bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Defects in Emerin–Nucleoskeleton Binding Disrupt Nuclear Structure and Promote Breast Cancer Cell Motility and Metastasis
Authors: Liddane Alexandra G. , McNamara Chelsea A. , Campbell Mallory C. , Mercier Isabelle , Holaska James M.
Published: April 2023

Abstract
Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamins are found in many cancers and its expression is correlated with better clinical outcomes. The nucleus is the largest organelle in the cell with a diameter between 10 and 20 μm. Nuclear size significantly impacts cell migration. Nuclear structural changes are predicted to impact cancer metastasis by regulating cancer cell migration. Here we show emerin regulates nuclear structure in invasive breast cancer cells to impact cancer metastasis. Invasive breast cancer cells had 40% to 50% less emerin than control cells, which resulted in decreased nuclear size. Overexpression of GFP-emerin in invasive breast cancer cells rescued nuclear size and inhibited migration through 3.0 and 8.0 μm pores. Mutational analysis showed emerin binding to nucleoskeletal proteins was important for its regulation of nuclear structure, migration, and invasion. Importantly, emerin expression inhibited lung metastasis by 91% in orthotopic mouse models of breast cancer. Emerin nucleoskeleton-binding mutants failed to inhibit metastasis. These results support a model whereby emerin binding to the nucleoskeleton regulates nuclear structure to impact metastasis. In this model, emerin plays a central role in metastatic transformation, because decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation.
Implications:
Modulating emerin expression and function represents new targets for therapeutic interventions of metastasis, because increased emerin expression rescued cancer metastasis.
Data from Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A Is Mediated by Replication Protein A in Ovarian Cancer
Authors: Sriramkumar Shruthi , Matthews Timothy D. , Ghobashi Ahmed H. , Miller Samuel A. , VanderVere-Carozza Pamela S. , Pawelczak Katherine S. , Nephew Kenneth P. , Turchi John J. , O'Hagan Heather M.
Published: April 2023

Abstract
Platinum resistance is a common occurrence in high-grade serous ovarian cancer and a major cause of ovarian cancer deaths. Platinum agents form DNA cross-links, which activate nucleotide excision repair (NER), Fanconi anemia, and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in ovarian cancer and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in ovarian cancer is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in ovarian cancer cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A, involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impairs the activation of the G2–M DNA damage checkpoint, reduces the ability of ovarian cancer cells to repair platinum DNA damage, and increases sensitivity to platinum.
Implications:
Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of ovarian cancer to standard chemotherapy regimens.
Data from Omega-3 Eicosapentaenoic Acid Reduces Prostate Tumor Vascularity
Authors: Gevariya Nikunj , Lachance Gabriel , Robitaille Karine , Joly Beauparlant Charles , Beaudoin Lisanne , Fournier Éric , Fradet Yves , Droit Arnaud , Julien Pierre , Marette André , Bergeron Alain , Fradet Vincent
Published: April 2023

Abstract
The impact of omega (ω)-3 fatty acids on prostate cancer is controversial in epidemiological studies but experimental studies suggest a protective effect. However, little is known about the mechanism of action. Here, we studied the effects of purified fatty acid molecules on prostate tumor progression using the TRAMP-C2 syngeneic immunocompetent mouse model. Compared with ω-6 or ω-9–supplemented animals, we observed that late-stage prostate tumor growth was reduced with a monoacylglyceride (MAG)-conjugated form of eicosapentaenoic acid (EPA) supplementation, whereas docosahexanenoic acid (DHA) caused an early reduction. MAG–EPA significantly decreased tumor blood vessel diameter (P < 0.001). RNA sequencing analysis revealed that MAG–EPA downregulated angiogenesis- and vascular-related pathways in tumors. We also observed this tissue vascular phenotype in a clinical trial testing MAG–EPA versus a high oleic sunflower oil placebo. Using anti-CD31 IHC, we observed that MAG–EPA reduced blood vessel diameter in prostate tumor tissue (P = 0.03) but not in normal adjacent tissue. Finally, testing autocrine and paracrine effects in an avascular tumor spheroid growth assay, both exogenous MAG–EPA and endogenous ω3 reduced VEGF secretion and in vitro endothelial cell tube formation and blocked tumor spheroid growth, suggesting that ω3 molecules can directly hinder prostate cancer cell growth. Altogether, our results suggest that fatty acids regulate prostate cancer growth and that a tumor-specific microenvironment is required for the anti-vascular effect of MAG–EPA in patients with prostate cancer.
Implications:
Increasing the amount of ingested EPA omega-3 subtype for patients with prostate cancer might help to reduce prostate tumor progression by reducing tumor vascularization.
Data from Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of the Nucleosome Remodeling Factor
Authors: Tyutyunyk-Massey Liliya , Sun Yilun , Dao Nga , Ngo Hannah , Dammalapati Mallika , Vaidyanathan Ashish , Singh Manjulata , Haqqani Syed , Haueis Joshua , Finnegan Ryan , Deng Xiaoyan , Kirberger Steve E. , Bos Paula D. , Bandyopadhyay Dipankar , Pomerantz William C.K. , Pommier Yves , Gewirtz David A. , Landry Joseph W.
Published: April 2023

