bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6167: Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth
Authors: Jonker Patrick , Muir Alexander 
Published: June 2022

Abstract
Both the cell-intrinsic metabolic network and the uniquely altered cell-extrinsic tumor microenvironment dictate tumor metabolism. However, while much is known about how cell-intrinsic factors regulate tumor metabolism, the effects of cell-extrinsic factors remain poorly understood. In particular, despite evidence that tumor nutrient availability extrinsically regulates tumor metabolism, further investigation has been hindered by the lack of models to study physiological nutrient availability in vitro.To accurately model the tumor nutrient microenvironment, our group quantified nutrient availability in pancreatic ductal adenocarcinoma (PDAC) tumor perfusate and created a medium to mimic this in vitro, called tumor interstitial fluid medium (TIFM). We compare the effects of TIFM-culture to maintenance in conventional culture medium (RPMI-1640) as a control for standard laboratory conditions. Using this model, I found that TIFM-cultured PDAC cells downregulate lipid synthesis, making TIFM-cultured cells uniquely reliant upon extracellular lipid uptake for growth. Analysis of murine PDAC tumors confirms downregulated lipogenesis in vivo, suggesting cell-extrinsic nutrients render lipogenesis dispensable—and lipid uptake necessary—for PDAC tumor growth. Notably, this contrasts studies in conventional culture media that claim lipogenesis is critical for PDAC growth.I am currently working to: (1) understand how the nutrient microenvironment alters lipid metabolism and (2) determine the extracellular lipids and transporters pancreatic cancer cells require for growth. Regarding the first question, transcriptomic analysis of TIFM-cultured cells revealed significant deactivation of SREBPs, master regulators of intracellular lipid and sterol synthesis, suggesting cell-extrinsic nutrient cues suppress lipogenesis by altering SREBP signaling. I am currently investigating which TIFM nutrients alter this signaling. I am also performing lipidomics analysis and lipid transporter knockdown experiments to identify lipids and transporters that TIFM-cultured cells require for growth. Collectively, these experiments will clarify the role extracellular nutrients play in driving changes to PDAC lipid metabolism and may suggest novel therapeutic treatment options for PDAC patients.
Citation Format: Patrick Jonker, Alexander Muir. Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth [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 6167.
Abstract 6181: Cell line panel with HIBIT tagged endogenous proteins to accelerate PROTAC drug discovery
Authors: Zhai Yunpeng , Tan Ming , Liu Defu , Wang Guoqian , Ning Jinying , Hao Feng 
Published: June 2022

Abstract
Recent years have seen great advancement of targeted protein degradation technology, in particular, proteolysis targeting chimeras (PROTACs) are now widely used in developing therapeutics for treating cancer. A PROTAC is a heterobifunctional small molecule with three distinct moieties: a ligand to bind a targeted protein of interest (POI), a second ligand to recruit E3 ubiquitin ligase to form a ternary complex, and a linker for bridging the two ligands. Through the E3 ubiquitin ligase pathway, properly designed PROTACs can effectively degrade POIs with high specificity, which can be pathogenic proteins, thus regulate related pathways and inhibit tumor growth. Currently, there is no high-throughput biochemical assay to measure the POI degradation in vitro, hindering the application of the PROTAC technology. Here we report the development of a high-throughput cell based assay to quantitatively measure the endogenous drug target degradation induced by PROTACs. This assay encompasses over 800 cancer cell lines, many of which are CRISPR-engineered ones on common drug targets. A unique feature of our assay is the incorporation of HiBiT short sequence tags on either N-terminal or C-terminal of endogenous protein in E3 ligase matched cell line through site-specific gene homologous recombination technology. By highly specific and sensitive detection of HiBiT tag content in cell lysates with biochemical assay, we can determine target protein degradation by PROTAC treatment. We demonstrate the utility of the assay on a wide array of drug targets including RAS, LDHA, BTK and HPK1, and show that it can accelerate PROTAC drug discovery.
Citation Format: Yunpeng Zhai, Ming Tan, Defu Liu, Guoqian Wang, Jinying Ning, Feng Hao. Cell line panel with HIBIT tagged endogenous proteins to accelerate PROTAC drug discovery [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 6181.
Abstract 6207: Ba/F3 kinase mutant cell panel, a powerful cell model for the discovery and development of inhibitors for kinase specific mutation
Authors: Wang Yu , Peng Yao , Tang Yao , Zhou Lin , Ning Jinying , Hao Feng 
Published: June 2022

