bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell–like Properties in Osteosarcoma
Authors: Lu Bing , He Yangyang , He Jincan , Wang Li , Liu Zhenguo , Yang Jiayan , Gao Zhuoxing , Lu Guohao , Zou Changye , Zhao Wei
Published: March 2024

Abstract
Osteosarcoma is an aggressive malignancy with poor prognosis. Super-enhancers (SE) have been highlighted as critical oncogenic elements required for maintaining the cancer cell characteristics. However, the regulatory role of SEs in osteosarcoma properties has not yet been elucidated. In the current study, we found that osteosarcoma cells and clinical specimens shared a significant fraction of SEs. Moreover, leukemia-inhibitory factor (LIF) was identified as an essential factor under the control of osteosarcoma-specific SE. The expression of LIF was positively correlated with the stem cell core factor genes in osteosarcoma. Furthermore, LIF recombinant protein–treated osteosarcoma cells displayed enhanced stem cell–like characteristics, such as increased sphere-forming potential, stimulated self-renewal, upregulated metastasis ability, and increased stemness-related gene expression. Notably, the histone 3 lysine 27 tri-methylation (H3K27me3) demethylase UTX was found as a key activator of LIF transcription in osteosarcoma. The UTX inhibitor, GSK-J4, induced H3K27me3 accumulation and impaired histone 3 lysine 27 acetylation (H3K27ac) at LIF gene locus, leading to LIF signaling pathway inhibition. GSK-J4 treatment resulted in profound defects in stem cell-like characteristics and stemness-related gene activation in osteosarcoma by modulating the H3K27ac of NOTCH1 signaling pathway gene loci. The NOTCH1 inhibitor Crenigacestat (TargetMol, T3633) repressed LIF-mediated activation of the stemness-related genes in osteosarcoma patient-derived primary tissues.
Implications:
This study reveals osteosarcoma SE profiles and uncovers a distinct tumor–stemness epigenetic regulatory mechanism in which an osteosarcoma-specific SE-mediated factor, LIF, promotes osteosarcoma stemness gene activation via NOTCH1 signaling pathway.
Data from Multi-omics Approach Reveals Distinct Differences in Left- and Right-Sided Colon Cancer
Authors: Hu Wangxiong , Yang Yanmei , Li Xiaofen , Huang Minran , Xu Fei , Ge Weiting , Zhang Suzhan , Zheng Shu
Published: March 2024

Abstract
Increasing evidence suggests that left-sided colon cancer (LCC) and right-sided colon cancer (RCC) are emerging as two different colorectal cancer types with distinct clinical characteristics. However, the discrepancy in the underlying molecular event between these types of cancer has not been thoroughly elucidated to date and warrants comprehensive investigation. To this end, an integrated dataset from The Cancer Genome Atlas was used to compare and contrast LCC and RCC, covering mutation, DNA methylation, gene expression, and miRNA. Briefly, the signaling pathway cross-talk is more prevalent in RCC than LCC, such as RCC-specific PI3K pathway, which often exhibits cross-talk with the RAS and P53 pathways. Meanwhile, methylation signatures revealed that RCC was hypermethylated relative to LCC. In addition, differentially expressed genes (n = 253) and differentially expressed miRNAs (n = 16) were determined between LCC and RCC. Especially for Prostate Cancer Susceptibility Candidate 1 (PRAC1), a gene that was closely associated with hypermethylation, was the top significantly downregulated gene in RCC. Multi-omics comparison of LCC and RCC suggests that there are more aggressive markers in RCC and that tumor heterogeneity occurs within the location-based subtypes of colon cancer. These results clarify the debate regarding the conflicting prognosis between LCC and RCC, as proposed by different studies.

Implications: The underlying molecular features present in LCC and RCC identified in this study are beneficial for adopting reasonable therapeutic approaches to prolong overall survival and progression-free survival in colorectal cancer patients. Mol Cancer Res; 16(3); 476–85. ©2017 AACR.
Data from The Altered Transcriptome and DNA Methylation Profiles of Docetaxel Resistance in Breast Cancer PDX Models
Authors: Gómez-Miragaya Jorge , Morán Sebastián , Calleja-Cervantes Maria Eréndira , Collado-Sole Alejandro , Paré Laia , Gómez Antonio , Serra Violeta , Dobrolecki Lacey E. , Lewis Michael T. , Diaz-Lagares Angel , Eroles Pilar , Prat Aleix , Esteller Manel , González-Suárez Eva
Published: March 2024

Abstract
Taxanes are standard therapy in clinical practice for metastatic breast cancer; however, primary or acquired chemoresistance are a common cause of mortality. Breast cancer patient-derived xenografts (PDX) are powerful tools for the study of cancer biology and drug treatment response. Specific DNA methylation patterns have been associated to different breast cancer subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel resistance mechanisms, we performed genome-wide DNA methylation in breast cancer PDX models, including luminal and triple-negative breast cancer (TNBC) models sensitive to docetaxel, their matched models after emergence of chemoresistance and residual disease after short-term docetaxel treatment. We found that DNA methylation profiles from breast cancer PDX models maintain the subtype-specific methylation patterns of clinical samples. Two main DNA methylation clusters were found in TNBC PDX and remain stable during the emergence of docetaxel resistance; however, some genes/pathways were differentially methylated according to docetaxel response. A DNA methylation signature of resistance able to segregate TNBC based on chemotherapy response was identified. Transcriptomic profiling of selected sensitive/resistant pairs and integrative analysis with methylation data demonstrated correlation between some differentially methylated and expressed genes in docetaxel-resistant TNBC PDX models. Multiple gene expression changes were found after the emergence of docetaxel resistance in TNBC. DNA methylation and transcriptional changes identified between docetaxel-sensitive and -resistant TNBC PDX models or residual disease may have predictive value for chemotherapy response in TNBC.
Implications:
Subtype-specific DNA methylation patterns are maintained in breast cancer PDX models. While no global methylation changes were found, we uncovered differentially DNA methylated and expressed genes/pathways associated with the emergence of docetaxel resistance in TNBC.
Data from Prostate Cancer in World Trade Center Responders Demonstrates Evidence of an Inflammatory Cascade
Authors: Gong Yixuan , Wang Li , Yu Haocheng , Alpert Naomi , Cohen Mitchell D. , Prophete Colette , Horton Lori , Sisco Maureen , Park Sung-Hyun , Lee Hyun-Wook , Zelikoff Judith , Chen Lung-Chi , Hashim Dana , Suarez-Farinas Mayte , Donovan Michael J. , Aaronson Stuart A. , Galsky Matthew , Zhu Jun , Taioli Emanuela , Oh William K.
Published: March 2024