Abstract
Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (TOP2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacologic inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231, but not ER-positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased TOP2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of TOP2 poisons, preventing the resolution of TOP2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small-molecule inhibitors to enhance the effectiveness of TOP2-targeted cancer chemotherapeutic drugs.
Implications:
These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.
Data from mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment
Authors: Haas Michael S. , Kagey Michael H. , Heath Heidi , Schuerpf Franziska , Rottman James B. , Newman Walter
Published: April 2023

Abstract
Dickkopf-1 (DKK1), a secreted modulator of Wnt signaling, is overexpressed in many cancers, is often associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in patients with gastric/gastroesophageal junction cancer. The purpose of this study is to characterize a murine version of DKN-01 (mDKN-01) and to better understand its mechanism of action. We examined the efficacy of mDKN-01 in both melanoma and metastatic breast cancer models. Immune depletion experiments revealed a requirement for natural killer (NK) but not B and T cells for tumor growth inhibition. mDKN-01 treatment promotes the induction of the NK-activating cytokines IL15 and IL33 as well as an enhanced recruitment of CD45+ cells. Other treatment-related changes include a reduction of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) in the tumor and spleen and the upregulation of PD-L1 on MDSCs. In addition, mDKN-01 has a marked effect at reducing pulmonary metastases in the mouse 4T1 breast cancer model. Finally, the mDKN-01/anti-PD-1 combination was more effective at inhibiting melanoma growth than mDKN-01 alone. Taken together, our data demonstrate that mDKN-01 has efficacy by blocking the immunosuppressive effects of DKK1 in the tumor microenvironment (TME) and provides insight into the clinical activity observed with DKN-01–based treatment.
Implications:
mDKN-01 reverses a DKK1-mediated innate immune suppression in the TME and has additive efficacy with a PD-1 inhibitor.
Data from RAD51AP1 Loss Attenuates Colorectal Cancer Stem Cell Renewal and Sensitizes to Chemotherapy
Authors: Bridges Allison E. , Ramachandran Sabarish , Tamizhmani Kavin , Parwal Utkarsh , Lester Adrienne , Rajpurohit Pragya , Morera Daley S. , Hasanali Sarrah L. , Arjunan Pachiappan , Jedeja Ravirajsinh N. , Patel Nikhil , Martin Pamela M. , Korkaya Hasan , Singh Nagendra , Manicassamy Santhakumar , Prasad Puttur D. , Lokeshwar Vinata B. , Lokeshwar Bal L. , Ganapathy Vadivel , Thangaraju Muthusamy
Published: April 2023

Abstract
DNA damage, induced by either chemical carcinogens or environmental pollutants, plays an important role in the initiation of colorectal cancer. DNA repair processes, however, are involved in both protecting against cancer formation, and also contributing to cancer development, by ensuring genomic integrity and promoting the efficient DNA repair in tumor cells, respectively. Although DNA repair pathways have been well exploited in the treatment of breast and ovarian cancers, the role of DNA repair processes and their therapeutic efficacy in colorectal cancer is yet to be appreciably explored. To understand the role of DNA repair, especially homologous recombination (HR), in chemical carcinogen-induced colorectal cancer growth, we unraveled the role of RAD51AP1 (RAD51-associated protein 1), a protein involved in HR, in genotoxic carcinogen (azoxymethane, AOM)–induced colorectal cancer. Although AOM treatment alone significantly increased RAD51AP1 expression, the combination of AOM and dextran sulfate sodium (DSS) treatment dramatically increased by several folds. RAD51AP1 expression is found in mouse colonic crypt and proliferating cells. RAD51AP1 expression is significantly increased in majority of human colorectal cancer tissues, including BRAF/KRAS mutant colorectal cancer, and associated with reduced treatment response and poor prognosis. Rad51ap1-deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer (ApcMin/+). Furthermore, chemotherapy-resistant colorectal cancer is associated with increased RAD51AP1 expression. This phenomenon is associated with reduced cell proliferation and colorectal cancer stem cell (CRCSC) self-renewal. Overall, our studies provide evidence that RAD51AP1 could be a novel diagnostic marker for colorectal cancer and a potential therapeutic target for colorectal cancer prevention and treatment.
Implications:
This study provides first in vivo evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.
Data from Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling
Authors: Dwyer Amy R. , Kerkvliet Carlos Perez , Krutilina Raisa I. , Playa Hilaire C. , Parke Deanna N. , Thomas Warner A. , Smeester Branden A. , Moriarity Branden S. , Seagroves Tiffany N. , Lange Carol A.
Published: April 2023

Abstract
Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of patients with breast cancer; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of triple-negative breast cancer (TNBC) remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e., via knock-out or add-back) had little effect on primary tumor volume, but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in-frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor–stimulated cell motility relative to SH3-del, KM, or wild-type PTK6 controls. Reverse-phase protein array revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model.
Implications:
The SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC via RhoA and AhR, identified herein as novel therapeutic targets in PTK6+ breast tumors.
Data from Quantitative Proteomics Identifies Secreted Diagnostic Biomarkers as well as Tumor-Dependent Prognostic Targets for Clear Cell Renal Cell Carcinoma
Authors: Senturk Aydanur , Sahin Ayse T. , Armutlu Ayse , Kiremit Murat C. , Acar Omer , Erdem Selcuk , Bagbudar Sidar , Esen Tarik , Tuncbag Nurcan , Ozlu Nurhan
Published: April 2023