Abstract
Although over 70 protein kinase inhibitors have been approved by FDA since 2001, the protein kinase is still the hot target class of molecularly targeted cancer therapy because of the discovery of new driver kinase fusion mutation and a large number of secondary kinase mutations after the inhibitor treatment in cancer patients with the sequencing technology advancement, the need for new generation specific small molecule kinase inhibitors is still unmet, and it urge the industry to development more accurate, efficient kinase cellular assay models.Ba/F3 line is a popular cell model because many protein kinases and their mutants can transform the Ba/F3 cells to be growth independent of exogenous IL-3 supplement, while their inhibitors can antagonize these effects. Our group have generated a large of cell line panel with over 300 different well validated (sequencing, Western Blot and inhibitor test) Ba/F3 kinase cell lines for kinase inhibitor screening and development, covering several hot kinases, such as EGFR, EML-ALK, FLT3, NTRK, ROS1, HER, BCR-ABL, RET, FGFR1, FGFR2, FGFR3, FGFR4, KRAS, cMET, et al. Except used in in vitro high-throughput compound screening, most of the transformed Ba/F3 lines can grow well in immune-deficient mice and were also used to evaluate the efficacy of drug candidate and its downstream signaling in vivo. Our data indicate that our Ba/F3 cell line panel is a powerful cell model for new kinase inhibitor discovery and development.
Citation Format: Yu Wang, Yao Peng, Yao Tang, Lin Zhou, Jinying Ning, Feng Hao. Ba/F3 kinase mutant cell panel, a powerful cell model for the discovery and development of inhibitors for kinase specific mutation [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 6207.
Abstract 6210: Loss of inflammation-related genes and inflammation inhibitors effectively targets ER- breast cancer cell metastasis
Authors: Song Chaeun (Christine) , Lowe Val J. , Lee SeungBaek 
Published: June 2022

Abstract
The anti-estrogen tamoxifen is a highly effective hormonal therapy for hormonal (HR+) breast cancer patients. However, the estrogen receptor-negative, progesterone receptor-positive (ER-/PR+) subtype does not receive the benefits of tamoxifen. Therefore ER-/PR+ breast cancer have a poor clinical outcome, but drug development for ER-/PR+ breast cancer is not well studied. Here, we found that gene expression in ER-/PR+ HR+ breast cancer is positively related to triple negative breast cancer (TNBC) and not HR+ breast cancer using 4,319 breast cancer patients database. Especially, inflammation-related genes, A20/TNFAIP3, CDC20 and CASP1/Caspase-1, which are highly expressed in TNBC, are also upregulated in ER-/PR+ HR+ breast cancer. Suppression of A20/TNFAIP3, CDC20 and CASP1 inhibit cancer cell growth and metastasis in ERα KO (ER-/PR+) cell lines. Interestingly, loss of ERα in HR+ cell lines is not responsive to tamoxifen, but highly sensitive to inflammation inhibitor, Ac-YVAD-CHO. In in vitro and ex vivo models, inflammation inhibitor specifically blocks ER-/PR+ tumor proliferation and migration. These findings suggest that the inflammation inhibitor might be the first potential target therapy for ER-/PR+ HR breast cancer patients.
Citation Format: Chaeun (Christine) Song, Val J. Lowe, SeungBaek Lee. Loss of inflammation-related genes and inflammation inhibitors effectively targets ER- breast cancer cell 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 6210.
Abstract 6265: Do epigenetic outliers impact racial disparities in colorectal cancer
Authors: Ghosh Jayashri , Schultz Bryant M. , Chan Joe , Wultsch Claudia , Shureiqi Imad , Chow Stephanie , Doymaz Ahmet , Varriano Sophia , Driscoll Melissa , Muse Jen , Kleiman Frida E. , Krampis Konstantinos , Issa Jean-Pierre J. , Sapienza Carmen 
Published: June 2022