Abstract
An excess incidence of prostate cancer has been identified among World Trade Center (WTC) responders. In this study, we hypothesized that WTC dust, which contained carcinogens and tumor-promoting agents, could facilitate prostate cancer development by inducing DNA damage, promoting cell proliferation, and causing chronic inflammation. We compared expression of immunologic and inflammatory genes using a NanoString assay on archived prostate tumors from WTC Health Program (WTCHP) patients and non-WTC patients with prostate cancer. Furthermore, to assess immediate and delayed responses of prostate tissue to acute WTC dust exposure via intratracheal inhalation, we performed RNA-seq on the prostate of normal rats that were exposed to moderate to high doses of WTC dust. WTC prostate cancer cases showed significant upregulation of genes involved in DNA damage and G2–M arrest. Cell-type enrichment analysis showed that Th17 cells, a subset of proinflammatory Th cells, were specifically upregulated in WTC patients. In rats exposed to WTC dust, we observed upregulation of gene transcripts of cell types involved in both adaptive immune response (dendritic cells and B cells) and inflammatory response (Th17 cells) in the prostate. Unexpectedly, genes in the cholesterol biosynthesis pathway were also significantly upregulated 30 days after acute dust exposure. Our results suggest that respiratory exposure to WTC dust can induce inflammatory and immune responses in prostate tissue.
Implications:
WTC-related prostate cancer displayed a distinct gene expression pattern that could be the result of exposure to specific carcinogens. Our data warrant further epidemiologic and cellular mechanistic studies to better understand the consequences of WTC dust exposure.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/8/1605/F1.large.jpg.
Data from The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients
Authors: Chatrath Ajay , Kiran Manjari , Kumar Pankaj , Ratan Aakrosh , Dutta Anindya
Published: March 2024

Abstract
Lower grade gliomas are invasive brain tumors that are difficult to completely resect neurosurgically. They often recur following resection and progress, resulting in death. Although previous studies have shown that specific germline variants increase the risk of tumor formation, no previous study has screened many germline variants to identify variants predictive of survival in patients with glioma. In this study, we present an approach to identify the small fraction of prognostic germline variants from the pool of over four million variants that we variant called in The Cancer Genome Atlas whole-exome sequencing and RNA sequencing datasets. We identified two germline variants that are predictive of poor patient outcomes by Cox regression, controlling for eleven covariates. rs61757955 is a germline variant found in the 3′ UTR of GRB2 associated with increased KRAS signaling, CIC mutations, and 1p/19q codeletion. rs34988193 is a germline variant found in the tumor suppressor gene ANKDD1a that causes an amino acid change from lysine to glutamate. This variant was found to be predictive of poor prognosis in two independent lower grade glioma datasets and is predicted to be within the top 0.06% of deleterious mutations across the human genome. The wild-type residue is conserved in all 22 other species with a homologous protein.
Implications:
This is the first study presenting an approach to screening many germline variants to identify variants predictive of survival and our application of this methodology revealed the germline variants rs61757955 and rs34988193 as being predictive of survival in patients with lower grade glioma.
Data from Bayesian Modeling Identifies PLAG1 as a Key Regulator of Proliferation and Survival in Rhabdomyosarcoma Cells
Authors: Zheng Yanbin , Xu Lin , Hassan Mohammed , Zhou Xiaoyun , Zhou Qinbo , Rakheja Dinesh , Skapek Stephen X.
Published: March 2024

Abstract
We recently developed a novel computational algorithm that incorporates Bayesian methodology to identify rhabdomyosarcoma disease genes whose expression level correlates with copy-number variations, and we identified PLAG1 as a candidate oncogenic driver. Although PLAG1 has been shown to contribute to other type of cancers, its role in rhabdomyosarcoma has not been elucidated. We observed that PLAG1 mRNA is highly expressed in rhabdomyosarcoma and is associated with PLAG1 gene copy-number gain. Knockdown of PLAG1 dramatically decreased cell accumulation and induced apoptosis in rhabdomyosarcoma cells, whereas its ectopic expression increased cell accumulation in vitro and as a xenograft and promoted G1 to S-phase cell-cycle progression. We found that PLAG1 regulates IGF2 expression and influences AKT and MAPK pathways in rhabdomyosarcoma, and IGF2 partially rescues cell death triggered by PLAG1 knockdown. The expression level of PLAG1 correlated with the IC50 of rhabdomyosarcoma cells to BMS754807, an IGF receptor inhibitor.
Implications:
Our data demonstrate that PLAG1 contributes to proliferation and survival of rhabdomyosarcoma cells at least partially by inducing IGF2, and this new understanding may have the potential for clinical translation.
Data from Aquaporin-9, Mediated by IGF2, Suppresses Liver Cancer Stem Cell Properties via Augmenting ROS/β-Catenin/FOXO3a Signaling
Authors: Zheng Xi , Li Chuanfei , Yu Keqi , Shi Shasha , Chen Hongyu , Qian Yanzhi , Mei Zhechuan
Published: March 2024

