bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 856: Coiled-coil domain containing 3 suppresses breast cancer growth by protecting p53 from proteasome-mediated degradation
Authors: Lee Hyemin , Li Caiyue , Jung Ji Hoon , Zhang Yiwei , Wang Jieqiong , Liu Chang , Segall Allyson M. , Sheffmaker Roger L. , Zeng Shelya X. , Lu Hua 
Published: June 2022

Abstract
Coiled-coil domain containing 3 (CCDC3) was previously shown to regulate liver lipid metabolism as a secretory protein. Our recent studies revealed an intracellular role of CCDC3 as a tumor suppressor in breast cancer (BrC). Bioinformatics datasets analysis showed that CCDC3 is under-expressed in BrCs, while its higher levels are correlated with higher overall survival and lower relapse of cancer patients. CCDC3 is positively correlated with p53 and its target genes. Ectopic CCDC3 markedly suppressed proliferation, colony formation, and xenograft tumor growth by augmenting p53 activity in BrC cells. In contrast, knockdown of endogenous CCDC3 using CRISPR led to reduction of p53 level and activity, consequently promoting the proliferation of BrC cells. Mechanistically, CCDC3 bound to the C-termini of p53 and MDM2, consequently stabilizing p53 in the nucleus and impairing MDM2 recruitment of p53 to the 26S proteosome without inhibiting p53 ubiquitination. Also, knockdown of CCDC3 caused the resistance of BrC cells to 5-FU to some degrees by alleviating p53 response to this drug. p53 induced CCDC3 expression by binding to its promoter specifically in BrC cells. Our results unveil a unique mechanism underlying CCDC3 activation of p53 in a positive feedback fashion to suppress BrC growth and suggest that CCDC3 deficiency could be a factor for drug resistance of BrCs.
Citation Format: Hyemin Lee, Caiyue Li, Ji Hoon Jung, Yiwei Zhang, Jieqiong Wang, Chang Liu, Allyson M. Segall, Roger L. Sheffmaker, Shelya X. Zeng, Hua Lu. Coiled-coil domain containing 3 suppresses breast cancer growth by protecting p53 from proteasome-mediated degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 856.
Abstract 859: Characterizing SMARCA4/STK11/KEAP1 co-mutant lung adenocarcinoma
Authors: Costa Emily , Wohlheiter Corrin , Tischfield Samuel , Funnell Alister , Poirier JT , Villalonga Álvaro Quintanal , Sen Triparna , Rudin Charles 
Published: June 2022

Abstract
Lung adenocarcinoma (LUAD), constituting 50% of non-small cell lung cancer, is classically defined by the presence of driver mutations in oncogenes such as KRAS, EGFR, and BRAF. While the development of driver-targeted therapies has significantly improved survival in subsets of patients with LUAD, studies examining tumor sequencing data and clinical outcomes have shown that intra-driver genetic and phenotypic heterogeneity underlie differential patient responses to these therapies. In particular, co-occurring alterations in the genes SMARCA4 (BRG1), STK11 (LKB1), and KEAP1 are predictive of exceptionally poor prognosis and worse overall survival in metastatic LUAD patients. SMARCA4 loss is also a hallmark of undifferentiated, highly chemoresistant NSCLC tumors. While these co-mutations most often appear in KRAS-driven tumors, their association with poor outcomes is maintained regardless of driver status. Studies exploring the molecular features of SMARCA4-deficient and STK11/KEAP1 co-mutant LUAD have yielded translational insights specific to these subsets, establishing a rationale to characterize the unique biology of SMARCA4/STK11/KEAP1 (BLK) triple-mutant LUAD. To this end, we are profiling BLK LUAD through a combination of genomic, transcriptomic, epigenomic, and phenotypic assays in in vitro models. We have generated paired isogenic in vitro models of BLK LUAD via CRISPR-Cas9 knockout. Phenotypic analyses of these cell lines, whose engineered genotypes model varying combinations of SMARCA4, KEAP1, and STK11 loss, have revealed growth rate differences in vitro, and pairwise comparisons of RNA-sequencing in these lines show downregulation of lung differentiation markers and upregulation of metastasis-associated genes concomitant with SMARCA4 loss. In conclusion, we have generated isogenic preclinical models showing molecular and phenotypic features consistent with observations reported in BLK LUADs. Further molecular and functional characterization of these models may reveal mechanistic insights into the biology of this subset of aggressive tumors.