Abstract
Clear cell renal cell carcinoma (ccRCC) is the third most common and most malignant urological cancer, with a 5-year survival rate of 10% for patients with advanced tumors. Here, we identified 10,160 unique proteins by in-depth quantitative proteomics, of which 955 proteins were significantly regulated between tumor and normal adjacent tissues. We verified four putatively secreted biomarker candidates, namely, PLOD2, FERMT3, SPARC, and SIRPα, as highly expressed proteins that are not affected by intratumor and intertumor heterogeneity. Moreover, SPARC displayed a significant increase in urine samples of patients with ccRCC, making it a promising marker for the detection of the disease in body fluids. Furthermore, based on molecular expression profiles, we propose a biomarker panel for the robust classification of ccRCC tumors into two main clusters, which significantly differed in patient outcome with an almost three times higher risk of death for cluster 1 tumors compared with cluster 2 tumors. Moreover, among the most significant clustering proteins, 13 were targets of repurposed inhibitory FDA-approved drugs. Our rigorous proteomics approach identified promising diagnostic and tumor-discriminative biomarker candidates which can serve as therapeutic targets for the treatment of ccRCC.
Implications:
Our in-depth quantitative proteomics analysis of ccRCC tissues identifies the putatively secreted protein SPARC as a promising urine biomarker and reveals two molecular tumor phenotypes.
Data from Distinct Biomarker Profiles and TCR Sequence Diversity Characterize the Response to PD-L1 Blockade in a Mouse Melanoma Model
Authors: El Meskini Rajaa , Atkinson Devon , Kulaga Alan , Abdelmaksoud Abdalla , Gumprecht Michelle , Pate Nathan , Hayes Susana , Oberst Michael , Kaplan Ian M. , Raber Patrick , Van Dyke Terry , Sharan Shyam K. , Hollingsworth Robert , Day Chi-Ping , Merlino Glenn , Weaver Ohler Zoë
Published: April 2023

Abstract
Only a subset of patients responds to immune checkpoint blockade (ICB) in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti–mouse PD-L1 antibody similar to the anti–human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti–PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T-cell infiltration, and T-cell receptor (TCR) signatures in regressing tumors compared with tumors exhibiting no response to anti–PD-L1 treatment. We found that CD8+ T-cell tumor infiltration corresponded to response to treatment, and that anti–PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine–cytokine receptor interaction, and natural killer cell–mediated cytotoxicity. TCR sequence data suggest that an anti–PD-L1–mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy.
Implications:
Our melanoma model recapitulates the variable response to anti–PD-L1 observed in patients and exhibits biomarkers that characterize early antibody response, including expansion of the TCR repertoire.
Data from Exosomal CD47 Plays an Essential Role in Immune Evasion in Ovarian Cancer
Authors: Shimizu Aasa , Sawada Kenjiro , Kobayashi Masaki , Yamamoto Misa , Yagi Taro , Kinose Yasuto , Kodama Michiko , Hashimoto Kae , Kimura Tadashi
Published: April 2023

Abstract
Ovarian cancer is largely diagnosed at advanced stages upon detection of multiple peritoneal dissemination, resulting in poor outcomes. CD47 is overexpressed in tumors, facilitates tumor immune evasion, and is located on exosomes. We aimed to investigate the role of exosomal CD47 in ovarian cancer progression. Prognostic significance of CD47 expression in ovarian cancer was examined using a public database including 1,435 patients and validated with 26 patients at our institution. CD47 expression was associated with poor progression-free survival and inversely correlated with macrophage infiltration in ovarian cancer tissues. Exosomes were collected from ovarian cancer cell lines, and CD47 expression on exosomes was confirmed via flow cytometry. Inhibition of exosome secretion with GW4869 and exosome uptake with 5-(N-ethyl-N-isopropyl)-amiloride inhibited the surface CD47 expression on ovarian cancer cells and promoted phagocytosis by macrophages. RAB27A (a key regulator of exosome release) knockdown inhibited exosome secretion and led to CD47 downregulation in ovarian cancer cells. In a xenograft mouse model, suppression of the release of tumor-derived exosomes by GW4869 or RAB27A knockdown suppressed tumor progression and enhanced M1 macrophage phagocytosis in cancer tissues. Collectively, CD47 expression was correlated with poor prognoses in patients with ovarian cancer, suggesting the importance of immune evasion. CD47 was expressed on exosomes and the inhibition of exosome secretion and/or uptake enhanced cancer cell phagocytosis by macrophages, and thus, suppressed peritoneal dissemination. This suggests the potential of a novel immune checkpoint therapeutic agent that focuses on exosomes.
Implications:
Mechanistic insight from the current study suggests that exosomal CD47 may be an advantageous therapeutic target in ovarian cancer.
Data from SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1
Authors: Pennington Katie L. , McEwan Colten M. , Woods James , Muir Colin M. , Pramoda Sahankumari A.G. , Eastmond Riley , Balasooriya Eranga R. , Egbert Christina M. , Kaur Sandeep , Heaton Tyler , McCormack Katherine K. , Piccolo Stephen R. , Kurokawa Manabu , Andersen Joshua L.
Published: April 2023