Abstract
Liver cancer stem cells (LCSCs) play a critical role in hepatocellular carcinoma (HCC) by virtue of their aggressive behavior and association with poor prognoses. Aquaporin-9 (AQP9) is a transmembrane protein that transports water and reportedly transports H2O2. Recent studies have shown that AQP9 expression has a negative effect on HCC cell invasion by inhibiting the epithelial-to-mesenchymal transition. However, the role of AQP9 in LCSCs remains obscure. We performed spheroid formation assay and flow cytometric analysis to investigate LCSCs stemness. CD133+ and CD133− cells were isolated by flow cytometry. Real-time quantitative PCR (qRT-PCR), Western blot analysis, and immunofluorescence assay were used to estimate gene expression. The protein association of β-catenin with TCF4 and the interaction of β-catenin with FOXO3a were detected by immunoprecipitation (IP). Here, we found that AQP9 was preferentially decreased in LCSCs. Upregulated AQP9 significantly suppressed LCSCs stemness. In contrast, the inhibition of AQP9 had the opposite effect. Mechanistically, AQP9 was shown to be downregulated by insulin-like growth factor 2 (IGF2), which was widely reported to contribute to maintaining CSCs stemness. Furthermore, AQP9 overexpression was found to result in reactive oxygen species (ROS) accumulation, which inhibited β-catenin activity by attenuating the interaction of β-catenin with TCF4 while concurrently enhancing the association of β-catenin with FOXO3a, ultimately inhibiting LCSCs stemness. Our study implies that stimulation of the AQP9 signaling axis may be a novel preventive and/or therapeutic approach for eliminating LCSCs.
Implications:
Our findings demonstrate that AQP9 signaling axis may be a novel preventive and/or therapeutic approach for eliminating LCSCs.
Data from CD44-Mediated Adhesion to Hyaluronic Acid Contributes to Mechanosensing and Invasive Motility
Authors: Kim Yushan , Kumar Sanjay
Published: March 2024

Abstract
The high-molecular-weight glycosaminoglycan, hyaluronic acid (HA), makes up a significant portion of the brain extracellular matrix. Glioblastoma multiforme (GBM), a highly invasive brain tumor, is associated with aberrant HA secretion, tissue stiffening, and overexpression of the HA receptor CD44. Here, transcriptomic analysis, engineered materials, and measurements of adhesion, migration, and invasion were used to investigate how HA/CD44 ligation contributes to the mechanosensing and invasive motility of GBM tumor cells, both intrinsically and in the context of Arg-Gly-Asp (RGD) peptide/integrin adhesion. Analysis of transcriptomic data from The Cancer Genome Atlas reveals upregulation of transcripts associated with HA/CD44 adhesion. CD44 suppression in culture reduces cell adhesion to HA on short time scales (0.5-hour postincubation) even if RGD is present, whereas maximal adhesion on longer time scales (3 hours) requires both CD44 and integrins. Moreover, time-lapse imaging demonstrates that cell adhesive structures formed during migration on bare HA matrices are more short lived than cellular protrusions formed on surfaces containing RGD. Interestingly, adhesion and migration speed were dependent on HA hydrogel stiffness, implying that CD44-based signaling is intrinsically mechanosensitive. Finally, CD44 expression paired with an HA-rich microenvironment maximized three-dimensional invasion, whereas CD44 suppression or abundant integrin-based adhesion limited it. These findings demonstrate that CD44 transduces HA-based stiffness cues, temporally precedes integrin-based adhesion maturation, and facilitates invasion.

Implications: This study reveals that the CD44 receptor, which is commonly overexpressed in GBM tumors, is critical for cell adhesion, invasion, and mechanosensing of an HA-based matrix. Mol Cancer Res; 12(10); 1416–29. ©2014 AACR.
Data from Extracellular ATP a New Player in Cancer Metabolism: NSCLC Cells Internalize ATP In Vitro and In Vivo Using Multiple Endocytic Mechanisms
Authors: Qian Yanrong , Wang Xuan , Li Yunsheng , Cao Yanyang , Chen Xiaozhuo
Published: March 2024

Abstract
Intratumoral extracellular ATP concentrations are 1000 times higher than those in normal tissues of the same cell origin. However, whether or not cancer cells use the abundant extracellular ATP was unknown until we recently reported that cancer cells internalize ATP. The internalized ATP was found to substantially increase intracellular ATP concentration and promote cell proliferation and drug resistance in cancer cells. Here, using a nonhydrolyzable fluorescent ATP (NHF-ATP), radioactive and regular ATP, coupled with high and low molecular weight dextrans as endocytosis tracers and fluorescence microscopy and ATP assays, cultured human NSCLC A549 and H1299 cells as well as A549 tumor xenografts were found to internalize extracellular ATP at concentrations within the reported intratumoral extracellular ATP concentration range. In addition to macropinocytosis, both clathrin- and caveolae-mediated endocytosis significantly contribute to the ATP internalization, which led to an approximately 30% (within 45 minutes) or more than 50% (within 4 hours) increase in intracellular ATP levels after ATP incubation. This increase could not be accounted for by either purinergic receptor signaling or increased intracellular ATP synthesis rates in the ATP-treated cancer cells. These new findings significantly deepen our understanding of the Warburg effect by shedding light on how cancer cells in tumors, which are heterogeneous for oxygen and nutrition supplies, take up extracellular ATP and use the internalized ATP to perform multiple previously unrecognized functions of biological importance. They strongly suggest the existence of ATP sharing among cancer and stromal cells in tumors and simultaneously identify multiple new anticancer targets.

