bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1166: APOBEC deaminases compete with tobacco smoking mutagenesis and affect age at onset of lung cancer
Authors: Zhang Tongwu , Sang Jian , Hoang Phuc H. , Zhao Wei , Rosenbaum Jennifer , Klimczak Leszek J. , McElderry John , Klein Alyssa , Wirth Christopher , Bergstrom Erik N. , Díaz-Gay Marcos , Vangara Raviteja , Hutchinson Amy , Lawrence Scott M. , Cole Nathan , Zhu Bin , Przytycka Teresa M. , Shi Jianxin , Caporaso Neil E. , Homer Robert , Pesatori Angela C. , Consonni Dario , Chanock Stephen J. , Wedge David C. , Gordenin Dmitry A. , Alexandrov Ludmil B. , Harris Reuben S. , Landi Maria Teresa 
Published: April 2023

Abstract
APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B interact with exogenous mutagenic processes in shaping tumor development is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence, apoptosis, and cell regeneration, as indicated by telomere shortening, high expression of pulmonary healing signaling pathway and stemness markers in HAS. The expected association of tobacco smoking exposure with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS tumors have slower clonal expansion and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells in HAS. These findings show how heterogeneity in mutational burden across competing mutational processes and cell types contributes to tumor development, with important clinical implications.
Citation Format: Tongwu Zhang, Jian Sang, Phuc H. Hoang, Wei Zhao, Jennifer Rosenbaum, Leszek J. Klimczak, John McElderry, Alyssa Klein, Christopher Wirth, Erik N. Bergstrom, Marcos Díaz-Gay, Raviteja Vangara, Amy Hutchinson, Scott M. Lawrence, Nathan Cole, Bin Zhu, Teresa M. Przytycka, Jianxin Shi, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Stephen J. Chanock, David C. Wedge, Dmitry A. Gordenin, Ludmil B. Alexandrov, Reuben S. Harris, Maria Teresa Landi. APOBEC deaminases compete with tobacco smoking mutagenesis and affect age at onset of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1166.
Abstract 1180: Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data
Authors: Jia Guochong , Yang Yaohua , Ping Jie , Xu Shuai , Liu Lili , Guo Xingyi , Tao Ran , Long Jirong , Zheng Wei 
Published: April 2023

Abstract
Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1,142 circulating proteins with breast cancer risk in 133,384 cases and 113,789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) &lt;0.05, including nine proteins encoded by genes located at least 500kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR &lt;0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling, and NF-kB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk.
Citation Format: Guochong Jia, Yaohua Yang, Jie Ping, Shuai Xu, Lili Liu, Xingyi Guo, Ran Tao, Jirong Long, Wei Zheng. Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1180.
Abstract 1251: Novel potential role of m6A-demethylase FTO (fat mass and obesity) protein in colorectal cancer
Authors: Landskron-Ramos Glauben T. , Domínguez-Beltrando Antonia L. , Zambra-Rojas Mauricio , Sanguineti Antonella , Vasquez Gonzalo , la Fuente Marjorie De , Simian Daniela , Valdebenito-Silva Silvana , Saavedra Juan , Gouet Solange , Soto-Rifo Ricardo , Sauma Daniela , Eugenin Eliseo , Abedrapo Mario , Hermoso Marcela A. , Hermoso Marcela A. 
Published: April 2023

