum-based anticancer drugs are widely used as a first-line drug for cancers, such as non–small cell lung carcinoma (NSCLC) and bladder cancer. However, the efficacy is limited due to intrinsic or acquired resistance to these drugs. DNA polymerase eta (PolH, Polη) belongs to the Y-family of DNA polymerases and mediates DNA translesion synthesis, a major mechanism for DNA damage tolerance. Here, we showed that a high level of PolH is associated with cisplatin resistance in lung and bladder cancer. Consistent with this, loss of PolH markedly attenuates cisplatin resistance in both cisplatin-sensitive and cisplatin-resistant lung cancer cells. Interestingly, we found that due to the presence of multiple polyadenylation sites, alternative polyadenylation (APA) produces three major PolH transcripts with various lengths of 3′untranslated region (3′UTR; 427-/2516-/6245-nt). We showed that the short PolH transcript with 427-nt 3′UTR is responsible for high expression of PolH in various cisplatin-resistant lung and bladder cancer cell lines. Importantly, loss of the short PolH transcript significantly sensitizes cancer cells to cisplatin treatment. Moreover, we found that miR-619 selectively inhibits the ability of the long PolH transcript with 6245-nt 3′UTR to produce PolH protein and, subsequently, PolH-dependent cell growth. Together, our data suggest that PolH expression is controlled by APA and that the short PolH transcript produced by APA can escape miR-619–mediated repression and, subsequently, confers PolH-mediated cisplatin resistance.
Significance:
A short PolH transcript produced by alternative polyadenylation escapes repression by miR-619 and confers resistance to cisplatin.
Data from BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents
Authors: Kanakkanthara Arun , Kurmi Kiran , Ekstrom Thomas L. , Hou Xiaonan , Purfeerst Emma R. , Heinzen Ethan P. , Correia Cristina , Huntoon Catherine J. , O'Brien Daniel , Wahner Hendrickson Andrea E. , Dowdy Sean C. , Li Hu , Oberg Ann L. , Hitosugi Taro , Kaufmann Scott H. , Weroha S. John , Karnitz Larry M.
Published: March 2023

Abstract
BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression.
Significance:
Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer.
Data from SET Domain–Containing Protein 4 Epigenetically Controls Breast Cancer Stem Cell Quiescence
Authors: Ye Sen , Ding Yan-Fu , Jia Wen-Huan , Liu Xiao-Li , Feng Jing-Yi , Zhu Qian , Cai Sun-Li , Yang Yao-Shun , Lu Qian-Yun , Huang Xue-Ting , Yang Jin-Shu , Jia Sheng-Nan , Ding Guo-Ping , Wang Yue-Hong , Zhou Jiao-Jiao , Chen Yi-Ding , Yang Wei-Jun
Published: March 2023

Abstract
Quiescent cancer stem cells (CSC) play important roles in tumorigenesis, relapse, and resistance to chemoradiotherapy. However, the determinants of CSC quiescence and how they sustain themselves to generate tumors and relapse beyond resistance to chemoradiotherapy remains unclear. Here, we found that SET domain–containing protein 4 (SETD4) epigenetically controls breast CSC (BCSC) quiescence by facilitating heterochromatin formation via H4K20me3 catalysis. H4K20me3 localized to the promoter regions and regulated the expression of a set of genes in quiescent BCSCs (qBCSC). SETD4-defined qBCSCs were resistant to chemoradiotherapy and promoted tumor relapse in a mouse model. Upon activation, a SETD4-defined qBCSC sustained itself in a quiescent state by asymmetric division and concurrently produced an active daughter cell that proliferated to produce a cancer cell population. Single-cell sequence analysis indicated that SETD4+ qBCSCs clustered together as a distinct cell type within the heterogeneous BCSC population. SETD4-defined quiescent CSCs were present in multiple cancer types including gastric, cervical, ovarian, liver, and lung cancers and were resistant to chemotherapy. SETD4-defined qBCSCs had a high tumorigenesis potential and correlated with malignancy and chemotherapy resistance in clinical breast cancer patients. Taken together, the results from our previous study and current study on six cancer types reveal an evolutionarily conserved mechanism of cellular quiescence epigenetically controlled by SETD4. Our findings provide insights into the mechanism of tumorigenesis and relapse promoted by SETD4-defined quiescent CSCs and have broad implications for clinical therapies.
Significance:
These findings advance our knowledge on the epigenetic determinants of quiescence in cancer stem cell populations and pave the way for future pharmacologic developments aimed at targeting drug-resistant quiescent stem cells.
Data from Super-Enhancer–Associated Long Noncoding RNA HCCL5 Is Activated by ZEB1 and Promotes the Malignancy of Hepatocellular Carcinoma
Authors: Peng Li , Jiang Binyuan , Yuan Xiaoqing , Qiu Yuntan , Peng Jiangyun , Huang Yongsheng , Zhang Chaoyang , Zhang Yin , Lin Zhaoyu , Li Jinsong , Yao Weicheng , Deng Weixi , Zhang Yaqin , Meng Meng , Pan Xi , Li Chunquan , Yin Dong , Bi Xinyu , Li Guancheng , Lin De-Chen
Published: March 2023