Implications: Extracellular ATP is taken up by human lung cancer cells and tumors via macropinocytosis and other endocytic processes to supplement their extra energy needs for cancer growth, survival, and drug resistance, thus providing novel targets for future cancer therapy. Mol Cancer Res; 14(11); 1087–96. ©2016 AACR.
Data from LEF1 Targeting EMT in Prostate Cancer Invasion Is Regulated by miR-34a
Authors: Liang Jiaqian , Li Yirong , Daniels Garrett , Sfanos Karen , De Marzo Angelo , Wei Jianjun , Li Xin , Chen Wenqiang , Wang Jinhua , Zhong Xuelin , Melamed Jonathan , Zhao Jun , Lee Peng
Published: March 2024

Abstract
The microRNA-34a (miR-34a), a tumor-suppressive microRNA (miRNA), is implicated in epithelial–mesenchymal transition (EMT) and cancer stem cells. Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor in the Wnt signaling pathway, and has been suggested to be involved in regulation of cell proliferation and invasion. Here, the molecular mechanism of miR-34a and LEF1 in cooperatively regulating prostate cancer cell invasion is described. Molecular profiling analysis of miRNA levels in prostate cancer cells revealed a negative correlation between miR-34a and LEF1 expression, and the downregulation of LEF1 by miR-34a was confirmed by luciferase assays. Furthermore, miR-34a specifically repressed LEF1 expression through direct binding to its 3′-untranslated regions (3′-UTR). miR-34a modulated the levels of LEF1 to regulate EMT in prostate cancer cells. Functionally, miR-34a negatively correlated with the migration and invasion of prostate cancer cells through LEF1. An analysis of miR-34a expression levels in matched human tumor and benign tissues demonstrated consistent and statistically significant downregulation of miR-34a in primary prostate cancer specimens. These data strongly suggest that miR-34a/LEF1 regulation of EMT plays an important role in prostate cancer migration and invasion.

Implications: The miR-34a–LEF1 axis represents a potential molecular target for novel therapeutic strategies in prostate cancer. Mol Cancer Res; 13(4); 681–8. ©2015 AACR.
Data from The YAP-Interacting Phosphatase SHP2 Can Regulate Transcriptional Coactivity and Modulate Sensitivity to Chemotherapy in Cholangiocarcinoma
Authors: Buckarma EeeLN H. , Werneburg Nathan W. , Conboy Caitlin B. , Kabashima Ayano , O'Brien Daniel R. , Wang Chen , Rizvi Sumera , Smoot Rory L.
Published: March 2024

Abstract
The Hippo pathway effector Yes-associated protein (YAP) is localized to the nucleus and transcriptionally active in a number of tumor types, including a majority of human cholangiocarcinomas. YAP activity has been linked to chemotherapy resistance and has been shown to rescue KRAS and BRAF inhibition in RAS/RAF-driven cancers; however, the underlying mechanisms of YAP-mediated chemoresistance have yet to be elucidated. Herein, we report that the tyrosine phosphatase SHP2 directly regulates the activity of YAP by dephosphorylating pYAPY357 even in the setting of RAS/RAF mutations, and that diminished SHP2 phosphatase activity is associated with chemoresistance in cholangiocarcinomas. A screen for YAP-interacting tyrosine phosphatases identified SHP2, and characterization of cholangiocarcinomas cell lines demonstrated an inverse relationship between SHP2 levels and pYAPY357. Human sequencing data demonstrated lower SHP2 levels in cholangiocarcinomas tumors as compared with normal liver. Cell lines with low SHP2 expression and higher levels of pYAPY357 were resistant to gemcitabine and cisplatin. In cholangiocarcinomas cells with high levels of SHP2, pharmacologic inhibition or genetic deletion of SHP2 increased YAPY357 phosphorylation and expression of YAP target genes, including the antiapoptotic regulator MCL1, imparting resistance to gemcitabine and cisplatin. In vivo evaluation of chemotherapy sensitivity demonstrated significant resistance in xenografts with genetic deletion of SHP2, which could be overcome by utilizing an MCL1 inhibitor.
Implications:
These findings demonstrate a role for SHP2 in regulating YAP activity and chemosensitivity, and suggest that decreased phosphatase activity may be a mechanism of chemoresistance in cholangiocarcinoma via a MCL1-mediated mechanism.
Data from Combined Exosomal GPC1, CD82, and Serum CA19-9 as Multiplex Targets: A Specific, Sensitive, and Reproducible Detection Panel for the Diagnosis of Pancreatic Cancer
Authors: Xiao Dong , Dong Zhanjun , Zhen Linqing , Xia Guanggai , Huang Xinyu , Wang Tiezhong , Guo Huaibin , Yang Binhui , Xu Cheng , Wu Weiwei , Zhao Xiaoyu , Xu Hong
Published: March 2024

