bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2974: A complex of tumor-suppressor NF1 and SPRED2 promotes pancreatic cancer tumorigenesis
Authors: Kim Sunny , Kastan Jonathan P. , Ting Hsiu-Chi , Park Youngkyu , Tuveson Dave 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor prognosis due to late detection and lack of effective therapeutic options. &gt;90% of PDAC tumors are driven by activating mutations in the KRAS oncogene, making it an appealing subject for further investigation into understanding PDAC biology and offering a potential genetic vulnerability to target in patients. Our laboratory has previously reported a mutant-KRAS-proximal complex at the plasma membrane that consists of tumor-suppressor Neurofibromatosis type 1 (NF1), Sprouty Related EVH1 Domain Containing 2 (SPRED2), and Ribosomal S6 Kinase 1 (RSK1). This complex mechanistically suppresses WT KRAS signaling via RSK1, a suppression which is then relieved upon mutant KRAS inhibition, ultimately promoting adaptive resistance for PDAC cells under these conditions. These data highlighted a potential paradoxical role for two canonical tumor-suppressors, NF1 and SPRED2, as promoters of PDAC tumorigenesis when mutant KRAS is inhibited. We find that knockout of NF1 in PDAC organoids induces a substantial growth defect in vivo, and our preliminary data indicates that SPRED2 knockout PDAC cells have reduced proliferation in vitro. Moreover, both SPRED2 and NF1 KO promotes a diminished migratory phenotype in vitro. Given NF1's well-established role as a tumor-suppressor, our observations of decreased tumorigenic properties upon NF1 deletion are unexpected. We hypothesize that NF1 and Spred2 promote tumorigenesis via recruitment of RSK1 to the plasma membrane, inducing the phosphorylation of putative substrates to stimulate a pro-migratory cellular behavior. Our work suggests the existence of a unique RSK1 program localized at the plasma membrane by mutant KRAS, providing a new facet of oncogenesis to investigate for fundamental understanding and potential therapeutic opportunities.
Citation Format: Sunny Kim, Jonathan P. Kastan, Hsiu-Chi Ting, Youngkyu Park, Dave Tuveson. A complex of tumor-suppressor NF1 and SPRED2 promotes pancreatic cancer tumorigenesis [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 2974.
Abstract 2979: ElevatedNRASexpression as a potential driver of DCIS progression to basal-like invasive breast cancer
Authors: Zheng Ze-yi , Elsarraj Hanan , Hong Yang , Lei Jonathan T. , Anurag Meenakshi , Shen Yichao , Lo Flora , Feng Long , Zhao Zifan , Zhang Xiang H. , Behbod Fariba , Chang Eric C. 
Published: June 2022

Abstract
Background: Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives a subset of luminal DCIS to transition to basal invasive breast cancers is unclear. Basal-like invasive breast cancers are aggressive and associated with the shortest overall survival and time to distant metastasis. We have previously shown that N-Ras is highly expressed selectively in the basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers.
Methods: Wilcoxon rank-sum test was conducted to assess the relative expression of NRAS in DCIS compared to invasive breast cancers in a patient cohort (GSE59248). NRAS levels were also determined by fluorescence in situ hybridization (FISH) in a collection of 21 patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and NRAS’s association with DCIS and invasive breast cancer was assessed by Wilcoxon signed rank test. How NRAS levels correlated with basal biomarkers in the TMAs, as well as in patient datasets GSE59248 and GSE3369 was determined by Pearson correlation. Gene expression changes in cell line were assessed by RNA-seq.
Results: Invasive breast cancers showed higher NRAS mRNA levels, as compared to DCIS samples. These NRAShigh lesions were also enriched with basal-like features, such as basal gene expression signature, lower ER, higher p53 protein levels, and higher Ki67 levels. We have shown previously that N-Ras is a driver for tumor growth in SUM102 cells, which is a DCIS-like cell line model displaying basal-like features. Here we found that NRAS-silencing in these cells induced a shift to a luminal gene expression pattern as determined by PAM50.
Conclusions: These data suggest that the rise of N-RAS levels in DCIS can not only mark but also control the emergence of basal-like features leading to more aggressive tumor activities. Targeting N-Ras and/or its downstream pathway may prevent the emergence of basal invasive breast cancers.
Citation Format: Ze-yi Zheng, Hanan Elsarraj, Yang Hong, Jonathan T. Lei, Meenakshi Anurag, Yichao Shen, Flora Lo, Long Feng, Zifan Zhao, Xiang H. Zhang, Fariba Behbod, Eric C. Chang. ElevatedNRASexpression as a potential driver of DCIS progression to basal-like invasive breast cancer [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 2979.
Abstract 2989: FAP facilitates ovary tumorigenesis through the NF-κB/survivin funcational axis
Authors: Li Bin , Huang Shuang 
Published: June 2022