Abstract
African Americans (AA) have a higher incidence and mortality rate for colorectal cancer (CRC) compared to Caucasians. DNA methylation profiling on normal colon mucosa from 77 CRC patients and 68 patients without cancer (controls) of AA and Caucasian descent identified a distinct subgroup of CRC patients (11AA and 4 Caucasians) who are statistical “outliers” at a large number of CpGs. Such highly epigenetically disrupted CRC patients are termed “Outlier Methylation Phenotype” (OMP). Comparison of methylome profiles of CRC patients and controls revealed that AA CRC patients have greater disruption of the normal colon methylome than do Caucasian patients. A large fraction of the overall methylation differences found between CRC patients and controls is attributable to OMPs. Estimation of epigenetic ages shows that OMPs have lower epigenetic ages compared to their chronological ages. In other words, OMPs undergo epigenetic age deceleration. Comparison of normal colon mucosa transcription profiles of OMP cancer patients with those of non-OMP cancer patients indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally down-regulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S RDNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with CRC risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections and KRAS mutations. In conclusion, our study suggests a distinct epigenetically disrupted OMP group in CRC that are responsible for disrupted methylome, altered gene expression and microbial dysbiosis. Furthermore, a higher frequency of OMPs among African Americans (11/42) than among Caucasians (5/35) may contribute to observed racial disparities in CRC incidence and outcome.
Citation Format: Jayashri Ghosh, Bryant M. Schultz, Joe Chan, Claudia Wultsch, Imad Shureiqi, Stephanie Chow, Ahmet Doymaz, Sophia Varriano, Melissa Driscoll, Jen Muse, Frida E. Kleiman, Konstantinos Krampis, Jean-Pierre J. Issa, Carmen Sapienza. Do epigenetic outliers impact racial disparities in colorectal 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 6265.
Abstract 6283: Reannotation and normalisation of Infinium 850k data for improved analysis of methylation at enhancers and non-coding RNAs
Authors: Bizet Martin , Defrance Matthieu , Calonne Emilie , Bontempi Gianluca , Fuks François , Jeschke Jana 
Published: June 2022

Abstract
In this study, we evaluated the MethylationEPIC BeadChip (850k) technology for enhancer methylation analysis with respect to RRBS, both high-throughput technologies commonly used to screen large patient cohorts. We developed and applied a new approach to re-annotate the 850k data, which greatly improved the association of probes to enhancers and show that 850k targets more enhancers than RRBS. We further investigated the reproducibility of the two technologies and applied various existing normalization methods to 850k data that reduce variability between replicates and variability with other technologies. We thereby showed that normalization methods developed for 450k greatly reduced variability in 850k data to a level below that of highly variable RRBS data. We finally performed differential methylation analysis with 850k data from breast cancer samples applying our new re-annotation method and highlight that the majority of differentially methylated cytosines were detected with probes specific to the 850k mapping to enhancers, confirming the deregulation of enhancer methylation in breast cancer. In summary, our study provides a new annotation for the 850k array, which greatly increases the number of cytosines mapping to enhancers and therefore allows for the improved analysis of enhancer methylation. Overall, we conclude that the 850k array allows for detection of methylation changes in regions not covered by previous Infinium arrays and is the best choice, as compared to RRBS, for high-throughput analysis of enhancer methylation in large clinical cohorts.
Citation Format: Martin Bizet, Matthieu Defrance, Emilie Calonne, Gianluca Bontempi, François Fuks, Jana Jeschke. Reannotation and normalisation of Infinium 850k data for improved analysis of methylation at enhancers and non-coding RNAs [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 6283.
Abstract 633: Delineating tumor-neural communication in brain metastasis with spatiotemporal transcriptomic analysis and multi-cellular crosstalk modeling
Authors: Wang Xin , Zhu Ying , Sheng Jianting , Zhao Hong , Wong Stephen 
Published: June 2022