Abstract
PTOV1 is an oncogenic protein, initially identified in prostate cancer, that promotes proliferation, cell motility, and invasiveness. However, the mechanisms that regulate PTOV1 remain unclear. Here, we identify 14-3-3 as a PTOV1 interactor and show that high levels of 14-3-3 expression, like PTOV1, correlate with prostate cancer progression. We discover an SGK2-mediated phosphorylation of PTOV1 at S36, which is required for 14-3-3 binding. Disruption of the PTOV1–14–3-3 interaction results in an accumulation of PTOV1 in the nucleus and a proteasome-dependent reduction in PTOV1 protein levels. We find that loss of 14-3-3 binding leads to an increase in PTOV1 binding to the E3 ubiquitin ligase HUWE1, which promotes proteasomal degradation of PTOV1. Conversely, our data suggest that 14-3-3 stabilizes PTOV1 protein by sequestering PTOV1 in the cytosol and inhibiting its interaction with HUWE1. Finally, our data suggest that stabilization of the 14-3-3–bound form of PTOV1 promotes PTOV1-mediated expression of cJun, which drives cell-cycle progression in cancer. Together, these data provide a mechanism to understand the regulation of the oncoprotein PTOV1.
Implications:
These findings identify a potentially targetable mechanism that regulates the oncoprotein PTOV1.
Data from SynPathy: Predicting Drug Synergy through Drug-Associated Pathways Using Deep Learning
Authors: Tang Yi-Ching , Gottlieb Assaf
Published: April 2023

Abstract
Drug combination therapy has become a promising therapeutic strategy for cancer treatment. While high-throughput drug combination screening is effective for identifying synergistic drug combinations, measuring all possible combinations is impractical due to the vast space of therapeutic agents and cell lines. In this study, we propose a biologically-motivated deep learning approach to identify pathway-level features from drug and cell lines' molecular data for predicting drug synergy and quantifying the interactions in synergistic drug pairs. This method obtained an MSE of 70.6 ± 6.4, significantly surpassing previous approaches while providing potential candidate pathways to explain the prediction. We further demonstrate that drug combinations tend to be more synergistic when their top contributing pathways are closer to each other on a protein interaction network, suggesting a potential strategy for combination therapy with topologically interacting pathways. Our computational approach can thus be utilized both for prescreening of potential drug combinations and for designing new combinations based on proximity of pathways associated with drug targets and cell lines.
Implications:
Our computational framework may be translated in the future to clinical scenarios where synergistic drugs are tailored to the patient and additionally, drug development could benefit from designing drugs that target topologically close pathways.
Data from cAMP-Mediated Autophagy Promotes Cell Survival via ROS-Induced Activation of PARP1: Implications for Treatment of Acute Lymphoblastic Leukemia
Authors: Richartz Nina , Pietka Wojciech , Gilljam Karin M. , Skah Seham , Skålhegg Bjørn S. , Bhagwat Sampada , Naderi Elin Hallan , Ruud Ellen , Blomhoff Heidi Kiil
Published: April 2023

Abstract
DNA-damaging therapy is the basis for treatment of most cancers, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL). We have previously shown that cAMP-activating factors present in the bone marrow render ALL cells less sensitive to DNA damage–induced apoptosis, by enhancing autophagy and suppressing p53. To sensitize ALL cells to DNA-damaging therapy, we have searched for novel targets that may counteract the effects induced by cAMP signaling. In the current study, we have identified PARP1 as a potential target. We show that the PARP1 inhibitors olaparib or PJ34 inhibit cAMP-mediated autophagy and thereby potentiate the DNA-damaging treatment. Furthermore, we reveal that cAMP-mediated PARP1 activation is preceded by induction of reactive oxygen species (ROS) and results in depletion of nicotinamide adenine dinucleotide (NAD), both of which are autophagy-promoting events. Accordingly, we demonstrate that scavenging ROS by N-acetylcysteine and repleting NAD independently reduce DNA damage-induced autophagy. In addition, olaparib augmented the effect of DNA-damaging treatment in a human xenograft model of ALL in NOD-scidIL2Rgammanull mice. On the basis of the current findings, we suggest that PARP1 inhibitors may enhance the efficiency of conventional genotoxic therapies and thereby provide a novel treatment strategy for pediatric patients with ALL.
Implications:
PARP1 inhibitors augment the DNA damage–induced killing of ALL cells by limiting the opposing effects of cAMP-mediated autophagy, which involves ROS-induced PARP1 activation and depletion of cellular NAD levels.
Data from Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer
Authors: Moore Grace , Majumdar Rahul , Powell Simon N. , Khan Atif J. , Weinhold Nils , Yin Shen , Higginson Daniel S.
Published: April 2023

