bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6931: Characterization of cancer evolution landscape based on accurate detection of somatic mutations in single tumor cells
Authors: Niu Muchun , Zhang Yang , Luo Jiayi , Sinson Jefferson C. , Thompson Alastair M. , Zong Chenghang 
Published: March 2024

Abstract
Accurate detection of somatic mutations in single tumor cells is greatly desired as it allows us to quantify the single-cell mutation burden and construct the mutation-based phylogenetic tree. Here we developed scNanoSeq chemistry and profiled 842 single cells from 21 human breast cancer samples. The majority of the mutation-based phylogenetic trees comprise a characteristic stem evolution followed by the clonal sweep. We observed the subtype-dependent lengths in the stem evolution. To explain this phenomenon, we propose that the differences are related to different reprogramming required for different subtypes of breast cancer. Furthermore, we reason that the time that the tumor-initiating cell took to acquire the critical clonal-sweep-initiating mutation by random chance set the time limit for the reprogramming process. We refer to this model as a reprogramming and critical mutation co-timing (RCMC) subtype model. Next, in the sweeping clone, we observed that tumor cells undergo a branched evolution with rapidly decreasing selection. In the most recent clades, effectively neutral evolution has been reached, resulting in a substantially large number of mutational heterogeneities. Integrative analysis with 522-713X ultra-deep bulk whole genome sequencing (WGS) further validated this evolution mode. Mutation-based phylogenetic trees also allow us to identify the early branched cells in a few samples, whose phylogenetic trees support the gradual evolution of copy number variations (CNVs). Overall, the development of scNanoSeq allows us to unveil novel insights into breast cancer evolution.
Citation Format: Muchun Niu, Yang Zhang, Jiayi Luo, Jefferson C. Sinson, Alastair M. Thompson, Chenghang Zong. Characterization of cancer evolution landscape based on accurate detection of somatic mutations in single tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6931.
Abstract 6951: The role of estrogen-dependent activation of p38 MAPK signaling pathway in inflammatory breast cancer
Authors: Ramirez Keyla V. , Bonilla-González Adrian D. , Guzman-Rivera Jeisac , Peterson-Peguero Esther A. 
Published: March 2024

Abstract
Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer in which the lymphatic vessels become blocked by cancer cells in the breast tissue. The five-year survival rate for this type of cancer is around 40%, one of the worst among breast cancer. Most IBCs are estrogen receptor (ER) and progesterone receptor (PR) negative and HER2 positive, with some presenting an amplification of HER2 while others are ER, PR, and HER2 negative, formally known as the triple-negative (TNBC) subtype. However, it has been reported that treatment with 17β-Estradiol (E2) of ER-negative IBC and non-IBC cells can exert rapid non-genomic signaling mediated by ERα-36, GPR30, and/or estrogen receptor beta, activating MAPK pathways involved in oncogenic phenotypes. Previous data generated in our lab showed that when cells were treated with estradiol it led to increased phosphorylation levels of p38. However, the specific role p38 MAPK signaling takes on in IBC is unknown. Thus, this study centers on examining the role of estradiol and p38 regulation in the triple-negative IBC cell line model, SUM149PT. We hypothesize that upon estradiol treatment p38 signaling pathway is activated resulting in the over-expression of pro-inflammatory cytokines which regulate pro-tumorigenic phenotypes including the growth and survival of IBC cells. Inflammatory cytokines can promote pro-oncogenic features by promoting cell proliferation, angiogenesis, and immune suppression. We treated SUM149 IBC cells with 10nM of estradiol and measured the levels of human cytokines using a Human Cytokine Antibody Array. In addition, treatment using SB202190, a potent p38 inhibitor, caused a significant decrease in cell viability of several breast cancer cell lines in a dose-dependent manner. Ongoing studies include assessing the effects of p38 inhibition proliferation, invasion, and migration. In summary, a better characterization of the effect of E2 and p38 activation in ER-negative cell lines may provide great insight into novel targeted therapies for IBC.
Citation Format: Keyla V. Ramirez, Adrian D. Bonilla-González, Jeisac Guzman-Rivera, Esther A. Peterson-Peguero. The role of estrogen-dependent activation of p38 MAPK signaling pathway in inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6951.
Abstract 6966: STAT3 integration of inflammatory signals and cellular stress promote tumor initiation and progression through the expression of integrin β3
Authors: Campos Alejandro D. , Shepard Ryan , Heumann Ingrid , Lam Justin , Weis Sara M. , Cheresh David 
Published: March 2024