Citation Format: Emily Costa, Corrin Wohlheiter, Samuel Tischfield, Alister Funnell, JT Poirier, Álvaro Quintanal Villalonga, Triparna Sen, Charles Rudin. Characterizing SMARCA4/STK11/KEAP1 co-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 859.
Abstract 902: Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells
Authors: Magrath Justin W. , Hartono Alifiani B. , Lee Sean B. 
Published: June 2022

Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive form of pediatric cancer caused by a translocation between chromosomes 11 and 22, creating the novel EWSR1-WT1 fusion gene. Current therapy including surgery and the P6 chemotherapy regimen is insufficient, leading to a 5-year survival rate of only 15-25%. One potential explanation for this poor prognosis is the existence of a cancer stem cell (CSC) population with the ability to resist chemotherapy and cause both tumor recurrence and metastasis. While a CSC population has been identified in the closely related Ewing Sarcoma, most commonly caused by the EWSR1-FLI1 fusion gene, no CSC population has yet been identified in DSRCT. In this study, novel culture conditions were developed that enabled the formation of tumorspheres in vitro in the two commonly available DSRCT cell lines: JN-DSRCT-1 and BER-DSRCT. These novel culture conditions led to upregulation of stemness genes at the RNA and protein level including NANOG and SOX2, two genes that are associated with poor survival outcomes in TCGA sarcomas data. CCK-8 assay demonstrated an increased chemoresistance for tumorspheres versus normal adherent culture especially for doxorubicin, which was confirmed by reduction in PARP cleavage. This chemoresistance may be partially explained by a more quiescent CSC state as shown by reduced cell proliferation and a lower percentage of cells in the S and G2/M phases. However, cells grown in tumorspheres still robustly formed tumors in vivo, thus demonstrating the two hallmark CSC traits of chemoresistance and tumor formation. RNA-seq was performed to elucidate key differences between the adherent and sphere culture conditions and identify potential targets for the therapeutically important CSC-like population. Overrepresentation analysis and gene set enrichment analysis both showed upregulation of pathways related to chromatin assembly and disassembly, suggesting epigenetic changes as DSRCT cells move to a more stem-like state. RNA-seq further revealed kinases upregulated in tumorspheres including B-lymphocyte kinase (BLK) which previous studies have demonstrated is oncogenic, regulated by EWSR1-WT1, and not necessary for normal survival. BLK knockdown reduced CSC-like properties including abrogation of tumorsphere formation and reduction in the levels of SOX2 and NANOG. Together, this work for the first time identifies a CSC-like population in DSRCT and BLK as a potential DSRCT CSC target.
Citation Format: Justin W. Magrath, Alifiani B. Hartono, Sean B. Lee. Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 902.