Abstract
Pancreatic cancer is a highly lethal malignancy with poor prognosis due to the lack of early symptoms and resultant late diagnosis. Thus, it is extremely urgent to establish a simple and effective method for the early diagnosis of pancreatic cancer. Although some studies have provided positive evidence for the use of exosomal surface protein glypican-1 (GPC1) as a biomarker for early screening, its clinical application is still controversial. Here, we systematically verified the role of exosomal GPC1 as a potential screening biomarker. First, bottleneck problems of a stable detection method and an identification standard were systematically studied, and a Python-based standardized data processing method was established to analyze exosomal GPC1 expression. Second, a detection panel consisting of exosomal GPC1, exosomal cluster of differentiation 82 (CD82), and serum carbohydrate antigen 19-9 (CA19-9) was employed for pancreatic cancer detection. This panel exhibited excellent diagnostic results (AUC = 0.942) and could effectively distinguish healthy people from patients with pancreatic cancer (P value threshold = 0.2282) and patients with pancreatitis from patients with pancreatic cancer (P value threshold = 0.5467).
Implications:
These results indicate that the combined detection of exosomal GPC1, exosomal CD82, and serum CA19-9 shows great promise as a standard method for pancreatic cancer detection and that this panel could be further applied for screening pancreatic cancer in Chinese populations.
Data from Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan
Authors: Wong Chen Khuan , Lambert Arthur W. , Ozturk Sait , Papageorgis Panagiotis , Lopez Delia , Shen Ning , Sen Zaina , Abdolmaleky Hamid M. , Győrffy Balázs , Feng Hui , Thiagalingam Sam
Published: March 2024

Abstract
Deciphering molecular targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers. Loss of function mutations of SMAD4 in colon cancer are associated with metastatic progression and resistance to 5-fluorouracil (5-FU), the most extensively used drug of almost all chemotherapy combinations used in the treatment of metastatic colon cancer. Here, we report that SMAD4 deficiency also confers resistance to irinotecan, another common chemotherapeutic frequently used alone or in combination with 5-FU against colon cancer. Mechanistically, we find that SMAD4 interacts with and inhibits RICTOR, a component of the mTORC2 complex, resulting in suppression of downstream effector phosphorylation of AKT at Serine 473. In silico meta-analysis of publicly available gene expression datasets derived from tumors indicates that lower levels of SMAD4 or higher levels of RICTOR/AKT, irrespective of the SMAD4 status, correlate with poor survival, suggesting them as strong prognostic biomarkers and targets for therapeutic intervention. Moreover, we find that overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases sensitivity to irinotecan in SMAD4-deficient colon cancer cells. Consistent with these observations, pharmacologic inhibition of AKT sensitizes SMAD4-negative colon cancer cells to irinotecan in vitro and in vivo. Overall, our study suggests that hyperactivation of the mTORC2 pathway is a therapeutic vulnerability that could be exploited to sensitize SMAD4-negative colon cancer to irinotecan.
Implications:
Hyperactivation of the mTORC2 pathway in SMAD4-negative colon cancer provides a mechanistic rationale for targeted inhibition of mTORC2 or AKT as a distinctive combinatorial therapeutic opportunity with chemotherapy for colon cancer.
Data from R-spondin2 Suppresses the Progression of Hepatocellular Carcinoma via MAPK Signaling Pathway
Authors: Zheng Chang , Zhou Fan , Shi Liang Liang , Xu Gui Fang , Zhang Bin , Wang Lei , Zhuge Yuzheng , Zou Xiao Ping , Wang Yi
Published: March 2024

Abstract
The R-spondin family plays important roles in embryonic development, including in humans. However, information on the relationship between R-spondin2 and hepatocellular carcinoma (HCC) is lacking. This study aimed was to explore the mechanisms of R-spondin2 action in the progression of HCC. By analyzing R-spondin2 expression levels in HCC tissues by IHC and database, we identified that HCC tissues had lower expression levels of R-spondin2, correlated with a poor prognosis. We also established R-spondin2–overexpressing and knockdown cell lines and measured their viabilities and invasion abilities in vitro and their oncogenic capacity in vivo. Human mRNA microarray analysis was performed to screen for mRNAs that were differentially expressed between R-spondin2–overexpressing and control HCC cells. Microarray and Western blot analyses showed significant changes in the MAPK signaling pathway after transfection. Furthermore, in vivo experiments indicated that R-spondin2 knockdown increased the tumorigenicity of HCC cells after subcutaneous implantation in mice. Altogether, our results indicate that the R-spondin2, which might be a novel tumor suppressor gene, were responsible for inhibiting the proliferation and invasion of HCC via the MAPK signaling pathway.
Implications:
R-spondin2 gene might be a novel tumor suppressor gene providing new clues to clarify the biological behavior of HCC and thus reduce patient mortality and prolong survival.
Data from Adapting a Drug Screening Platform to Discover Associations of Molecular Targeted Radiosensitizers with Genomic Biomarkers
Authors: Liu Qi , Wang Meng , Kern Ashley M. , Khaled Saman , Han Jing , Yeap Beow Y. , Hong Theodore S. , Settleman Jeff , Benes Cyril H. , Held Kathryn D. , Efstathiou Jason A. , Willers Henning
Published: March 2024

Abstract
Large collections of annotated cancer cell lines are powerful tools for precisely matching targeted drugs with genomic alterations that can be tested as biomarkers in the clinic. Whether these screening platforms, which utilize short-term cell survival to assess drug responses, can be applied to precision radiation medicine is not established. To this end, 32 cancer cell lines were screened using 18 targeted therapeutic agents with known or putative radiosensitizing properties (227 combinations). The cell number remaining after drug exposure with or without radiation was assessed by nonclonogenic assays. We derived short-term radiosensitization factors (SRF2Gy) and calculated clonogenic survival assay–based dose enhancement factors (DEFSF0.1). Radiosensitization was characterized by SRF2Gy values of mostly ∼1.05 to 1.2 and significantly correlated with drug-induced changes in apoptosis and senescence frequencies. SRF2Gy was significantly correlated with DEFSF0.1, with a respective sensitivity and specificity of 91.7% and 81.5% for a 3-day endpoint, and 82.8% and 84.2% for a robotic 5-day assay. KRAS mutations (codons 12/13) were found to be a biomarker of radiosensitization by midostaurin in lung cancer, which was pronounced under conditions that enriched for stem cell–like cells. In conclusion, although short-term proliferation/survival assays cannot replace the gold-standard clonogenic survival assay for measuring cellular radiosensitivity, they capture with high accuracy the relative change in radiosensitivity that is caused by a radiosensitzing targeted agent.