Abstract
STAT3 represents an oncogene whose transcriptional regulation is known to drive tumor initiation, progression, and drug resistance. Although STAT3 can regulate many genes, it remains unclear which genes are critical for STAT3-mediated cancer progression. Here, we report that inflammatory cytokines and cellular stress induce STAT3 activation leading to tumor initiation and progression, which we show depends on its ability to drive transcription of the β3 integrin gene leading to αvβ3 expression. Specifically, CRISPR KO of either STAT3 or integrin β3 in pancreatic cancer cells, is sufficient to impede their tumor initiating capacity in mice, while ectopic STAT3 or β3 expression in STAT3 KO cells rescues their tumor initiation capacity. Mechanistically, STAT3 activation induces β3 expression based on its ability to engage enhancer regions that modulate β3 gene expression. These findings implicate integrin αvβ3 as a critical downstream effector of STAT3, thereby contributing to its role as a driver of tumor initiation and progression.
Citation Format: Alejandro D. Campos, Ryan Shepard, Ingrid Heumann, Justin Lam, Sara M. Weis, David Cheresh. STAT3 integration of inflammatory signals and cellular stress promote tumor initiation and progression through the expression of integrin β3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6966.
Abstract 6971: The impact of lecithin retinol acyltransferase in squamous cell carcinoma: Tissue formation, cell mechanics, and gene transcription
Authors: Peterson Emily , Feng Kuan-Che , Gao Jay , Rafailovich Miriam , Simon Marcia 
Published: March 2024

Abstract
Squamous cell carcinoma, along with several other cancers, has been found to lack expression of lecithin retinol acyltransferase (LRAT), a protein which catalyzes retinol esterification and thereby mediates retinoic acid biosynthesis. When expression of LRAT was reintroduced in squamous cell carcinoma, the protein promoted cell differentiation in addition to retinoid status normalization—whether this effect was dependent on the known enzymatic activity of LRAT in retinol esterification, versus another function, has not yet been established. Cell elasticity differences have also been reported between squamous cell carcinoma and normal keratinocytes. In this study, the role of LRAT expression and activity was evaluated in human squamous cell carcinoma cell line SCC13. LRAT was integrated into the genome of SCC13 via retroviral transduction, both as wild-type LRAT and LRAT with a cysteine-to-serine mutation at the active site for retinol esterification (C161-S). In these transformed cell lines, LRAT promoted formation of a cohesive sheet of tissue which remained intact after its removal from the tissue culture plastic surface, as evaluated at two weeks post-confluence. SCC13 alone produced tissue which easily fragmented during this scraping assay. In an evaluation of cell elasticity with shear modulation force microscopy, relative cell modulus measurements of pre-confluent SCC13 with LRAT expression were found to be significantly greater and consistent with the cell modulus of human keratinocytes (DO33). These effects persisted with mutation of the retinol esterification active site, suggesting that LRAT possesses an additional function which has yet to be described. Variation in transcription levels of multiple genes—urokinase-type plasminogen activator, plasminogen activator inhibitor 1, tissue inhibitor of metalloproteinases 1, and kallikrein 5—was also found based on LRAT expression and level of confluence. These findings suggest that the presence of LRAT influences tissue formation, cell elasticity, and gene transcription in SCC13.
Citation Format: Emily Peterson, Kuan-Che Feng, Jay Gao, Miriam Rafailovich, Marcia Simon. The impact of lecithin retinol acyltransferase in squamous cell carcinoma: Tissue formation, cell mechanics, and gene transcription [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6971.
Abstract 6993: SLC1A4 is associated with metabolic reprogramming in triple-negative breast cancer
Authors: Park Soo Young , Kim Da Sol , Kim Hayeon , Song Min Ji , Ryu Han Suk 
Published: March 2024