Abstract
Ovarian cancer is the deadliest gynecologic cancer, mainly attributing to lack of early diagnosis of the diseases. Current mainstay treatment for ovarian cancer is surgical removal followed by chemotherapy. Although patients initially respond well, most of patients suffer from relapse and die from metastasis. Therefore, developing successful approaches combatting metastasis is most likely to prolong patients’ survival and improve their life quality. Toward this goal, we analyzed The Cancer Genome Atlas ovarian cancer patient dataset to reach for targetable genes preferentially elevated in advanced ovarian cancer. Among them, we found that knockdown of fibroblast activation protein alpha (FAP) led to dramatic apoptosis in mesenchymal-like ovarian cancer cells. To elucidate the underlying mechanism, we performed RNAseq and identified that TNF-alpha/NF-κB signaling pathway was impaired in FAP-knockdown cells. NF-κB signaling pathway is well characterized to promote cell survival by elevating the expression of pro-survival genes. In fact, the level of survivin was diminished upon FAP-knockdown. As forced expression of survivin almost completely abrogated apoptosis elicited by FAP-knockdown and survivin inhibitor also induced robust apoptosis in ovarian cancer cells, we reason that FAP participates in ovarian cancer development by promoting cell survival through activation of NF-κB/survivin axis. With the aid of EpCAM aptamer as delivering cargo, we demonstrated that FAP siRNA was able to suppress intraperitoneal ovarian cancer development. This study suggests that FAP is an ideal therapeutic target against mesenchymal-like ovarian cancer.
Citation Format: Bin Li, Shuang Huang. FAP facilitates ovary tumorigenesis through the NF-κB/survivin funcational axis [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 2989.
Abstract 3: Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice
Authors: Shen Yuelei , Yao Jiawei , Kokabee Mostafa , Guo Yanan , BaI Yang , Shang Chengzhang 
Published: June 2022

Abstract
Glucagon-like peptide-1 (GLP1) is a pleiotropic hormone released from gut enteroendocrine cells following nutrient ingestion. In addition to promoting insulin secretion and inhibiting glucagon secretion, GLP1 acts via the glucagon-like peptide-1 receptor (GLP1R) to reduce gastric emptying and food intake. Therefore, development of GLP1R agonists appears to be a promising therapeutic option for type 2 diabetes. To evaluate the efficacy of GLP1 analogs in preclinical studies, Biocytogen has successfully generated a novel humanized GLP1R (B-hGLP1R) knock-in mouse line to support related drug development studies. In this mouse model, the full coding sequence of the human GLP1R gene was inserted into the mouse Glp1r gene locus. Human GLP1R mRNA expression was detected by RT-PCR in B-hGLP1R mice but not in wild-type mice. Protein expression of human GLP1R in B-hGLP1R mice was confirmed by western blot analysis and immunohistochemistry using pancreatic tissues. Furthermore, flow cytometry analysis of leukocyte subpopulations showed that B-hGLP1R mice do not exhibit a change in the overall development, differentiation, or distribution of immune cell types in the spleen, blood, and lymph nodes. Additionally, our in vivo efficacy study confirmed Dulaglutide, a GLP1 receptor agonist, reduced the non-fasting blood glucose, fasting blood glucose, glucagon, and food intake levels in B-hGLP1R obese mice and increased plasma insulin and GLP1 secretion. In B-hGLP1R mice, glucose tolerance (GTT) was also improved by Dulaglutide treatment, similar GTT results were observed after treatment with PF-06882961, a phase II agent specifically recognizing human GLP1R. Altogether, B-hGLP1R mice provide an efficacious preclinical animal model to evaluate novel GLP1 based therapeutic drugs. Keywords: Humanized mice, GLP1R, agonist
Citation Format: Yuelei Shen, Jiawei Yao, Mostafa Kokabee, Yanan Guo, Yang BaI, Chengzhang Shang. Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice [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 3.
Abstract 3005: Inflammasome-independent pyroptosis mediates DHA-led ovarian cancer cell death
Authors: Calbay Ozlem , Huang Shuang 
Published: June 2022