Implications: This study supports a paradigm shift regarding the utility of short-term assays for precision radiation medicine, which should facilitate the identification of genomic biomarkers to guide the testing of novel drug/radiation combinations. Mol Cancer Res; 13(4); 713–20. ©2015 AACR.
Data from NF-κB–Activated miR-574 Promotes Multiple Malignant and Metastatic Phenotypes by Targeting BNIP3 in Thyroid Carcinoma
Authors: Zhang Zhe-Jia , Xiao Qian , Li Xin-Ying
Published: March 2024

Abstract
Thyroid cancer is the most common endocrine malignancy, and miR-574 is significantly upregulated in thyroid cancer. However, the role and underlying mechanism of miR-574 in thyroid cancer development are poorly understood. In this study, we showed that NF-κB/p65 signaling pathway was activated and miR-574 was upregulated in thyroid cancer cells. p65 directly bound to the promoter of miR-574 and activated miR-574 transcription. Functionally, miR-574 inhibited apoptosis, promoted proliferation and migration of thyroid cancer cells, and stimulated thyroid cancer–induced tube formation of endothelial cells. On the molecular level, miR-574 inhibited the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) by binding to 3′-UTR of BNIP3. miR-574 also downregulated the expression of apoptosis-inducing factor (AIF), while elevated the levels of MMP2, MMP9, and VEGFA. In vivo, miR-574 promoted xenograft growth, which was associated with reduced apoptosis and enhanced angiogenesis. NF-κB/miR-574 signaling presents multiple oncogenic activities on thyroid cancer development by directly regulating the BNIP3/AIF pathway. Therefore, targeting NF-κB/miR-574 signaling may reduce the aggressiveness of thyroid cancer.
Implications:
miR-574, directly regulated by NF-κB/p65, promotes tumorigenesis of thyroid cancer via inhibiting BNIP3/AIF pathway.
Data from A PSCA/PGRN–NF-κB–Integrin–α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential
Authors: Zhao Zhigang , Li Ermao , Luo Lianmin , Zhao Shankun , Liu Luhao , Wang Jiamin , Kang Ran , Luo Jintai
Published: March 2024

Abstract
Distant metastasis, predominantly to bone, is the leading cause of morbidity and mortality in prostate cancer. However, the mechanisms underlying prostate cancer metastases remain unknown. Prostate cancer cells exhibited discrete adhesion to bone marrow endothelial cells (BMEC), resulting in osteotropic metastasis. Prior data showed an increased metastatic propensity of prostate stem cell antigen (PSCA)–positive prostate cancer cells. The current study sought to characterize the roles of PSCA in the adhesion of prostate cancer cells to BMECs. Cell adhesion was assessed using the adhesion assay and transendothelial migration. The expression and regulation of integrins were evaluated by qRT-PCR, Western blot, promoter-luciferase activity, and chromatin immunoprecipitation (ChIP). Functionally, the potential interacting partners of PSCA in prostate cancer cells were identified by coimmunoprecipitation and mass spectrometry (MS) analysis. The association of PSCA expression with bone metastasis was further analyzed in an in vivo model and prostate cancer patients. We found that overexpression of PSCA enhanced the adhesion capability of prostate cancer cells to BMECs through upregulating integrin-α4 expression, concurrent with transcriptionally activated NF-κB. Growth factor progranulin (PGRN) was identified as a potential interacting partner of PSCA in prostate cancer cells. Functional studies showed that downregulation of PGRN and PSCA with siRNAs in prostate cancer cells significantly suppressed the integrin-α4 expression and the adhesion to BMECs in vitro, respectively, which were restorable by exogenous PGRN. Importantly, PSCA depletion significantly reduced tumors' presence in the bone of a mouse model. Furthermore, PSCA expression is elevated in prostate cancer tissue, and significantly associated with increased Gleason score, advanced stage, bone metastasis, and poor prognosis in prostate cancer patients. We conclude that PSCA/PGRN promoted the adhesion of prostate cancer cells to BMECs through NF-κB/integrin-α4 pathways, to facilitate metastases.
Implications:
The findings presented here suggest PSCA/PGRN as a potential therapeutic target for prostate cancer metastases, especially for bone metastasis.
Data from A p53/ARF-Dependent Anticancer Barrier Activates Senescence and Blocks Tumorigenesis without Impacting Apoptosis
Authors: Sinha Vidya C. , Qin Lan , Li Yi
Published: March 2024

Abstract
In response to oncogene activation and oncogene-induced aberrant proliferation, mammalian cells activate apoptosis and senescence, usually via the p53–ARF tumor-suppressor pathway. Apoptosis is a known barrier to cancer and is usually downregulated before full malignancy, but senescence as an anticancer barrier is controversial due to its presence in the tumor environment. In addition, senescence may aid cancer progression via releasing senescence-associated factors that instigate neighboring tumor cells. Here, it is demonstrated that apoptosis unexpectedly remains robust in ErbB2 (ERBB2/HER2)-initiated mammary early lesions arising in adult mice null for either p53 or ARF. These early lesions, however, downregulate senescence significantly. This diminished senescence response is associated with accelerated progression to cancer in ARF-null mice compared with ARF–wild-type mice. Thus, the ARF–p53 pathway is dispensable for the apoptosis anticancer barrier in the initiation of ErbB2 breast cancer, the apoptosis barrier alone cannot halt mammary tumorigenesis, and senescence is a key barrier against carcinogenesis.