Abstract
Hepatocellular carcinoma (HCC) is one of the most dominant causes of neoplasm-related deaths worldwide. In this study, we identify and characterize HCCL5, a novel cytoplasmic long noncoding RNA (lncRNA), as a crucial oncogene in HCC. HCCL5 promoted cell growth, G1–S transition, invasion, and metastasis while inhibiting apoptosis of HCC cells both in vitro and in vivo. Moreover, HCCL5 was upregulated in TGF-β1-induced classical epithelial-to-mesenchymal transition (EMT) models, and this lncRNA in turn accelerated the EMT phenotype by upregulating the expression of transcription factors Snail, Slug, ZEB1, and Twist1. HCCL5 was transcriptionally driven by ZEB1 via a super-enhancer and was significantly and frequently overexpressed in human HCC tissues, correlating with worse overall survival of patients with HCC. Together, this study characterizes HCCL5 as a super-enhancer–driven lncRNA promoting HCC cell viability, migration, and EMT. Our data also suggest that HCCL5 may serve as a novel prognostic biomarker and therapeutic target in HCC.
Significance:
These findings identify the lncRNA HCCL5 as a super-enhancer–driven oncogenic factor that promotes the malignancy of hepatocellular carcinoma.
Data from Eomes+T-betlow CD8+ T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia
Authors: Jia Bei , Zhao Chenchen , Rakszawski Kevin L. , Claxton David F. , Ehmann W. Christopher , Rybka Witold B. , Mineishi Shin , Wang Ming , Shike Hiroko , Bayerl Michael G. , Sivik Jeffrey M. , Schell Todd D. , Drabick Joseph J. , Hohl Raymond J. , Zheng Hong
Published: March 2023

Abstract
Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8+ T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8+ T-cell immunity in AML patients. We report that the frequency of Eomes+T-betlow CD8+ T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes+T-betlow CD8+ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics.
Significance:
These findings reveal that a high frequency of Eomes+T-betlow CD8+ T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.
Data from Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy
Authors: Principe Daniel R. , Narbutis Matthew , Kumar Sandeep , Park Alex , Viswakarma Navin , Dorman Matthew J. , Kamath Suneel D. , Grippo Paul J. , Fishel Melissa L. , Hwang Rosa F. , Thummuri Dinesh , Underwood Patrick W. , Munshi Hidayatullah G. , Trevino Jose G. , Rana Ajay
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term gemcitabine administration on the tumor microenvironment to identify potential therapeutic options for chemorefractory PDAC. Using a combination of mouse models, primary cell line–derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGFβ1 biosynthesis. Combined gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signaling deficiency, gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of gemcitabine-refractory PDAC.
Significance:
These data suggest that long-term treatment with gemcitabine leads to extensive reprogramming of the pancreatic tumor microenvironment and that patients who progress on gemcitabine-based regimens may benefit from multidrug immunotherapy.