Abstract
Brain metastases are diagnosed in 20-40% of all cancer patients. Despite the advancements in neurosurgery, radiotherapy, and chemotherapy, one-year survival of metastatic brain tumor patients still within a single digit such that brain metastases constitute about 20% of annual cancer deaths. These facts clearly indicate a critical need for better understanding of mechanisms that promote the growth of brain metastases. Emerging data, including ours, indicate that different types of metastatic cancer cells leverage dissimilar sets of neurotransmitters to favor their outgrowth in the brain. However, there are over sixty types of neurotransmitters in the brain being synthesized and released by various types of neural cells, we need a systemic investigation of how they mediate the pathogenesis of brain metastases in concert. Since neurotransmitters, gliotransmitters, neurotrophic factors, and neural cytokines, called neuroactive substances, are the most abundant and key intercellular communication signals in the brain, we hypothesize that tumor cells leverage these neuroactive substances to assimilate into neural circuitry via communicating with neural cells including neurons, astrocytes, microglia, oligodendrocyte, and others, in promoting the vicious circle of tumor-neural crosstalk during brain metastasis development. By performing spatial transcriptomics analysis on mouse brain sections bearing metastatic tumors, we found that tumor lesions at different locations and even tumor-surrounding areas in the brain regions could be differentiated into different cellular clusters based on gene transcriptomic expressions. We further predicted several paracrine and autocrine signaling between and within tumors as well as tumor-surrounding neural niches in different tumor locations (e.g., centers or edges), of different tumor sizes, and at various tumor development stages, using our Cell-Cell Communication Explorer (CCC-Explorer) modeling software. Functional experiments were conducted to demonstrate that cell type-specific depletion of the secreted NSs deactivated the activities of corresponding receptors and downstream signaling in co-cultured metastatic brain tumor cells. Characterizing spatiotemporal tumor-neural crosstalk in the brain metastatic niche would provide a new strategy in the development of novel and effective therapeutics of brain metastases.
Citation Format: Xin Wang, Ying Zhu, Jianting Sheng, Hong Zhao, Stephen Wong. Delineating tumor-neural communication in brain metastasis with spatiotemporal transcriptomic analysis and multi-cellular crosstalk modeling [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 633.
Abstract 6339: Deep plasma proteomics at scale enabling proteogenomic analyses in a lung cancer (NSCLC) study
Authors: Zamanighomi Mahdi , Guturu Harendra , Wang Jian , Alavi Amir , Brown Tristan , Hornburg Daniel , Hasan Moaraj , Ferdosi Shadi , Motamedchaboki Khatereh , Donovan Margaret , Platt Theodore , Benz Ryan , Siddiqui Asim , Batzoglou Serafim 
Published: June 2022

Abstract
Our ~20,000 genes encode over one million protein variants, given alternative splice forms, allelic variation, and protein modification. Though large-scale genomics studies have expanded our understanding of biology, similarly, scaled deep and untargeted proteomics studies of biofluids have remained impractical due to complex workflows. To address this need, we have previously described Proteograph࣪, a novel platform that leverages the protein-corona interactions of nanoparticles for deep and untargeted proteomic sampling at scale.
Using Proteograph࣪ in a non-small cell lung cancer (NSCLC) cohort, we previously conducted a deep interrogation of plasma from 141 subjects: 61 early-stage NSCLC subjects and 80 non-cancer controls. We identified 2,499 plasma proteins, with 1,992 present in ≥ 25% of the samples. Leveraging this data, we created a biomarker classifier distinguishing NSCLC from controls with area under the receiver operating characteristic curve of 0.911. In this study, we now re-analyze the data with the more sensitive DIA-NN software to enhance protein depth while preserving the accuracy of the classifier. In addition, to show the added value of our platform in combination with genomic data, we integrate previously sequenced exome data with our proteomic data to build a multi-modal proteogenomic deep learning classifier. Our results outline proteogenomic workflows for robust biomarker discovery and cohort subtyping.
The Proteograph࣪ platform interrogates the plasma proteome at previously impractical combinations of scale, depth and coverage, and enables the development of improved classification models and the study of proteogenomics.
1Blume et al. Nat. Comm. (2020)
Citation Format: Mahdi Zamanighomi, Harendra Guturu, Jian Wang, Amir Alavi, Tristan Brown, Daniel Hornburg, Moaraj Hasan, Shadi Ferdosi, Khatereh Motamedchaboki, Margaret Donovan, Theodore Platt, Ryan Benz, Asim Siddiqui, Serafim Batzoglou. Deep plasma proteomics at scale enabling proteogenomic analyses in a lung cancer (NSCLC) study [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 6339.
Abstract 6352: Ascites derived exosomes promote progression of advanced gastric cancers
Authors: Hyung Sujin , Ko Jihoon , Lee In-kyung , Jeon Noo Li , Lee Jeeyun 
Published: June 2022