Implications: Findings in this relevant mouse model of HER2-driven breast cancer suggest that effective prevention relies upon preserving both ARF/p53–independent apoptosis and ARF/p53–dependent senescence. Mol Cancer Res; 13(2); 231–8. ©2014 AACR.
Data from CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation
Authors: Yao Min , Fang Wei , Smart Curtis , Hu Qingting , Huang Shixia , Alvarez Nehemiah , Fields Patrick , Cheng Nikki
Published: March 2024

Abstract
Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor, and Her2 expression, and are resistant to antihormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage-dependent mechanisms. Here, we demonstrated important biological roles for CCL2/CCR2 signaling in breast cancer cells. Using the MCF10CA1d xenograft model of basal-like breast cancer, primary tumor growth was significantly increased with cotransplantation of patient-derived fibroblasts expressing high levels of CCL2, and was inhibited with CRISP/R gene ablation of stromal CCL2. CRISP/R gene ablation of CCR2 in MCF10CA1d breast cancer cells inhibited breast tumor growth and M2 macrophage recruitment and validated through CCR2 shRNA knockdown in the 4T1 model. Reverse phase protein array analysis revealed that cell-cycle protein expression was associated with CCR2 expression in basal-like breast cancer cells. CCL2 treatment of basal-like breast cancer cell lines increased proliferation and cell-cycle progression associated with SRC and PKC activation. Through pharmacologic approaches, we demonstrated that SRC and PKC negatively regulated expression of the cell-cycle inhibitor protein p27KIP1, and are necessary for CCL2-induced breast cancer cell proliferation.
Implications:
This report sheds novel light on CCL2/CCR2 chemokine signaling as a mitogenic pathway and cell-cycle regulator in breast cancer cells.
Data from Nucleoside Diphosphate Kinase-3 (NME3) Enhances TLR5-Induced NFκB Activation
Authors: Flentie Kelly , Gonzalez Caleb , Kocher Brandon , Wang Yue , Zhu Hongtu , Marasa Jayne , Piwnica-Worms David
Published: March 2024

Abstract
Bacterial flagellin is a potent activator of NFκB signaling, inflammation, and host innate immunity, and recent data indicate that flagellin represents a novel antitumor ligand acting through toll-like receptor 5 (TLR5) and the NFκB pathway to induce host immunity and aid in the clearance of tumor xenografts. To identify innate signaling components of TLR5 responsible for these antitumor effects, a loss-of-function high-throughput screen was employed utilizing carcinoma cells expressing a dynamic NFκB bioluminescent reporter stimulated by Salmonella typhimurium expressing flagellin. A live cell screen of a siRNA library targeting 691 known and predicted human kinases to identify novel tumor cell modulators of TLR5-induced NFκB activation uncovered several interesting positive and negative candidate regulators not previously recognized, including nucleoside diphosphate kinase 3 (NME3), characterized as an enhancer of signaling responses to flagellin. Targeted knockdown and overexpression assays confirmed the regulatory contribution of NME3 to TLR5-mediated NFκB signaling, mechanistically downstream of MyD88. Furthermore, Kaplan–Meier survival analysis showed that NME3 expression correlated highly with TLR5 expression in breast, lung, ovarian, and gastric cancers, and furthermore, high-level expression of NME3 increased overall survival for patients with breast, lung, and ovarian cancer, but the opposite in gastric cancer. Together, these data identify a previously unrecognized proinflammatory role for NME3 in signaling downstream of TLR5 that may potentiate cancer immunotherapies.

Implications: Proinflammatory signaling mediated by innate immunity engagement of flagellin-activated TLR5 in tumor cells results in antitumor effects through NME3 kinase, a positive downstream regulator of flagellin-mediated NFκB signaling, enhancing survival for several human cancers. Mol Cancer Res; 16(6); 986–99. ©2018 AACR.
Data from Unraveling the Cellular Mechanism of Assembling Cholesterols for Selective Cancer Cell Death
Authors: Wang Huaimin , Feng Zhaoqianqi , Yang Cuihong , Liu Jinjian , Medina Jamie E. , Aghvami S. Ali , Dinulescu Daniela M. , Liu Jianfeng , Fraden Seth , Xu Bing
Published: March 2024

Abstract
Acquired drug resistance remains a challenge in chemotherapy. Here we show enzymatic, in situ assembling of cholesterol derivatives to act as polypharmaceuticals for selectively inducing death of cancer cells via multiple pathways and without inducing acquired drug resistance. A conjugate of tyrosine and cholesterol (TC), formed by enzyme-catalyzed dephosphorylation of phosphorylate TC, self-assembles selectively on or in cancer cells. Acting as polypharmaceuticals, the assemblies of TC augment lipid rafts, aggregate extrinsic cell death receptors (e.g., DR5, CD95, or TRAILR), modulate the expression of oncoproteins (e.g., Src and Akt), disrupt the dynamics of cytoskeletons (e.g., actin filaments or microtubules), induce endoplasmic reticulum stress, and increase the production of reactive oxygen species, thus resulting in cell death and preventing acquired drug resistance. Moreover, the assemblies inhibit the growth of platinum-resistant ovarian cancer tumor in a murine model. This work illustrates the use of instructed assembly (iA) in cellular environment to form polypharmaceuticals in situ that not only interact with multiple proteins, but also modulate membrane dynamics for developing novel anticancer therapeutics.
Implications:
As a multifaceted strategy for controlling cancer cell death, iA minimized acquired resistance of cancer cells, which is a new strategy to amplify the genetic difference between cancer and normal cells and provides a promise for overcoming drug resistance in cancer therapy.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/4/907/F1.large.jpg.
Data from Endothelial Cells Promote Colorectal Cancer Cell Survival by Activating the HER3-AKT Pathway in a Paracrine Fashion
Authors: Wang Rui , Bhattacharya Rajat , Ye Xiangcang , Fan Fan , Boulbes Delphine R. , Ellis Lee M.
Published: March 2024