See related commentary by Carpenter et al., p. 3070
Data from IL26, a Noncanonical Mediator of DNA Inflammatory Stimulation, Promotes TNBC Engraftment and Progression in Association with Neutrophils
Authors: Trotter Timothy N. , Shuptrine Casey W. , Tsao Li-Chung , Marek Robert D. , Acharya Chaitanya , Wei Jun-Ping , Yang Xiao-Yi , Lei Gangjun , Wang Tao , Lyerly Herbert Kim , Hartman Zachary C.
Published: March 2023

Abstract
IL26 is a unique amphipathic member of the IL10 family of cytokines that participates in inflammatory signaling through a canonical receptor pathway. It also directly binds DNA to facilitate cellular transduction and intracellular inflammatory signaling. Although IL26 has almost no described role in cancer, our in vivo screen of inflammatory and cytokine pathway genes revealed IL26 to be one of the most significant inflammatory mediators of mammary engraftment and lung metastatic growth in triple-negative breast cancer (TNBC). Examination of human breast cancers demonstrated elevated IL26 transcripts in TNBC specimens, specifically in tumor cells as well as in Th17 CD4+ T cells within clinical TNBC specimens. IL26 did not have an autocrine effect on human TNBC cells, but rather its effect on engraftment and growth in vivo required neutrophils. IL26 enhanced mouse-derived DNA induction of inflammatory cytokines, which were collectively important for mammary and metastatic lung engraftment. To neutralize this effect, we developed a novel IL26 vaccine to stimulate antibody production and suppress IL26-enhanced engraftment in vivo, suggesting that targeting this inflammatory amplifier could be a unique means to control cancer-promoting inflammation in TNBC and other autoimmune diseases. Thus, we identified IL26 as a novel key modulator of TNBC metastasis and a potential therapeutic target in TNBC as well as other diseases reliant upon IL26-mediated inflammatory stimulation.
Significance:
These findings identify IL26 as a unique, clinically relevant, inflammatory amplifier that enhances TNBC engraftment and dissemination in association with neutrophils, which has potential as a therapeutic target.
Data from Computational Staining of Pathology Images to Study the Tumor Microenvironment in Lung Cancer
Authors: Wang Shidan , Rong Ruichen , Yang Donghan M. , Fujimoto Junya , Yan Shirley , Cai Ling , Yang Lin , Luo Danni , Behrens Carmen , Parra Edwin R. , Yao Bo , Xu Lin , Wang Tao , Zhan Xiaowei , Wistuba Ignacio I. , Minna John , Xie Yang , Xiao Guanghua
Published: March 2023

Abstract
The spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). To facilitate the study of cellular spatial organization and interactions, we developed Histology-based Digital-Staining, a deep learning-based computation model, to segment the nuclei of tumor, stroma, lymphocyte, macrophage, karyorrhexis, and red blood cells from standard hematoxylin and eosin–stained pathology images in lung adenocarcinoma. Using this tool, we identified and classified cell nuclei and extracted 48 cell spatial organization-related features that characterize the TME. Using these features, we developed a prognostic model from the National Lung Screening Trial dataset, and independently validated the model in The Cancer Genome Atlas lung adenocarcinoma dataset, in which the predicted high-risk group showed significantly worse survival than the low-risk group (P = 0.001), with a HR of 2.23 (1.37–3.65) after adjusting for clinical variables. Furthermore, the image-derived TME features significantly correlated with the gene expression of biological pathways. For example, transcriptional activation of both the T-cell receptor and programmed cell death protein 1 pathways positively correlated with the density of detected lymphocytes in tumor tissues, while expression of the extracellular matrix organization pathway positively correlated with the density of stromal cells. In summary, we demonstrate that the spatial organization of different cell types is predictive of patient survival and associated with the gene expression of biological pathways.
Significance:
These findings present a deep learning-based analysis tool to study the TME in pathology images and demonstrate that the cell spatial organization is predictive of patient survival and is associated with gene expression.

See related commentary by Rodriguez-Antolin, p. 1912
Data from Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma
Authors: Mastrella Giorgia , Hou Mengzhuo , Li Min , Stoecklein Veit M. , Zdouc Nina , Volmar Marie N.M. , Miletic Hrvoje , Reinhard Sören , Herold-Mende Christel C. , Kleber Susanne , Eisenhut Katharina , Gargiulo Gaetano , Synowitz Michael , Vescovi Angelo L. , Harter Patrick N. , Penninger Josef M. , Wagner Ernst , Mittelbronn Michel , Bjerkvig Rolf , Hambardzumyan Dolores , Schüller Ulrich , Tonn Jörg-Christian , Radke Josefine , Glass Rainer , Kälin Roland E.
Published: March 2023

Abstract
Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes.
Significance:
Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis.