Abstract 928: USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model
Authors: Kwon Juntae , Choi Hyungja , Ware Anna D. , Morillo Bernadette Cecilia , Wang Haiyang , Han Cecil 
Published: June 2022

Abstract
Epithelial ovarian cancer is the most lethal gynecologic malignancy and one of the most common causes of cancer mortality among women worldwide. Ubiquitin-Specific Peptidase 13 (USP13) gene copy is strongly amplified in human epithelial ovarian cancer, and high USP13 expression is correlated with poor survival outcomes, yet its pathological contribution to ovarian tumorigenesis remains unknown. Here, we crossed a conditional Usp13 overexpressing knock-in mouse with a conditional knockout of Trp53 and Pten mouse, and generated a novel ovarian cancer genetically engineered mouse model (GEMM), which closely recapitulates the genetic changes driving ovarian cancer in humans. Overexpression of USP13 with deletion of Trp53 and Pten in murine ovarian surface epithelium accelerated ovarian tumorigenesis and led to decreased survival in mice. Notably, USP13 greatly enhanced peritoneal metastasis of ovarian tumors with frequent development of hemorrhagic ascites. The primary and metastatic tumors exhibited morphology and clinical behavior similar to human high-grade serous ovarian cancer. Co-inhibition of USP13 and AKT significantly decreased the viability of the primary murine ovarian cancer cells isolated from the GEMM. USP13 also increased the tumorigenic and metastatic abilities of primary murine ovarian cancer cells in a syngeneic mouse study. These findings suggest a critical role of USP13 in ovarian cancer development and reveal USP13 as a potential therapeutic target for ovarian cancer.
Citation Format: Juntae Kwon, Hyungja Choi, Anna D. Ware, Bernadette Cecilia Morillo, Haiyang Wang, Cecil Han. USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 928.
Abstract 950: Role of epithelial-mesenchymal plasticity in immune remodeling during metastasis
Authors: Visal Tanvi H. 
Published: June 2022

Abstract
Introduction: Breast cancer is the most prevalent type of cancer in women, accounting for 12% of all annual cancer cases worldwide with most deaths attributed to metastasis. It displays both inter- and intra-tumoral heterogeneity which is linked to epithelial-mesenchymal transition (EMT). This program involves the acquisition of a mesenchymal-like phenotype allowing cells to disseminate from the primary tumor and metastasize. However, recent studies show that tumor cells do not need to undergo complete EMT to gain invasive potential; instead, co-expression of both epithelial and mesenchymal markers is critical for metastasis. Such tumor cells are thought to display epithelial-mesenchymal plasticity (EMP) which bestows them with enhanced fitness and flexibility to fulfill diverse requirements of the metastatic cascade. Additionally, hybrid EM phenotype has been linked to immunesuppression but has been understudied due to lack to suitable models with intact immune system. Thus, this necessitates the mechanistic dissection of tumor immune microenvironment (TIME) in models with EM plasticity. To characterize the contribution of EMP to metastasis, we utilized syngeneic mouse mammary tumor cell lines, which are hybrid EM and investigated their proteomic and cytokine profile and identified several novel cytokines.
Methods: Reverse Phase Protein Array (RPPA) was performed to determine the proteomic profile of tumors with EM plasticity. In addition, Luminex assay was performed to assess the cytokine/chemokine profile in above tumor models.
Results: The RPPA involved a panel of 450 antibodies and showed that tumors with EM plasticity were enriched in specific immunesuppressive proteins. At the same time, Luminex analysis was suggestive of recruitment of tumor-associated macrophages (TAMs) in models with EM plasticity. Additionally, cells with EM plasticity showed the ability to induce tumor-promoting/M2-like macrophages (in vitro).
Conclusions: Our data indicates that cells/tumors with EM plasticity show differential protein expression than E and M counterparts and are enriched in specific immunesuppressive proteins. Moreover, such cells have immune networks (cytokines/chemokines) that promote recruitment of TAMs - the largest myeloid infiltrate in the microenvironment of solid tumors. Thus, our study invites more attention to investigate the mechanisms of immunesuppression and metastasis in tumors with EM plasticity.
Citation Format: Tanvi H. Visal. Role of epithelial-mesenchymal plasticity in immune remodeling during metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 950.