Abstract
The solute carrier protein (SLC) family is transporters as integral membrane proteins that transport solutes in an ATP-independent manner. The SLC1 family consists of five high-affinity glutamate transporters and two neutral amino acid transporters, among which SLC1A4 transports the neutral amino acids and is known to participate in various biological processes, including metabolism and tumorigenesis. However, the relationship between SLC1A4 and breast cancer remains unclear. Here, we aimed to verify the role of SLC1A4 in triple-negative breast cancer (TNBC). To reveal the characteristics of SLC1A4 in TNBC cell lines, five cell lines (HCC38/OE, HCC1395/OE, HCC1937/OE, MDA-MB-468/KD, and Hs578T/KD) that regulate gene expression of SLC1A4 were established using a lentiviral system. The two major energy-producing pathways, glycolysis and oxidative phosphorylation, were measured according to SLC1A4 gene expression. In addition, cell proliferation, cell migration, and cell invasion ability were confirmed upon overexpression or knock-down of SLC1A4. To confirm cancer stem cell function according to SLC1A4 gene expression, ALDH activity and sphere formation ability were evaluated. To ensure transcript changes due to SLC1A4 expression, RNA sequencing was performed. Anti-cancer drug (cisplatin, carboplatin, paclitaxel, and doxorubicin) sensitivity was also tested. The result showed that energy production efficiency was significantly reduced in cells where SLC1A4 expression was suppressed. In addition, in cells overexpressing the SLC1A4 gene, the presence of SLC1A4 was confirmed to increase cell proliferation, migration, and invasion ability significantly. Transcriptome analysis results showed notable changes in genes related to signaling receptor binding. Regarding material transport, to investigate whether there was a change in amino acid uptake ability according to SLC1A4 gene expression, no difference was observed. In the drug responses, doxorubicin showed a significant sensitive response in the absence of SLC1A4 gene expression. Taken together, SLC1A4 is a potential oncogene that not only induces rapid proliferation, aggressive invasion, and migration through metabolic reprogramming but also contributes to increasing cancer stem cell capabilities. In addition, it shows the sensitive response to ADR when SLC1A4 is low or absent, so it can be used as a treatment strategy for TNBC.
Citation Format: Soo Young Park, Da Sol Kim, Hayeon Kim, Min Ji Song, Han Suk Ryu. SLC1A4 is associated with metabolic reprogramming in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6993.
Abstract 7078: Targeting eIF6 to modulate ribosomal subunit association dynamics in cancers
Authors: Harish Kavya Meena , Roshan Poonam , Biswas Aparna , Anagnos Stella , Luebbers Riley , Origanti Sofia 
Published: March 2024