Abstract
Cancer cells defective in homologous recombination (HR) are responsive to DNA-crosslinking chemotherapies, PARP inhibitors, and inhibitors of polymerase theta (Pol θ), a key mediator of the backup pathway alternative end-joining. Such cancers include those with pathogenic biallelic alterations in core HR genes and another cohort of cases that exhibit sensitivity to the same agents and harbor genomic hallmarks of HR deficiency (HRD). These HRD signatures include a single-base substitution pattern, large rearrangements, characteristic tandem duplications, and small deletions. Here, we used what is now known about the backup pathway alternative end-joining (Alt-EJ) through the key factor Pol θ to design and test novel signatures of polymerase theta–mediated (TMEJ) repair. We generated two novel signatures; a signature composed of small deletions with microhomology and another consisting of small, templated insertions (TINS). We find that TINS consistent with TMEJ repair are highly specific to tumors with pathogenic biallelic mutations in BRCA2 and that high TINS genomic signature content in advanced ovarian cancers associate with overall survival following treatment with platinum agents. In addition, the combination of TINS with other HRD metrics significantly improves the association of platinum sensitivity with survival compared with current state-of-the-art signatures.
Implications:
Small, templated insertions indicative of theta-mediated end-joining likely can be used in conjunction with other HRD mutational signatures as a prognostic tool for patient response to therapies targeting HR deficiency.
Data from Identifying Phased Mutations and Complex Rearrangements in Human Prostate Cancer Cell Lines through Linked-Read Whole-Genome Sequencing
Authors: Pham Minh-Tam , Gupta Anuj , Gupta Harshath , Vaghasia Ajay , Skaist Alyza , Garrison McKinzie A. , Coulter Jonathan B. , Haffner Michael C. , Zheng S. Lilly , Xu Jianfeng , DeStefano Shields Christina , Isaacs William B. , Wheelan Sarah J. , Nelson William G. , Yegnasubramanian Srinivasan
Published: April 2023

Abstract
A limited number of cell lines have fueled the majority of preclinical prostate cancer research, but their genomes remain incompletely characterized. Here, we utilized whole-genome linked-read sequencing for comprehensive characterization of phased mutations and rearrangements in the most commonly used cell lines in prostate cancer research including PC3, LNCaP, DU145, CWR22Rv1, VCaP, LAPC4, MDA-PCa-2b, RWPE-1, and four derivative castrate-resistant (CR) cell lines LNCaP_Abl, LNCaP_C42b, VCaP-CR, and LAPC4-CR. Phasing of mutations allowed determination of “gene-level haplotype” to assess whether genes harbored heterozygous mutations in one or both alleles. Phased structural variant analysis allowed identification of complex rearrangement chains consistent with chromothripsis and chromoplexy. In addition, comparison of parental and derivative CR lines revealed previously known and novel genomic alterations associated with the CR phenotype.
Implications:
This study therefore comprehensively characterized phased genomic alterations in the commonly used prostate cancer cell lines, providing a useful resource for future prostate cancer research.
Data from Transcriptome Profiling of ADAR1 Targets in Triple-Negative Breast Cancer Cells Reveals Mechanisms for Regulating Growth and Invasion
Authors: Baker Allison R. , Miliotis Christos , Ramírez-Moya Julia , Marc Talia , Vlachos Ioannis S. , Santisteban Pilar , Slack Frank J.
Published: April 2023

Abstract
ADARs catalyze adenosine-to-inosine (A-to-I) editing of double-stranded RNA and regulate global gene expression output through interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is a critical gene for triple-negative breast cancer cells, as ADAR1 loss results in reduced growth (viability and cell cycle progression), invasion, and mammosphere formation. Whole transcriptome sequencing analyses demonstrate that ADAR1 regulates both coding and noncoding targets by altering gene expression level, A-to-I editing, and splicing. We determine that a recoding edit in filamin B (FLNB chr3:58156064) reduces the tumor suppressive activities of the protein to promote growth and invasion. We also show that several tumor suppressor miRNAs are upregulated upon ADAR1 loss and suppress cell-cycle progression and invasion. This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple-negative breast cancer, providing support to strategies targeting ADAR1 in this aggressive cancer type that has few treatment options.
Implications:
Targeting ADAR1 and thus downstream FLNB editing and miRNA regulation represents a possible novel therapeutic strategy in triple-negative breast cancer.
Data from Ceramide Kinase Inhibition Drives Ferroptosis and Sensitivity to Cisplatin in Mutant KRAS Lung Cancer by Dysregulating VDAC-Mediated Mitochondria Function
Authors: Vu Ngoc T. , Kim Minjung , Stephenson Daniel J. , MacKnight H. Patrick , Chalfant Charles E.
Published: April 2023

Abstract
Ceramide kinase (CERK) is the mammalian lipid kinase from which the bioactive sphingolipid, ceramide-1-phosphate (C1P), is derived. CERK has been implicated in several promalignant phenotypes with little known as to mechanistic underpinnings. In this study, the mechanism of how CERK inhibition decreases cell survival in mutant (Mut) KRAS non–small cell lung cancer (NSCLC), a major lung cancer subtype, was revealed. Specifically, NSCLC cells possessing a KRAS mutation were more responsive to inhibition, downregulation, and genetic ablation of CERK compared with those with wild-type (WT) KRAS regarding a reduction in cell survival. Inhibition of CERK induced ferroptosis in Mut KRAS NSCLC cells, which required elevating VDAC-regulated mitochondria membrane potential (MMP) and the generation of cellular reactive oxygen species (ROS). Importantly, through modulation of VDAC, CERK inhibition synergized with the first-line NSCLC treatment, cisplatin, in reducing cell survival and in vivo tumor growth. Further mechanistic studies indicated that CERK inhibition affected MMP and cell survival by limiting AKT activation and translocation to mitochondria, and thus, blocking VDAC phosphorylation and tubulin recruitment.
Implications:
Our findings depict how CERK inhibition may serve as a new key point in combination therapeutic strategy for NSCLC, specifically precision therapeutics targeting NSCLC possessing a KRAS mutation.
Supplementary Table 1 from Effects of Ginger Supplementation on Cell-Cycle Biomarkers in the Normal-Appearing Colonic Mucosa of Patients at Increased Risk for Colorectal Cancer: Results from a Pilot, Randomized, and Controlled Trial
Authors: Citronberg Jessica , Bostick Roberd , Ahearn Thomas , Turgeon D. Kim , Ruffin Mack T. , Djuric Zora , Sen Ananda , Brenner Dean E. , Zick Suzanna M.
Published: April 2023