See related commentary by Amoozgar et al., p. 2104
Data from Optical Radiomic Signatures Derived from Optical Coherence Tomography Images Improve Identification of Melanoma
Authors: Turani Zahra , Fatemizadeh Emad , Blumetti Tatiana , Daveluy Steven , Moraes Ana Flavia , Chen Wei , Mehregan Darius , Andersen Peter E. , Nasiriavanaki Mohammadreza
Published: March 2023

Abstract
The current gold standard for clinical diagnosis of melanoma is excisional biopsy and histopathologic analysis. Approximately 15–30 benign lesions are biopsied to diagnose each melanoma. In addition, biopsies are invasive and result in pain, anxiety, scarring, and disfigurement of patients, which can add additional burden to the health care system. Among several imaging techniques developed to enhance melanoma diagnosis, optical coherence tomography (OCT), with its high-resolution and intermediate penetration depth, can potentially provide required diagnostic information noninvasively. Here, we present an image analysis algorithm, “optical properties extraction (OPE),” which improves the specificity and sensitivity of OCT by identifying unique optical radiomic signatures pertinent to melanoma detection. We evaluated the performance of the algorithm using several tissue-mimicking phantoms and then tested the OPE algorithm on 69 human subjects. Our data show that benign nevi and melanoma can be differentiated with 97% sensitivity and 98% specificity. These findings suggest that the adoption of OPE algorithm in the clinic can lead to improvements in melanoma diagnosis and patient experience.
Significance:
This study describes a noninvasive, safe, simple-to-implement, and accurate method for the detection and differentiation of malignant melanoma versus benign nevi.
Data from LncSpA: LncRNA Spatial Atlas of Expression across Normal and Cancer Tissues
Authors: Lv Dezhong , Xu Kang , Jin Xiyun , Li Junyi , Shi Yuchen , Zhang Mengying , Jin Xiaoyan , Li Yongsheng , Xu Juan , Li Xia
Published: March 2023

Abstract
Long noncoding RNAs (lncRNA) play important roles in maintaining morphology and function of tissues, and their regulatory effectiveness is closely associated with spatial expression. To provide a comprehensive spatial atlas of expression for lncRNA, we propose LncSpA (http://bio-bigdata.hrbmu.edu.cn/LncSpA) to explore tissue-elevated (TE) lncRNA across human normal and adult and pediatric cancer tissues. In total, 71,131 and 12,007 TE lncRNAs and 634 clinical-related TE lncRNAs were identified across 38 normal and 33 adult cancer tissues. Moreover, 4,688 TE and 413 clinical-related lncRNAs were identified in pediatric cancer. By quick searching or query options, users can obtain eight major types of detailed information for lncRNA via various visualization techniques, including qualitative and quantitative spatial expression in different resources, coexpressed mRNAs, predicted function, known disease association, and the potential to serve as diagnostic or prognostic markers. LncSpA will be a valuable resource to understand lncRNA functions across tissues and cancers, leading to enhanced therapeutic strategies in precision oncology.
Significance:
LncSpA is a new interactive resource that provides the spatial expression pattern of lncRNA across thousands of normal and cancer samples representing major tissue types.
Data from Long Noncoding RNA MRPL23-AS1 Promotes Adenoid Cystic Carcinoma Lung Metastasis
Authors: Chen Chu-Wen , Fu Min , Du Zhi-Hao , Zhao Fei , Yang Wen-Wen , Xu Li-Hua , Li Sheng-Lin , Ge Xi-Yuan
Published: March 2023