Abstract
The regulation of colorectal cancer cell survival pathways remains to be elucidated. Previously, it was demonstrated that endothelial cells (EC) from the liver (liver parenchymal ECs or LPEC), the most common site of colorectal cancer metastases, secrete soluble factors in the conditioned medium (CM) that, in turn, increase the cancer stem cell phenotype in colorectal cancer cells. However, the paracrine effects of LPECs on other colorectal cancer cellular functions have not been investigated. Here, results showed that CM from LPECs increased cell growth and chemoresistance by activating AKT in colorectal cancer cells in vitro. Using an unbiased receptor tyrosine kinase array, it was determined that human epidermal growth factor receptor 3 (ERBB3/HER3) was activated by CM from LPECs, and it mediated AKT activation, cell growth, and chemoresistance in colorectal cancer cells. Inhibition of HER3, either by an inhibitor AZD8931 or an antibody MM-121, blocked LPEC-induced HER3-AKT activation and cell survival in colorectal cancer cells. In addition, CM from LPECs increased in vivo tumor growth in a xenograft mouse model. Furthermore, inhibiting HER3 with AZD8931 significantly blocked tumor growth induced by EC CM. These results demonstrated a paracrine role of liver ECs in promoting cell growth and chemoresistance via activating HER3-AKT in colorectal cancer cells.
Implications:
This study suggested a potential of treating patients with metastatic colorectal cancer with HER3 antibodies/inhibitors that are currently being assessed in clinical trials for various cancer types.
Data from Novel lncRNA LINC00844 Regulates Prostate Cancer Cell Migration and Invasion through AR Signaling
Authors: Lingadahalli Shreyas , Jadhao Sudhir , Sung Ying Ying , Chen Mi , Hu Lingling , Chen Xin , Cheung Edwin
Published: March 2024

Abstract
The human genome is mostly transcribed, yielding a rich repository of noncoding transcripts that are involved in a myriad of biological processes including cancer. However, how many noncoding transcripts such as long noncoding RNAs (lncRNA) function in cancer is still unclear. This study identified a novel set of clinically relevant androgen-regulated lncRNAs in prostate cancer. Among this group, LINC00844 was demonstrated to be a direct androgen-regulated target that is actively transcribed in androgen receptor (AR)–dependent prostate cancer cells. The expression of LINC00844 is higher in normal prostate compared with malignant and metastatic prostate cancer clinical specimens, and patients with low expression had a poor prognosis and significantly increased biochemical recurrence, suggesting LINC00844 functions in suppressing tumor progression and metastasis. Indeed, in vitro loss-of-function studies revealed that LINC00844 prevents prostate cancer cell migration and invasion. Moreover, findings from gene expression profiling analysis indicated that LINC00844 functions in trans, affecting global androgen-regulated gene transcription. Mechanistic evidence reveals that LINC00844 is important in facilitating AR binding to the chromatin. Finally, LINC00844 mediates its phenotypic effects in part by activating the expression of NDRG1, a crucial cancer metastasis suppressor. Collectively, LINC00844 is a novel coregulator of AR that plays a central role in the androgen transcriptional network and the development and progression of prostate cancer.
Implications:
This study highlights the function of the lncRNA, LINC00844, in regulating global AR-regulated genes in prostate cancer by modulating AR binding to chromatin.
Data from The Clonal Evolution of Metastatic Osteosarcoma as Shaped by Cisplatin Treatment
Authors: Brady Samuel W. , Ma Xiaotu , Bahrami Armita , Satas Gryte , Wu Gang , Newman Scott , Rusch Michael , Putnam Daniel K. , Mulder Heather L. , Yergeau Donald A. , Edmonson Michael N. , Easton John , Alexandrov Ludmil B. , Chen Xiang , Mardis Elaine R. , Wilson Richard K. , Downing James R. , Pappo Alberto S. , Raphael Benjamin J. , Dyer Michael A. , Zhang Jinghui
Published: March 2024

Abstract
To investigate the genomic evolution of metastatic pediatric osteosarcoma, we performed whole-genome and targeted deep sequencing on 14 osteosarcoma metastases and two primary tumors from four patients (two to eight samples per patient). All four patients harbored ancestral (truncal) somatic variants resulting in TP53 inactivation and cell-cycle aberrations, followed by divergence into relapse-specific lineages exhibiting a cisplatin-induced mutation signature. In three of the four patients, the cisplatin signature accounted for >40% of mutations detected in the metastatic samples. Mutations potentially acquired during cisplatin treatment included NF1 missense mutations of uncertain significance in two patients and a KIT G565R activating mutation in one patient. Three of four patients demonstrated widespread ploidy differences between samples from the sample patient. Single-cell seeding of metastasis was detected in most metastatic samples. Cross-seeding between metastatic sites was observed in one patient, whereas in another patient a minor clone from the primary tumor seeded both metastases analyzed. These results reveal extensive clonal heterogeneity in metastatic osteosarcoma, much of which is likely cisplatin-induced.
Implications:
The extent and consequences of chemotherapy-induced damage in pediatric cancers is unknown. We found that cisplatin treatment can potentially double the mutational burden in osteosarcoma, which has implications for optimizing therapy for recurrent, chemotherapy-resistant disease.