PDF file - 65K, Adverse Events (AE)Reported by Participant
Supplementary Figure 1 from Effects of Ginger Supplementation on Cell-Cycle Biomarkers in the Normal-Appearing Colonic Mucosa of Patients at Increased Risk for Colorectal Cancer: Results from a Pilot, Randomized, and Controlled Trial
Authors: Citronberg Jessica , Bostick Roberd , Ahearn Thomas , Turgeon D. Kim , Ruffin Mack T. , Djuric Zora , Sen Ananda , Brenner Dean E. , Zick Suzanna M.
Published: April 2023

PDF file - 63K, Cell Cycle Biomarkers of Risk
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Authors: McConkey David J. , Dinney Colin P.
Published: April 2023

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Authors: Ravdin Peter M.
Published: April 2023

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Supplementary Figure Legend from Combined Serum CA19-9 and miR-27a-3p in Peripheral Blood Mononuclear Cells to Diagnose Pancreatic Cancer
Authors: Wang Wan-Sheng , Liu Ling-Xiao , Li Guo-Ping , Chen Yi , Li Chang-Yu , Jin Da-Yong , Wang Xiao-Lin
Published: April 2023

PDF file - 110K
Supplementary Figure 1 from Combined Serum CA19-9 and miR-27a-3p in Peripheral Blood Mononuclear Cells to Diagnose Pancreatic Cancer
Authors: Wang Wan-Sheng , Liu Ling-Xiao , Li Guo-Ping , Chen Yi , Li Chang-Yu , Jin Da-Yong , Wang Xiao-Lin
Published: April 2023

PDF file - 108K, Hierarchical clustering of microRNA expression profiles in three group comparisons. A total of 581 microRNAs were identified via Hiseq sequencing
Supplementary Figures 1 - 2 from Molecular Imaging of Cyclooxygenase-2 in Canine Transitional Cell Carcinomas In Vitro and In Vivo
Authors: Cekanova Maria , Uddin Md. Jashim , Bartges Joseph W. , Callens Amanda , Legendre Alfred M. , Rathore Kusum , Wright Laura , Carter Amanda , Marnett Lawrence J.
Published: April 2023

PDF file - 429K, Supplemental Figure S1: Lymphocytic and neutrophilic inflammation of canine bladder. Supplemental Figure S2: Characterization of K9TCC#2Dakota and UMUC-3 tumors.
Supplementary Figure Legend from Molecular Imaging of Cyclooxygenase-2 in Canine Transitional Cell Carcinomas In Vitro and In Vivo
Authors: Cekanova Maria , Uddin Md. Jashim , Bartges Joseph W. , Callens Amanda , Legendre Alfred M. , Rathore Kusum , Wright Laura , Carter Amanda , Marnett Lawrence J.
Published: April 2023

PDF file - 55K
Supplementary Table 1 from Programmable Bio-Nano-Chip Systems for Serum CA125 Quantification: Toward Ovarian Cancer Diagnostics at the Point-of-Care
Authors: Raamanathan Archana , Simmons Glennon W. , Christodoulides Nicolaos , Floriano Pierre N. , Furmaga Wieslaw B. , Redding Spencer W. , Lu Karen H. , Bast Robert C. , McDevitt John T.
Published: April 2023

PDF file - 29K, Matched Pair Optimization Summary
Supplementary Methods from Programmable Bio-Nano-Chip Systems for Serum CA125 Quantification: Toward Ovarian Cancer Diagnostics at the Point-of-Care
Authors: Raamanathan Archana , Simmons Glennon W. , Christodoulides Nicolaos , Floriano Pierre N. , Furmaga Wieslaw B. , Redding Spencer W. , Lu Karen H. , Bast Robert C. , McDevitt John T.
Published: April 2023

PDF file - 29K, p-BNC construction, sample collection, Image analysis
Supplementary Table 1 from Sunitinib Prolongs Survival in Genetically Engineered Mouse Models of Multistep Lung Carcinogenesis
Authors: Gandhi Leena , McNamara Kate L. , Li Danan , Borgman Christa L. , McDermott Ultan , Brandstetter Kathleyn A. , Padera Robert F. , Chirieac Lucian R. , Settleman Jeffrey E. , Wong Kwok-Kin
Published: April 2023

Supplementary Table 1 from Sunitinib Prolongs Survival in Genetically Engineered Mouse Models of Multistep Lung Carcinogenesis
Supplementary Materials 1 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
Authors: Abba Martín C. , Hu Yuhui , Levy Carla C. , Gaddis Sally , Kittrell Frances S. , Hill Jamal , Bissonnette Reid P. , Brown Powel H. , Medina Daniel , Aldaz C. Marcelo
Published: April 2023