Abstract
Colorectal cancer (CRC) is the one of the most frequent and deadly cancer worldwide. The regulation mediated by the N6methyladenosine (m6A) demethylase protein called FTO in CRC is quite controversial. As previously studied in obesity and food intake, currently is being linked to stemness, epithelial-mesenchymal transition, chemotherapy resistance and proliferation in colon cancer cells, however, its localization and function in the tumor microenvironment (TME) and how it connects with progression remains unclear. The aim of this study was to evaluate FTO protein in tumor and healthy corresponding tissue from 22 colorectal cancer patients with different histological TNM stages (hTNM) by immunohistochemistry and multiple immunofluorescence analysis; classifying the tumor and stromal FTO localization and associating this data with clinical and histopathological features. As for content, the frequency of FTO+ cells in stromal compartments increases in more invasive stages compared to non-tumor tissue and in tumors with low desmoplasia. Regarding to localization, FTO is mostly nuclear and present in the lamina propria cells in non-tumor tissues and in immune and fibro-immune compartments in the TME, such as T cells, cancer associated fibroblasts and macrophages. In tumor cells, the percentage of FTO+ cells increase in early carcinogenic stages (hTNM I vs healthy tissue) and in moderately differentiated tumors. In addition, nuclear FTO expression increases in normal T cells and fibroblasts with a particular pattern after exposure for 24h to a colon adenocarcinoma cell-derived conditioned media, suggesting FTO activity in the TME interaction following a paracrine signal. In conclusion, the increase of the FTO protein in both tumor and stroma from CRC suggests its participation mediating TME communication.
Citation Format: Glauben T. Landskron-Ramos, Antonia L. Domínguez-Beltrando, Mauricio Zambra-Rojas, Antonella Sanguineti, Gonzalo Vasquez, Marjorie De la Fuente, Daniela Simian, Silvana Valdebenito-Silva, Juan Saavedra, Solange Gouet, Ricardo Soto-Rifo, Daniela Sauma, Eliseo Eugenin, Mario Abedrapo, Marcela A. Hermoso, Marcela A. Hermoso. Novel potential role of m6A-demethylase FTO (fat mass and obesity) protein in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1251.
Abstract 1278: ID3 controlled dynamic Pyk2 localization is important for the mobility of cancer stem cells
Authors: Das Jayanta , Deoraj Alok , Roy Deodutta , Felty Quentin 
Published: April 2023

Abstract
Treatment of brain metastases remains a clinical barrier in breast cancer patients. Secondary breast tumors in the brain are reported to be enriched with breast cancer stem cell (BCSC) markers suggesting that BCSCs infiltrate the brain. Brain infiltration by BCSCs is complex involving detachment from the primary tumor, entering the blood, surviving the microvascular niche, and crossing the blood brain barrier (BBB). It is critical to understand how BCSCs move through the BBB to prevent brain metastases. Nuclear respiratory factor 1 (NRF1) transcription factor, Pyk2 non-receptor tyrosine kinase, and inhibitor of differentiation protein 3 (ID3) have been shown to contribute to the pathogenesis of cancer through inducing CSCs or increasing mobility of these cells. Recently, we showed that NRF1-induced BCSCs crossed the BBB which were guided by ID3 overexpressing endothelial stem cells. In this study, we investigated the NRF1/ID3/Pyk2 axis contributing to BCSCs mobility. NRF1 promoted migration of BCSCs and mesenchymal MDAMB231 cells through brain endothelial cells cultured with astrocytes. ID3 overexpressing endothelial cells promoted adhesion with BCSCs and mobility of BCSCs across the BBB model. In addition, ID3 controlled Pyk2 localization which is important for mobility of stem cells and cancer cells. Endothelial cells were treated with a known risk factors for breast cancer, 17β-estradiol (E2) and environmental pollutant PCB153. Treatment with PCB153 or E2 showed increased growth of BCSCs tumor spheroids and mobility of ESCs. Exosomal ID3 released from endothelial cells also supported the growth of BCSCs and provide the basis for paracrine effects by endothelial stem cells associated with breast tumors. These findings show for the first time a novel role for ID3 and Pyk2 by which endothelial stem cells support breast tumor metastases where they most likely facilitate the colonization, survival, and proliferation of BCSCs. This knowledge is important for pre-clinical testing of NRF1/ID3/Pyk2 modifying agents to prevent the spread of breast cancer to the brain.
Citation Format: Jayanta Das, Alok Deoraj, Deodutta Roy, Quentin Felty. ID3 controlled dynamic Pyk2 localization is important for the mobility of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1278.
Abstract 1286: UNC5B promotes EMT and metastasis of pancreatic adenocarcinomas and expresses different isoforms that impact sensitivity to Netrin-1 blockade
Authors: Harris Chris R. , Prela Orjola , Wang Lan , Casabianca Anthony , Narrow Wade , Sechrist Zachary , Withers Tracy , Shields Cory , Asad Asra , Hezel Aram , Carpizo Darren 
Published: April 2023