Abstract 964: Tumor cell plasticity promotes metastasis across heterogeneous tumors
Authors: Winkler Juliane , Tan Weilun , Pisco Angela O. , Goga Andrei , Darmanis Spyros , Werb Zena 
Published: June 2022

Abstract
Metastasis, the growth of secondary tumors in distant organs, is the major cause of cancer-related deaths due to insufficient therapeutic effects of conventional treatment. Individual tumor cells exhibit heterogeneous features and growth potentials within the same tumor that may influence metastasis formation. During the metastatic cascade, tumor cells adapt their phenotype to various microenvironments that are distinct from their original site resulting in heterogeneous metastatic cells that often are resistant to conventional treatment. The underlying mechanisms of why some tumor cells can give rise to metastases, whereas others cannot are remarkably poorly understood.
We established patient-derived xenograft (PDX) models of breast cancer with different metastatic potential and preserved tumor heterogeneity. We analyzed the intrinsic cellular programs of individual tumor cells that influence the metastatic potential of breast cancers using different single-cell RNA-sequencing protocols (MULTI-Seq and Smart-Seq2). Using gene expression profiling of matched primary tumor and metastatic cells of 13 human breast cancers, we demonstrated that while human tumors showed profound inter-patient heterogeneity, they also shared signatures of differentially expressed genes between primary tumor and metastatic cells. Tumors with similar metastatic capabilities shared similar signatures, suggesting potential targets to directly treat metastasis. Additionally, we found that the plasticity of tumor cells is a common feature across tumors that is beneficial for the formation of metastasis. Tumors with higher levels of plastic tumor cells have a greater ability to form metastases. Moreover, we identified a subset of tumor cells expressing both markers of epithelial and mesenchymal characteristics, demonstrating in-vivo evidence for tumor epithelial-mesenchymal plasticity (EMP) in the metastatic cascade. The EMP is a continuum of states with epithelial and mesenchymal cell states as the two extremes of this continuum. The identified transition cells express distinct markers suggesting that these cells may represent a novel and overlooked cell type within the EMP continuum. Given the importance of tumor plasticity in the metastatic cascade, inhibiting the subset of tumor cells that are currently undergoing EMP may represent a novel treatment strategy for metastasis.
Citation Format: Juliane Winkler, Weilun Tan, Angela O. Pisco, Andrei Goga, Spyros Darmanis, Zena Werb. Tumor cell plasticity promotes metastasis across heterogeneous tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 964.
Abstract 992: MUC13 enhances colorectal cancer metastasis through molecular interaction with YAP1 transcription factor
Authors: Doxtater Kyle , Tripathi Manish K. , Sekhri Radhika , Kotnala Sudhir , Hafeez Bilal , Khan Sheema , Zafar Nadeem , Yallapu Murali , Jaggi Meena , Chauhan Subhash 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. About 90% of all cancer-related deaths are due to the development of metastatic sites in the body. 40-50% of colorectal cancer patients develop metastasis at some point during their fight with the disease. Understanding the mechanism of metastasis in colorectal cancer is vital. Metastasis is a multistep process; anchorage-independent survival after intravasation of cells from the primary tumor site is a crucial step. In our lab, we have previously demonstrated that MUC13 plays an essential role in the CRC progression by modulating anti-apoptotic pathways and survival proteins expression. Under anchorage-independent growth conditions, we have identified that MUC13, in correspondence with YAP1, is the key upregulated protein and is responsible for increased survival. Isogenic CRC cell lines SW480 (non-metastatic) and SW620 (metastatic) on low adherence growth conditions are applied in these studies. In addition, lentiviral transduced stable overexpression and knockdown cell lines were generated for MUC13 and YAP1 mechanistic studies. The overexpression of MUC13 in non-metastatic SW480 cells (low MUC13 expressing) increased anchorage-independent survival and enhanced tumorigenesis compared to SW480+Vector cells, contrary results were found upon MUC13 knockdown in SW620 cells (high MUC13 expressing). In vitro results were recapitulated in the in vivo mouse model system and human CRC tissues. In Proximity Ligation Assays (PLA), we found an increased nuclear localization of the survival complex YAP1/β-catenin in MUC13 overexpressing cells. In contrast, MUC13 knockdown resulted to the lower aboudance of survival complex in the nucleus. Immunoprecipitation validates the protein-protein interaction between MUC13 and YAP1. YAP1 knockdown in MUC13 overexpressing cells showed a decrease in survival, indicating the necessary functional complex formation between MUC13 and YAP1. MUC13 and YAP1 expression in human CRC tissue were highest at Stage II. However, YAP1 expression increased when MUC13 was observed in the nucleus. This supports the notion that MUC13 is critical in enhancing CRC metastasis through molecular interaction with YAP1. For the first time, this study demonstrates complex formation between MUC13 and YAP1 and defines their role in CRC progression and metastasis.