Supplementary Materials 1 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
Supplementary Figure 1 from Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia
Authors: Gümüş Zeynep H. , Du Baoheng , Kacker Ashutosh , Boyle Jay O. , Bocker Jennifer M. , Mukherjee Piali , Subbaramaiah Kotha , Dannenberg Andrew J. , Weinstein Harel
Published: April 2023

Supplementary Figure 1 from Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia
Supplementary Figure 1 Legend from Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia
Authors: Gümüş Zeynep H. , Du Baoheng , Kacker Ashutosh , Boyle Jay O. , Bocker Jennifer M. , Mukherjee Piali , Subbaramaiah Kotha , Dannenberg Andrew J. , Weinstein Harel
Published: April 2023

Supplementary Figure 1 Legend from Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia
Supplementary Table 1 from The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I.
Published: April 2023

XLS file - 17K, Primers
Perspective on this Article from A Pilot Surrogate Endpoint Biomarker Study of Celecoxib in Oral Premalignant Lesions
Authors: Wirth Lori J. , Krane Jeffrey F. , Li Yi , Othus Megan , Moran Amy E. , Dorfman David M. , Norris Charles M. , Goguen Laura , Posner Marshall R. , Haddad Robert I. , Bertagnolli Monica M.
Published: April 2023

Perspective on this Article from A Pilot Surrogate Endpoint Biomarker Study of Celecoxib in Oral Premalignant Lesions
Related Article from Profiles in Variation: Lung Carcinogenesis
Authors: Carbone David P.
Published: April 2023

Related Article from Profiles in Variation: Lung Carcinogenesis
Perspective on this Article from An Expanded Risk Prediction Model for Lung Cancer
Authors: Spitz Margaret R. , Etzel Carol J. , Dong Qiong , Amos Christopher I. , Wei Qingyi , Wu Xifeng , Hong Waun Ki
Published: April 2023

Perspective on this Article from An Expanded Risk Prediction Model for Lung Cancer
Perspective on This Article from Racial Survival Disparity in Head and Neck Cancer Results from Low Prevalence of Human Papillomavirus Infection in Black Oropharyngeal Cancer Patients
Authors: Settle Kathleen , Posner Marshall R. , Schumaker Lisa M. , Tan Ming , Suntharalingam Mohan , Goloubeva Olga , Strome Scott E. , Haddad Robert I. , Patel Shital S. , Cambell Earl V. , Sarlis Nicholas , Lorch Jochen , Cullen Kevin J.
Published: April 2023

Perspective on This Article from Racial Survival Disparity in Head and Neck Cancer Results from Low Prevalence of Human Papillomavirus Infection in Black Oropharyngeal Cancer Patients
Supplementary Information from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial
Authors: Bertagnolli Monica M. , Eagle Craig J. , Zauber Ann G. , Redston Mark , Breazna Aurora , Kim KyungMann , Tang Jie , Rosenstein Rebecca B. , Umar Asad , Bagheri Donya , Collins Neal T. , Burn John , Chung Daniel C. , Dewar Thomas , Foley T. Raymond , Hoffman Neville , Macrae Finlay , Pruitt Ronald E. , Saltzman John R. , Salzberg Bruce , Sylwestrowicz Thomas , Hawk Ernest T.
Published: April 2023

Supplementary Information from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial
Perspective on this Article from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial
Authors: Bertagnolli Monica M. , Eagle Craig J. , Zauber Ann G. , Redston Mark , Breazna Aurora , Kim KyungMann , Tang Jie , Rosenstein Rebecca B. , Umar Asad , Bagheri Donya , Collins Neal T. , Burn John , Chung Daniel C. , Dewar Thomas , Foley T. Raymond , Hoffman Neville , Macrae Finlay , Pruitt Ronald E. , Saltzman John R. , Salzberg Bruce , Sylwestrowicz Thomas , Hawk Ernest T.
Published: April 2023

Perspective on this Article from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial
Supplementary Table 1 from A Clinical Risk Prediction Model for Barrett Esophagus
Authors: Thrift Aaron P. , Kendall Bradley J. , Pandeya Nirmala , Vaughan Thomas L. , Whiteman David C.
Published: April 2023

PDF file - 80K, Final multivariate logistic model for dysplastic Barrett's esophagus
Supplementary Figure 1 from Phase II Prospective Randomized Trial of a Low-Fat Diet with Fish Oil Supplementation in Men Undergoing Radical Prostatectomy
Authors: Aronson William J. , Kobayashi Naoko , Barnard R. James , Henning Susanne , Huang Min , Jardack Patricia M. , Liu Bingrong , Gray Ashley , Wan Junxiang , Konijeti Ramdev , Freedland Stephen J. , Castor Brandon , Heber David , Elashoff David , Said Jonathan , Cohen Pinchas , Galet Colette
Published: April 2023

PDF file - 53K
Supplementary Figures 1-2 from Relative Distribution of Folate Species Is Associated with Global DNA Methylation in Human Colorectal Mucosa
Authors: Liu Jia , Hesson Luke B. , Meagher Alan P. , Bourke Michael J. , Hawkins Nicholas J. , Rand Keith N. , Molloy Peter L. , Pimanda John E. , Ward Robyn L.
Published: April 2023