Abstract
Lung metastasis is a major factor affecting long-term survival in patients with adenoid cystic carcinoma. Here, we showed that the long noncoding RNA (lncRNA) MRPL23 antisense RNA 1 (MRPL23-AS1) was highly expressed and correlated with lung metastasis and overall survival in patients with salivary adenoid cystic carcinoma (SACC). MRPL23-AS1 positively regulated epithelial–mesenchymal transition by forming an RNA–protein complex with enhancer of zeste homolog 2 (EZH2). MRPL23-AS1 increased the binding of EZH2 and H3K27me3 on the E-cadherin promoter region. Moreover, MRPL23-AS1 levels were higher in exosomes isolated from the blood plasma of patients with SACC, and exosomal MRPL23-AS1 affected pulmonary microvascular endothelial cells in an “exosomecrine” manner. MRPL23-AS1–enriched exosomes increased microvascular permeability and facilitated the metastasis of SACC in vivo. Collectively, these findings highlight a molecular mechanism of lung metastasis in SACC. MRPL23-AS1 may represent a biomarker and target for clinical intervention to control this intractable disease.
Significance:
This study identifies a novel metastasis-promoting lncRNA MRPL23-AS1, which mediates the transcriptional silencing of E-cadherin through forming an RNA–protein complex with EZH2.
Data from Overexpression of RUNX3 Represses RUNX1 to Drive Transformation of Myelodysplastic Syndrome
Authors: Yokomizo-Nakano Takako , Kubota Sho , Bai Jie , Hamashima Ai , Morii Mariko , Sun Yuqi , Katagiri Seiichiro , Iimori Mihoko , Kanai Akinori , Tanaka Daiki , Oshima Motohiko , Harada Yuka , Ohyashiki Kazuma , Iwama Atsushi , Harada Hironori , Osato Motomi , Sashida Goro
Published: March 2023

Abstract
RUNX3, a RUNX family transcription factor, regulates normal hematopoiesis and functions as a tumor suppressor in various tumors in humans and mice. However, emerging studies have documented increased expression of RUNX3 in hematopoietic stem/progenitor cells (HSPC) of a subset of patients with myelodysplastic syndrome (MDS) showing a worse outcome, suggesting an oncogenic function for RUNX3 in the pathogenesis of hematologic malignancies. To elucidate the oncogenic function of RUNX3 in the pathogenesis of MDS in vivo, we generated a RUNX3-expressing, Tet2-deficient mouse model with the pancytopenia and dysplastic blood cells characteristic of MDS in patients. RUNX3-expressing cells markedly suppressed the expression levels of Runx1, a critical regulator of hemaotpoiesis in normal and malignant cells, as well as its target genes, which included crucial tumor suppressors such as Cebpa and Csf1r. RUNX3 bound these genes and remodeled their Runx1-binding regions in Tet2-deficient cells. Overexpression of RUNX3 inhibited the transcriptional function of Runx1 and compromised hematopoiesis to facilitate the development of MDS in the absence of Tet2, indicating that RUNX3 is an oncogene. Furthermore, overexpression of RUNX3 activated the transcription of Myc target genes and rendered cells sensitive to inhibition of Myc-Max heterodimerization. Collectively, these results reveal the mechanism by which RUNX3 overexpression exerts oncogenic effects on the cellular function of and transcriptional program in Tet2-deficient stem cells to drive the transformation of MDS.
Significance:
This study defines the oncogenic effects of transcription factor RUNX3 in driving the transformation of myelodysplastic syndrome, highlighting RUNX3 as a potential target for therapeutic intervention.
Data from Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma
Authors: Hoffman Mary , Gillmor Aaron H. , Kunz Daniel J. , Johnston Michael J. , Nikolic Ana , Narta Kiran , Zarrei Mehdi , King Jennifer , Ellestad Katrina , Dang Ngoc Ha , Cavalli Florence M.G. , Kushida Michelle M. , Coutinho Fiona J. , Zhu Yuankun , Luu Betty , Ma Yussanne , Mungall Andrew J. , Moore Richard , Marra Marco A. , Taylor Michael D. , Pugh Trevor J. , Dirks Peter B. , Strother Douglas , Lafay-Cousin Lucie , Resnick Adam C. , Scherer Stephen , Senger Donna L. , Simons Benjamin D. , Chan Jennifer A. , Morrissy A. Sorana , Gallo Marco
Published: March 2023