Abstract
Docosahexaenoic acid (DHA) is a natural compound, which exhibits anti-cancer capability in various cancer types in experimental models. Similar to previous reports in other cancer cell types, we demonstrated that DHA inhibited ovarian cancer cell growth by inducing cell death. In our model, distinct from the effect of DHA on other cancer cell types, we revealed that DHA-induced cell death was only slightly blocked by apoptosis inhibitor (caspase 3 inhibitor DEVD). We characterized the mechanism associated with DHA-led cell death and found that DHA-induced cell death was effectively blocked by caspase 1 inhibitor, indicating that DHA kills ovarian cancer cells by inducing pyroptosis. This mechanism was further supported by the observation that Disulfiram, a Gasdermin D inhibitor, prevented DHA-induced cell death and DHA treatment leads to the cleavage of Gasdermin D. Surprisingly, known inflammasome inhibitors did not affect DHA-induced cell death and Gasdermin D cleavage, ruling out the involvement of the inflammasome for caspase 1 activation. Instead, DHA remarkably elevated the amount of both caspase I and cleaved caspase 1 in ovarian cancer cells. This suggests that DHA activates caspase 1 by augmenting the abundance of caspase 1. Furthermore, we showed that DHA increased the level of intracellular reactive oxygen species (ROS). Use of ROS inhibitor (NAC) abrogated DHA-induced pyroptosis. This study uncovers pyroptosis as the mechanism for DHA-induced ovarian cancer cell death and reveals a previously unknown mechanism for caspase 1 activation.
Citation Format: Ozlem Calbay, Shuang Huang. Inflammasome-independent pyroptosis mediates DHA-led ovarian cancer cell death [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 3005.
Abstract 3014: PHGDH- A therapeutic vulnerability in melanoma
Authors: Jasani Neel N. , Karreth Florian 
Published: June 2022

Abstract
Recurrently amplified oncogenes may represent melanoma vulnerabilities that can be exploited for therapy. The genomic locus containing the Phosphoglycerate Dehydrogenase (PHGDH) gene at chromosome 1p12 is frequently amplified in melanoma. PHGDH is the rate limiting enzyme that converts the glycolytic intermediate 3-Phospho Glycerate (3-PG) to serine through the serine synthesis pathway (SSP). Serine is utilized to make glycine, glutathione, one carbon metabolites, proteins and lipids. PHGDH inhibition suppresses proliferation of 1p12 amplified melanoma cells. However, the role of PHGDH in chromosome 1p12 non-amplified melanoma is poorly understood. We observed that 1p12 non-amplified melanoma cell lines have enhanced expression of the SSP enzymes as compared to melanocytes cultured in tetradecanoyl-phorbol acetate (TPA, a growth factor that stimulates MAPK pathway). Moreover, TPA starvation in melanocytes increased PHGDH expression. This led us to hypothesize that activation of oncogenic MAPK signaling leads to high expression of PHGDH which can serve as therapeutic vulnerability in melanomagenesis. Acute expression of oncogenic BRAFV600E in melanocytes resulted in upregulation of SSP enzymes, while treatment of melanoma cells with either BRAF or MEK inhibitor resulted in downregulation of SSP enzymes. We confirmed that PHGDH is regulated by BRAF-ERK-mTOR axis. Downregulation of PHGDH in 1p12 non-amplified melanoma cell lines decreased their cell proliferation and colony formation ability in vitro. We also observed that Phgdh knockdown in a BrafV600E/WT and Pten-/- (BPP) melanoma mouse model significantly increased survival. Furthermore, serine-glycine starvation (external source of Serine-glycine) in BPP chimeras did not affect the survival of these mice while on the other end, it suppressed the growth of the xenograft tumors injected in the NSG mice, which warrants further investigation. These results suggest the importance of PHGDH for melanoma cell proliferation and tumor growth irrespective of its amplification status. The exact mechanism of PHGDH regulation by BRAFV600E and the therapeutic effect of PHGDH inhibition in melanoma initiation and progression are the focus of our studies.
Citation Format: Neel N. Jasani, Florian Karreth. PHGDH- A therapeutic vulnerability in melanoma [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 3014.
Abstract 3030: Integrated in vitro and in silico screening of breast cancer reveals serine metabolism as a precision oncology target
Authors: Slayton Mark Daniel , Achreja Abhinav , Jeon Jin Heon , Bao Liwei , Liu Alisa , Collard Mason , Nagrath Deepak , Merajver Sofia 
Published: June 2022