Abstract
Gastric cancer (GC) with peritoneal metastasis accompanied by a sequential buildup of malignant ascites currently has no curative therapy; accordingly, developing novel biomarkers is critical for reducing the severity of this disease. Recently, the significance of exosomes as a biomarker has gradually increased; exosomes act as a critical mediator of cell-cell intracellular communication in cancer progression. In this study, we characterized exosomes derived from ascites (ExoAscites) of four patients with GC; the high concentration of ExoAscites was observed with the morphology of round-cup shape. Our results showed that ExoAscites were actively endocytosed into cancer spheroid with time. The tropism of ExoAscites showed a predominance to GC rather than stromal cells.Furthermore, their importance on cancer invasiveness and angiogenesis are verified in the 3D microfluidic cancer spheroid model. Interestingly, tumor progression was gradually promoted by treatment with increasing ExoAscites concentrations. Collectively, these results support the view that exosomes from ascites fluids act as mediators of the tumor microenvironment, thus providing conditions favorable for future tumor progression.
Citation Format: Sujin Hyung, Jihoon Ko, In-kyung Lee, Noo Li Jeon, Jeeyun Lee. Ascites derived exosomes promote progression of advanced gastric cancers [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 6352.
Abstract 6370: Assessing the effect of blocking CCL2-CCR2 axis on breast cancer brain metastasis
Authors: Duan Yimin , Qi Yutao , Zhang Lin , Yuan Xiangliang , Yu Dihua 
Published: June 2022

Abstract
Among the 300,000 newly diagnosed breast cancer patients every year, 5~20% of them will develop symptomatic brain metastasis, whose 1-year survival rate is lower than 20%. Our group previously reported that brain tumor microenvironment (TME)-mediated PTEN downregulation in brain metastatic tumor cells increases the secretion of the chemokine CCL2, which enhances the infiltration of CCR2+ bone marrow derived myeloid cells, eventually promoting brain metastasis outgrowth. However, the mechanism of CCL2-CCR2 axis promoting brain metastasis is not clear, and the efficacy of targeting either CCR2 or CCL2 remained to be assessed. Here we show that Ccr2 antagonism significantly blocked Ccr2high myeloid cells trafficking in the blood and infiltration into the brain TME. However, Ccr2 antagonism did not sufficiently impede breast cancer brain metastasis in multiple preclinical models. Nevertheless, knocking down CCL2 or targeting CCL2 exhibited significant inhibition of brain metastasis growth. Subsequent analysis of the brain TME through mass cytometry demonstrated dramatically decreased infiltration of both Ccr2high and Ccr2low myeloid cell populations in the CCL2 targeted group, implying that the Ccr2low myeloid cells are also involved in promoting brain metastasis growth. Our data highlights the differential responses between targeting CCR2 or CCL2 in multiple preclinical brain metastasis models, which direct us to explore the function of Ccr2low myeloid cells in regulating brain metastasis progression. Our findings also suggest that carefully choosing between CCR2 or CCL2 as a target to control brain metastasis is important in clinical practice.
Citation Format: Yimin Duan, Yutao Qi, Lin Zhang, Xiangliang Yuan, Dihua Yu. Assessing the effect of blocking CCL2-CCR2 axis on breast cancer brain 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 6370.