Abstract
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of nonsynonymous single-nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole-genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to nondividing cells. Interestingly, radiation and antimitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, because slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.
Significance:
This work challenges several assumptions regarding the genetic organization of pediatric GBM and highlights mutagenic programs that start during early prenatal development.
Data from Consumption of the Fish Oil High-Fat Diet Uncouples Obesity and Mammary Tumor Growth through Induction of Reactive Oxygen Species in Protumor Macrophages
Authors: Liu Lianliang , Jin Rong , Hao Jiaqing , Zeng Jun , Yin Di , Yi Yanmei , Zhu Mingming , Mandal Anita , Hua Yuan , Ng Chin K. , Egilmez Nejat K. , Sauter Edward R. , Li Bing
Published: March 2023

Abstract
Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA–mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP–dependent manner.
Significance:
This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic.
Data from Picosecond Infrared Laser Desorption Mass Spectrometry Identifies Medulloblastoma Subgroups on Intrasurgical Timescales
Authors: Woolman Michael , Kuzan-Fischer Claudia M. , Ferry Isabelle , Kiyota Taira , Luu Betty , Wu Megan , Munoz David G. , Das Sunit , Aman Ahmed , Taylor Michael D. , Rutka James T. , Ginsberg Howard J. , Zarrine-Afsar Arash
Published: March 2023

Abstract
Medulloblastoma (MB) is a pediatric malignant brain tumor composed of four different subgroups (WNT, SHH, Group 3, Group 4), each of which are a unique biological entity with distinct clinico-pathological, molecular, and prognostic characteristics. Although risk stratification of patients with MB based on molecular features may offer personalized therapies, conventional subgroup identification methods take too long and are unable to deliver subgroup information intraoperatively. This limitation prevents subgroup-specific adjustment of the extent or the aggressiveness of the tumor resection by the neurosurgeon. In this study, we investigated the potential of rapid tumor characterization with Picosecond infrared laser desorption mass spectrometry (PIRL-MS) for MB subgroup classification based on small molecule signatures. One hundred and thirteen ex vivo MB tumors from a local tissue bank were subjected to 10- to 15-second PIRL-MS data collection and principal component analysis with linear discriminant analysis (PCA-LDA). The MB subgroup model was established from 72 independent tumors; the remaining 41 de-identified unknown tumors were subjected to multiple, 10-second PIRL-MS samplings and real-time PCA-LDA analysis using the above model. The resultant 124 PIRL-MS spectra from each sampling event, after the application of a 95% PCA-LDA prediction probability threshold, yielded a 98.9% correct classification rate. Post-ablation histopathologic analysis suggested that intratumoral heterogeneity or sample damage prior to PIRL-MS sampling at the site of laser ablation was able to explain failed classifications. Therefore, upon translation, 10-seconds of PIRL-MS sampling is sufficient to allow personalized, subgroup-specific treatment of MB during surgery.
Significance:
This study demonstrates that laser-extracted lipids allow immediate grading of medulloblastoma tumors into prognostically important subgroups in 10 seconds, providing medulloblastoma pathology in an actionable manner during surgery.
Data from Spleen Tyrosine Kinase–Mediated Autophagy Is Required for Epithelial–Mesenchymal Plasticity and Metastasis in Breast Cancer
Authors: Shinde Aparna , Hardy Shana D. , Kim Dongwook , Akhand Saeed Salehin , Jolly Mohit Kumar , Wang Wen-Hung , Anderson Joshua C. , Khodadadi Ryan B. , Brown Wells S. , George Jason T. , Liu Sheng , Wan Jun , Levine Herbert , Willey Christopher D. , Krusemark Casey J. , Geahlen Robert L. , Wendt Michael K.
Published: March 2023

Abstract
The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells.
Significance:
These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy.