Citation Format: Kyle Doxtater, Manish K. Tripathi, Radhika Sekhri, Sudhir Kotnala, Bilal Hafeez, Sheema Khan, Nadeem Zafar, Murali Yallapu, Meena Jaggi, Subhash Chauhan. MUC13 enhances colorectal cancer metastasis through molecular interaction with YAP1 transcription factor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 992.
Abstract CT543: 18F-FDG PET/CT detects potentially malignant bone metastases in patients with suspected lesions: A prospective clinical trial
Authors: Zhao Hui , Chang Yujie , Jiang Zhiyuan , Wang Zhiyu , Ruan Shunyi 
Published: June 2022

Abstract
Tumor metastasis to the skeleton affects over 70% cancer patients, more than any other site of metastasis Skeletal related events (SREs) included spinal cord compression, fracture, bone radiation or surgery, and tumor-related hypercalcemia are severe complications of bone metastases, which impair patients life quality and require particular treatments The gold standard for the definitive diagnosis is still pathological examination, which needs pre-biopsy imaging review to improve the diagnosis efficacy Classic imaging review method for being CT (Computed Tomography) and 18F-FDG PET/CT Research has shown that 18F-FDG PET/CT is superior to CT in detecting bone metastasis, however, it is not validated by a prospective study Besides, as SUVmax is a metabolic parameter in oncology imaging, we can serve as a reliable semiquantitative indicator to differentiate bone lesions We conducted a prospective clinical trial at Shanghai Sixth People’s Hospital Inclusion criteria were as follows: referred for diagnostic biopsy on a suspicion of metastatic disease Exclusion criteria included contraindications for biopsy 205 patients participated in the cohort study, then were randomized into PET/CT and CT group They underwent 18F-FDG PET/CT and CT separately to confirm accurate location, then both received CT-guided bone biopsy to confirm The sensitivity, specificity and accuracy were calculated In PET/CT group, malignant bone metastases were found in 83/137 patients and biopsies proved 80 were actual metastases In CT group, 48 malignant bone metastases were spotted and 47 were truly decisive The sensitivity, specificity and accuracy of 18F-FDG PET/CT and CT are 99% vs 87%, 95% vs 93%, and 97% vs 88% A chi-square test was utilized to analyze The sensitivity of 18F-FDG PET/CT is better than CT (P=0 0065), but the specificity and accuracy had no differences, indicating 18F-FDG PET/CT could detect more bone metastatic lesions potentially than CT We also found metastasis malignant lesions had higher bone SUVmax than benign (median 9 3 vs 4 25, p &lt;0 001) ROC curves were asked to evaluate the differential efficacy of SUVmax In all 137 patients, the SUVmax 6 3 showed an AUC of 0 874 to predict malignant metastases Our research shows that [18F]FDG PET/CT has greater sensitivity in detecting malignant bone metastases than CT, and SUVmax can be different criteria for determining the malignancy of bone lesions
Citation Format: Hui Zhao, Yujie Chang, Zhiyuan Jiang, Zhiyu Wang, Shunyi Ruan. 18F-FDG PET/CT detects potentially malignant bone metastases in patients with suspected lesions: A prospective clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT543.