PDF file - 107K, Supplemental Figure 1: Correlation between blood and colonic total folate concentration (r = 0.38; P = 0.002) in a subset (n=66) of Cancer Participants. Supplemental Figure 2: Correlation between blood and colonic formyl-H4folate distribution (r = 0.34; P = 0.005) in a subset (n=66) of Cancer Participants
Related Article from Beyond the Scalpel: Targeting Hedgehog in Skin Cancer Prevention
Authors: Rudin Charles M.
Published: April 2023

Related Article from Beyond the Scalpel: Targeting Hedgehog in Skin Cancer Prevention
Perspective on This Article from Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps
Authors: Yurgelun Matthew B. , Goel Ajay , Hornick Jason L. , Sen Ananda , Turgeon Danielle Kim , Ruffin Mack T. , Marcon Norman E. , Baron John A. , Bresalier Robert S. , Syngal Sapna , Brenner Dean E. , Boland C. Richard , Stoffel Elena M.
Published: April 2023

Perspective on This Article from Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps
Supplementary Tables 1-2 from Genetic Variation in 3-Hydroxy-3-Methylglutaryl CoA Reductase Modifies the Chemopreventive Activity of Statins for Colorectal Cancer
Authors: Lipkin Steven M. , Chao Elizabeth C. , Moreno Victor , Rozek Laura S. , Rennert Hedy , Pinchev Mila , Dizon Diana , Rennert Gad , Kopelovich Levy , Gruber Stephen B.
Published: April 2023

Supplementary Tables 1-2 from Genetic Variation in 3-Hydroxy-3-Methylglutaryl CoA Reductase Modifies the Chemopreventive Activity of Statins for Colorectal Cancer
Supplementary Tables 1 - 2 from Inactivating Mutation in the Prostaglandin Transporter Gene, SLCO2A1, Associated with Familial Digital Clubbing, Colon Neoplasia, and NSAID Resistance
Authors: Guda Kishore , Fink Stephen P. , Milne Ginger L. , Molyneaux Neil , Ravi Lakshmeswari , Lewis Susan M. , Dannenberg Andrew J. , Montgomery Courtney G. , Zhang Shulin , Willis Joseph , Wiesner Georgia L. , Markowitz Sanford D.
Published: April 2023

PDF file - 28KB, Table S1: PCR primer sequences for amplification of SLCO2A1 (c.584C>A, p.104G>STOP) mutant position in germline DNA. Table S2: PCR primer sequences for amplification of SLCO2A1 coding sequence in formalin-fixed paraffin-embedded colon tumor DNA.
Supplementary Table 4 from Effects of Energy Restriction and Wheel Running on Mammary Carcinogenesis and Host Systemic Factors in a Rat Model
Authors: Zhu Zongjian , Jiang Weiqin , Zacher Jarrod H. , Neil Elizabeth S. , McGinley John N. , Thompson Henry J.
Published: April 2023

PDF file - 73K
Supplementary Table 3 from Effects of Energy Restriction and Wheel Running on Mammary Carcinogenesis and Host Systemic Factors in a Rat Model
Authors: Zhu Zongjian , Jiang Weiqin , Zacher Jarrod H. , Neil Elizabeth S. , McGinley John N. , Thompson Henry J.
Published: April 2023

PDF file - 84K
Supplementary Table 1 from Effects of Energy Restriction and Wheel Running on Mammary Carcinogenesis and Host Systemic Factors in a Rat Model
Authors: Zhu Zongjian , Jiang Weiqin , Zacher Jarrod H. , Neil Elizabeth S. , McGinley John N. , Thompson Henry J.
Published: April 2023

PDF file - 64K
Supplementary Table 5 from Characterizing the Impact of Smoking and Lung Cancer on the Airway Transcriptome Using RNA-Seq
Authors: Beane Jennifer , Vick Jessica , Schembri Frank , Anderlind Christina , Gower Adam , Campbell Joshua , Luo Lingqi , Zhang Xiao Hui , Xiao Ji , Alekseyev Yuriy O. , Wang Shenglong , Levy Shawn , Massion Pierre P. , Lenburg Marc , Spira Avrum
Published: April 2023

Supplementary Table 5 from Characterizing the Impact of Smoking and Lung Cancer on the Airway Transcriptome Using RNA-Seq
Supplementary Figure 1 from Dietary Resveratrol Prevents Development of High-Grade Prostatic Intraepithelial Neoplastic Lesions: Involvement of SIRT1/S6K Axis
Authors: Li Guiming , Rivas Paul , Bedolla Roble , Thapa Dinesh , Reddick Robert L. , Ghosh Rita , Kumar Addanki P.
Published: April 2023

PDF file - 62KB, Effect of Nicotinamide on proliferation of PC-3 and DU145 cells
Supplementary Table 1 from Methylselenocysteine Resets the Rhythmic Expression of Circadian and Growth-Regulatory Genes Disrupted by Nitrosomethylurea In vivo
Authors: Fang Ming Zhu , Zhang Xun , Zarbl Helmut
Published: April 2023

Supplementary Table 1 from Methylselenocysteine Resets the Rhythmic Expression of Circadian and Growth-Regulatory Genes Disrupted by Nitrosomethylurea In vivo