See related commentary by Farrington and Narla, p. 1756
Data from Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis
Authors: Giurisato Emanuele , Lonardi Silvia , Telfer Brian , Lussoso Sarah , Risa-Ebrí Blanca , Zhang Jingwei , Russo Ilaria , Wang Jinhua , Santucci Annalisa , Finegan Katherine G. , Gray Nathanael S. , Vermi William , Tournier Cathy
Published: March 2023

Abstract
The presence of immunosuppressive macrophages that become activated in the tumor microenvironment constitutes a major factor responsible for tumor growth and malignancy. In line with this knowledge, we report here that macrophage proliferation is a significant feature of advanced stages of cancer. Moreover, we have found that a high proportion of proliferating macrophages in human tumors express ERK5. ERK5 was required for supporting the proliferation of macrophages in tumor grafts in mice. Furthermore, myeloid ERK5 deficiency negatively impacted the proliferation of both resident and infiltrated macrophages in metastatic lung nodules. ERK5 maintained the capacity of macrophages to proliferate by suppressing p21 expression to halt their differentiation program. Collectively, these data provide insight into the mechanism underpinning macrophage proliferation to support malignant tumor development, thereby strengthening the value of ERK5-targeted therapies to restore antitumor immunity through the blockade of protumorigenic macrophage activation.
Significance:
These findings offer a new rationale for anti-ERK5 therapy to improve cancer patient outcomes by blocking the proliferative activity of tumor macrophages.
Data from An ABC Transporter Drives Medulloblastoma Pathogenesis by Regulating Sonic Hedgehog Signaling
Authors: Wijaya Juwina , Vo BaoHan T. , Liu Jingjing , Xu Beisi , Wu Gang , Wang Yao , Peng Junmin , Zhang Jin , Janke Laura J. , Orr Brent A. , Yu Jiyang , Roussel Martine F. , Schuetz John D.
Published: March 2023

Abstract
Mutations in Sonic hedgehog (SHH) signaling promote aberrant proliferation and tumor growth. SHH-medulloblastoma (MB) is among the most frequent brain tumors in children less than 3 years of age. Although key components of the SHH pathway are well-known, we hypothesized that new disease-modifying targets of SHH-MB might be identified from large-scale bioinformatics and systems biology analyses. Using a data-driven systems biology approach, we built a MB-specific interactome. The ATP-binding cassette transporter ABCC4 was identified as a modulator of SHH-MB. Accordingly, increased ABCC4 expression correlated with poor overall survival in patients with SHH-MB. Knockdown of ABCC4 expression markedly blunted the constitutive activation of the SHH pathway secondary to Ptch1 or Sufu insufficiency. In human tumor cell lines, ABCC4 knockdown and inhibition reduced full-length GLI3 levels. In a clinically relevant murine SHH-MB model, targeted ablation of Abcc4 in primary tumors significantly reduced tumor burden and extended the lifespan of tumor-bearing mice. These studies reveal ABCC4 as a potent SHH pathway regulator and a new candidate to target with the potential to improve SHH-MB therapy.
Significance:
These findings identify ABCC4 transporter as a new target in SHH-MB, prompting the development of inhibitors or the repurporsing of existing drugs to target ABCC4.
Data from HIF2-Induced Long Noncoding RNA RAB11B-AS1 Promotes Hypoxia-Mediated Angiogenesis and Breast Cancer Metastasis
Authors: Niu Yanling , Bao Lei , Chen Yan , Wang Chenliang , Luo Maowu , Zhang Bo , Zhou Mi , Wang Jennifer E. , Fang Yisheng V. , Kumar Ashwani , Xing Chao , Wang Yingfei , Luo Weibo
Published: March 2023

Abstract
Hypoxia induces a vast array of long noncoding RNAs (lncRNA) in breast cancer cells, but their biological functions remain largely unknown. Here, we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF2), but not HIF1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells in vitro. Gain- and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion in vitro and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis.
Significance:
This study reveals the molecular mechanism by which the lncRNA RAB11B-AS1 regulates hypoxia-induced angiogenesis and breast cancer metastasis, and provides new insights into the functional interaction between a lncRNA and tumor microenvironment.
Data from Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma
Authors: Turner Joel G. , Cui Yan , Bauer Alexis A. , Dawson Jana L. , Gomez Juan A. , Kim Jongphil , Cubitt Christopher L. , Nishihori Taiga , Dalton William S. , Sullivan Daniel M.
Published: March 2023

Abstract
High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609).
Significance:
Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.