Abstract
Deregulation of ribosomal subunit levels and accessibility are hallmarks of cancer. Eukaryotic translation initiation factor 6 (eIF6) is a key regulator of ribosomal subunit association that is over expressed in many cancers including lung, colon, ovarian and breast cancers, and deregulation of eIF6 is correlated with a poor cancer prognosis. Association of eIF6 with 60S is critical for 60S assembly. However, eIF6 must be released from 60S prior to translation to permit inter subunit interactions between 60S and 40S and to facilitate the formation of translationally proficient 80S monosome. Release of eIF6 is deregulated in the ribosomopathy- Shwachman Diamond Syndrome that is predisposed to leukemias. Also, loss of eIF6 markedly delays tumorigenesis without affecting normal growth, which presents eIF6 as a viable therapeutic target. A potential therapeutic strategy is to target the eIF6 and 60S ribosomal interaction interface. Through biophysical analyses we had identified residues that are critical for the interaction between eIF6 and 60S ribosomal subunit. We show that targeting these key residues in the eIF6-60S interaction interface markedly delays colonic cancer growth and inhibits protein synthesis. Furthermore, we show that the levels of other eIFs and the release factors: SBDS, and EFL1-GTPase are unaltered in the mutant cells suggesting that the translational inhibition is primarily attributed to the deregulation of eIF6. Interestingly, targeting eIF6 leads to an upregulation of p53 independent of the DNA damage response, suggesting that ribosomal stress contributes to the stabilization of p53. Previously, it was shown that translation of Cdc42 was upregulated by eIF6 to promote invasiveness. However, Cdc42 levels were unaltered in the mutant cells. Future studies will determine the mRNA substrates that are translationally deregulated in the mutants. We will also determine the effect of disrupting eIF6 function in inhibiting tumor growth and progression in vivo.
Category: MCB, Subcategory: MCB07-Gene regulation sub classification: Translational Control
Citation Format: Kavya Meena Harish, Poonam Roshan, Aparna Biswas, Stella Anagnos, Riley Luebbers, Sofia Origanti. Targeting eIF6 to modulate ribosomal subunit association dynamics in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7078.
Abstract 7079: The Wnt/β-catenin signaling pathway regulates cellular metabolism through the suppression of HAL and ARG1 in liver cancer cells
Authors: Nakagawa Saya , Yamaguchi Kiyoshi , Takane Kiyoko , Tabata Sho , Ikenoue Tsuneo , Furukawa Yoichi 
Published: March 2024

Abstract
Aberrant activation of the Wnt/β-catenin signaling pathway plays a crucial role in a wide range of human tumors including colorectal and liver cancer. The activated signaling causes nuclear accumulation of β-catenin, which leads to the elevated expression of target genes of TCF/LEF (T-cell factor/lymphoid enhancer factor) transcription factors through their interaction with nuclear β-catenin. Recent studies have identified a lot of genes induced by this pathway such as MYC, CCND1, AXIN2, and LGR5, and clarified their roles in tumorigenesis. However, the roles of the genes down-regulated by the pathway remain to be elucidated. Our previous study revealed that the histidine ammonia-lyase gene (HAL) encoding an enzyme involved in the catabolism of histidine was down-regulated by the signaling pathway in liver cancer. In addition, we identified a region that is involved in the Wnt-dependent regulation of HAL. To clarify the regulatory mechanism of HAL by the pathway, we searched for transcription factors that are associated with the regulatory region, and identified CEBPA and FOXA1, two liver-enriched transcription factors. It is of note that the expression of these factors was reduced by the TCF/β-catenin complex. Further investigation identified arginase 1 (ARG1) encoding an enzyme that catalyzes the hydrolysis of arginine as another target gene of CEBPA and FOXA1. Consistent with these data, inhibition of the Wnt signaling increased the expression of ARG1 as well as HAL in liver cancer cells. Furthermore, the up-regulation of HAL and ARG1 by the inhibition of this pathway decreased intracellular concentrations of histidine and arginine, suggesting that the Wnt signaling plays an important role in cellular metabolism through the regulation of the two transcription factors. These findings shed light on the role of the Wnt/β-catenin signaling pathway in the metabolism of amino acids in liver cancer cells.
Citation Format: Saya Nakagawa, Kiyoshi Yamaguchi, Kiyoko Takane, Sho Tabata, Tsuneo Ikenoue, Yoichi Furukawa. The Wnt/β-catenin signaling pathway regulates cellular metabolism through the suppression of HAL and ARG1 in liver cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7079.
Abstract 7098: Identifying of potential therapeutic targets of Taiwanese breast cancer by functional proteomics
Authors: Huang Chi-Cheng , Ku Wei-Chi , Huang Chi-Jung , Tseng Ling-Ming 
Published: March 2024