Abstract
Cellular metabolism sits at the forefront of growth and has been identified as an essential element for the progression of cancer. Large-scale chromosomal alterations and mutations incurred by cancerous cells can predispose cancer cells to dysfunctional metabolic programming independent of microenvironmental pressure. Cancer cells are adaptable to this reprogramming and find alternative measures to sustain elevated metabolic demands. However, this process reduces the number of functional metabolic pathways. Dysregulated metabolic pathways within cancerous cells create an opportunity for therapeutic intervention by targeting genetic chokepoints within these pathways. We analyzed metabolic landscape of breast cancers by combining genomic and transcriptomic data from cancer patient datasets, to identify metabolic pathways prone to dysregulation due to genomic influence. Our platform identified disruption in the serine biosynthesis, which some cancerous cells rely upon to sustain elevated growth in a subset of breast carcinoma. We utilized gain- and loss-of-function techniques in multiple breast cancer cell lines to recapitulate metabolic disruption observed in tumors. These in vitro screens are complemented by metabolic flux analysis and stable-isotope tracer analysis that reveal the vulnerable metabolic pathways in breast cancers with dysregulated serine metabolism. Our data demonstrate that specific metabolic targets can be identified through this integrated screening and validated empirically to confirm their significance as avenues for potential therapeutics.
Citation Format: Mark Daniel Slayton, Abhinav Achreja, Jin Heon Jeon, Liwei Bao, Alisa Liu, Mason Collard, Deepak Nagrath, Sofia Merajver. Integrated in vitro and in silico screening of breast cancer reveals serine metabolism as a precision oncology target [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 3030.
Abstract 3055: Field cancerization and microbiome in lung cancer
Authors: Alhammad Rayan I. , Vuong Ngoc B. , Zhou Weidong , Mueller Claudius , Johann Donald J , Katta Amith R. , Hoek Monique V. , Alsaab Fahad M. , Luchini Alessandra , Liotta Lance 
Published: June 2022

Abstract
Lung Cancer carcinogenesis is the outcome of a field of premalignant changes that occur in the bronchial tree leading to the overt emergence of the malignant lung cancer. We sought to study the proteome of the microbiome associated with the premalignant bronchial mucosa epithelia. The overall goal is the identify functional relationships between the bronchial mucosa microbiome and the risk of developing lung cancer. We evaluated the proteome of the microbiome using mass spectrometry and specialized microbiome authentication software. This method was applied to a case-control study of plasma samples donors of physician health study who donated plasma at different times prior to the onset of Non-Small Cell Lung Cancer. We also examined bronchial mucosa tissue samples near to, and distant from, the tumor harvested from surgical lobectomy specimens. Highly significant protein biomarker differences were found in the plasma and in the tissue samples that were blindly associated with cancer. These included specific proteins from the mucosal microbiome that may have functional role in the carcinogenic process. These key diagnostic risk markers were shared between the premalignant bronchial mucosa tissue and the plasma, supporting the concept that risk markers of bronchial mucosa lung cancer carcinogenesis can be detected in the peripheral circulation.
Citation Format: Rayan I. Alhammad, Ngoc B. Vuong, Weidong Zhou, Claudius Mueller, Donald J Johann Jr, Amith R. Katta, Monique V. Hoek, Fahad M. Alsaab, Alessandra Luchini, Lance Liotta. Field cancerization and microbiome in lung cancer [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 3055.
Abstract 3066: Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations
Authors: Arana Alexa Morales , Halmai Nicole B. , Zhang Hongyong , Lott Paul , Estrada-Florez Ana , Toal Ted W. ,   University of California Minority Patient-DerivedXenograft (PDX) Development and Trial (UCaMP) Cent, Carvajal-Carmona Luis G. 
Published: June 2022

Abstract
Gastric cancer (GC) is the 5th most common neoplasm and the 2nd most deadly cancer worldwide, with an estimated 783,000 deaths in 2018. Furthermore, Hispanic/Latino Americans continue to be underrepresented in GC genomic studies despite being twice as likely to be diagnosed with and die from GC compared to non-Hispanic whites (NHW). In order to address this pervasive health disparity, our lab has led efforts to characterize tumor biopsies from racial/ethnic minority cancer patients to inform more effective cancer treatment and advance precision medicine among these high-risk populations. We performed whole-exome sequencing of 31 GC patient tumors with more than 60% of the samples coming from minority patients. We identified higher somatic mutation frequencies in the ARID1A, BRCA2, and APC genes compared with the TCGA GC cohort, which is made up of mostly NHW patients. To better understand the role these genes play in cancer tumorigenesis among racial/ethnic minority GC patients, our lab has established a CRISPR/Cas9 genome-editing platform in minority patient-derived organoids (mPDOs). In this study, we utilized our platform to generate mPDO models of APC-TP53 double knockouts (dKO), ARID1A-TP53 dKO, and TP53-ARID1A-BRCA2 triple knockouts in organoid lines derived from normal gastric tissue. We developed medium to select for functional mutants following organoid cell electroporation that yielded near-complete selection for the desired gene knockouts, allowing us to generate isogenic mPDO lines modeling each gene KO combination. Our organoid models will provide a critical method to elucidate therapeutic sensitivity and resistance mechanisms in minority groups towards the ultimate goal of addressing GC health disparities in US racial/ethnic minorities.
Citation Format: Alexa Morales Arana, Nicole B. Halmai, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Ted W. Toal, University of California Minority Patient-DerivedXenograft (PDX) Development and Trial (UCaMP) Cent, Luis G. Carvajal-Carmona. Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations [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 3066.