Abstract
The aim of the study is to conduct translational research of crucial breast cancer prognostic genes with functional proteomics. We have collected 61 breast cancer core biopsy samples, which were used for targeted sequencing for genetic variant analysis, mass-spectrometry analysis for protein expression and stain with H&E for whole slide image with Aperio Scanncer.
After analysis of variant (ANOVA) of LC-MS/MS data, we found 17 proteins with highly differential expression between these 5 molecular subtypes from 61 patients. We then search for the protein-protein interaction (PPI) network from STRING database and found the strong network including 6 proteins namely Collagen Type II Alpha 1 Chain (COL2A1), Collagen alpha-1(XI) chain (COL11A1), Collagen alpha-1(VI) chain (COL6A1), Collagen alpha-2(VI) chain (COL6A2), Thrombospondin 1 (THBS1) and Lumican (LUM).
To further investigate on the expression of these 6 target proteins in literature, we used Oncomine for data mining to query their mRNA expression profiles. Intriguingly, we discovered the mRNA expression of these targets are intensively distributed in many cancer types. This finding suggested the high potency of COL2A1, COL11A1, COL6A1, COL6A2, THBS1 and LUM as potential targets in breast cancer treatment. Our study has the potential contributing to the knowledge of breast cancer susceptibility, early detection, surveillance, and potential actionable targets, developing optimized screening programs and treatment protocols for distinct molecular subtypes.
Citation Format: Chi-Cheng Huang, Wei-Chi Ku, Chi-Jung Huang, Ling-Ming Tseng. Identifying of potential therapeutic targets of Taiwanese breast cancer by functional proteomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7098.
Abstract 7119: Clinic-ready Polθ inhibitor SYX1097 suppresses solid tumors in vivo
Authors: Zhang Yilan , Jiang Kai , Xu Xiaokang , Wu Liu , Ge Chongxun , Xie Yue , He Hu , Liu Song , Tang Xuzhen , Shi Song 
Published: March 2024

Abstract
A large fraction of tumors with BRCA1 or BRCA2 mutations only have weak responses to PARP inhibitor (PARPi) treatment, and often develop PARPi resistance. To address these challenges, we have developed SYX1097, a selective and potent oral Polθ inhibitor as a single agent or in combination with PARPi for treating tumors with BRCA mutations. Both Polθ and PARP1 play key roles in microhomology-mediated end joining for DNA double-strand repair and in single-strand DNA gap filling during DNA replication.
Using in vitro cellular assays and in vivo animal models, we show that SYX1097 alone or combined with PARPi without obvious side effects. SYX1097 dramatically inhibited proliferation in BRCA -/- isogenic cells with IC50 &lt;20 nM, while only had very weak effect on their parental cells (&gt;10000nM). SYX1097 also enhanced tumor cell sensitivity to Olaparib 5 to 15 times. SYX1097 in vivo efficacious started at 50mg/kg mono-therapy, and generate &gt;50% tumor regression at 5mg/kg when combined with Olaparib. In a 20-day repeated dosing study, SYX1097 200mg/kg BID was fully tolerated by mice. When considering additive hematological toxicity, comparing with “ATRi + PARPi”, “SYX1097 + PARPi” manifested deep and durable tumor regression without significant body weight loss or reticulocytes decrease. Moreover, SYX1097 is found synthetic lethal with defect of genes not involved in homologous recombination repair and able to suppress tumors with specific gene defect in vivo, which indicated SYX1097 can be used as single agent guided by specific biomarker.SYX1097 has a clean safety profile tested with Safety-Screen 44TM Panel, and is well tolerated in mice, rats and dogs. It possesses remarkable pharmacokinetic properties in various species, with no hematological toxicity observed during the preclinical toxicity studies. SYX1097 is advancing towards IND filing in 2024.Collectively, SYX1097 is a promising small molecule that may be utilized as a single agent or in combination with PARPi for cancer treatment not only limited by HR deficiency.
Citation Format: Yilan Zhang, Kai Jiang, Xiaokang Xu, Liu Wu, Chongxun Ge, Yue Xie, Hu He, Song Liu, Xuzhen Tang, Song Shi. Clinic-ready Polθ inhibitor SYX1097 suppresses solid tumors in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7119.