Abstract
The axonal guidance receptor UNC5B is considered to be a tumor suppressor because it promotes apoptosis in the absence of its protein ligand, NTN1. But we find that UNC5B is not a tumor suppressor of pancreatic ductal adenocarcinomas (PDAC), and instead promotes metastasis. In TCGA data, UNC5B expression associates with poor patient outcome. In vivo, pancreatic cancer metastasis was completely eliminated by knocking out UNC5B from the genetically engineered KPC mouse model of PDACs, and was reduced upon knockout of UNC5B in a splenectomy model of liver metastasis. An inhibitor of NTN1, NP137, also reduced metastasis in vivo. In vitro, knockout of UNC5B from mesenchymal pancreatic cell lines was sufficient to reduce many metastatic traits including invasiveness, EMT, and aerobic glycolysis. YAP1 is a known target of UNC5B and was overexpressed in high UNC5B expressing cell lines, which were sensitive to the YAP1 inhibitor CA3. NP137 is currently in clinical trial for several tumor types and we have been investigating which patients might respond best to this drug. Using an antibody (D9M7Z) that recognizes an epitope in UNC5B that overlaps with the caspase-3 cleavage site that is critical for UNC5B's apoptotic functions, we found two isoforms in murine and human PDACs: one isoform that contains the caspase-3-containing epitope as well as a previously-unreported isoform that to lack it. Cells expressing the caspase-3 site were much more sensitive to NP137. We also discovered genetic alterations in patient samples that induce expression of UNC5B. For instance, UNC5B was recurrently amplified in PDACs and these amplifications were highly focal to the UNC5B locus; also, UNC5B expression was increased by mutations of ARID1A, a component of the SWI/SNF transcription complex that is recurrently mutated in pancreatic adenocarcinomas. ARID1A mutations caused cell lines to become mesenchymal, but the cells returned to an epithelial phenotype upon knockout of UNC5B. In current and future clinical trials, NP137 may particularly benefit patients with tumors that harbor mutations in ARID1A or ARID1B, focal amplifications of UNC5B, and/or high expression of the caspase-3-containing isoform of UNC5B.
Citation Format: Chris R. Harris, Orjola Prela, Lan Wang, Anthony Casabianca, Wade Narrow, Zachary Sechrist, Tracy Withers, Cory Shields, Asra Asad, Aram Hezel, Darren Carpizo. UNC5B promotes EMT and metastasis of pancreatic adenocarcinomas and expresses different isoforms that impact sensitivity to Netrin-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1286.
Abstract 1316: Immune cell dysfunction is enhanced in a mouse model of obesity-associated breast cancer lung metastasis
Authors: Williams Abbey E. , Arendt Lisa M. 
Published: April 2023

Abstract
Obesity is known to worsen the overall prognosis of breast cancer patients. Breast cancer patients with a body mass index (BMI) of ≥30 kg/m2 have an increased risk for metastatic disease compared to patients with a BMI in the normal range. Further studies are necessary to understand the mechanisms driving increased breast cancer metastasis in obese patients, particularly to the lung. Although immune cells like neutrophils and myeloid derived suppressor cells have been studied in breast cancer metastasis of the lung, little is known how adaptive immune cells function in metastatic niche of the lung in obesity. To investigate these gaps, we fed 3-week-old female FVB/N mice either a low-fat diet (LFD) or high-fat diet (HFD) for 16 weeks to induce obesity. We then injected estrogen receptor positive (ER+) TC2 cells into the mammary fat pad. Tumors grew to 0.5 cm in diameter then were surgically removed. Lung tissue was collected 8 weeks after tumor removal to examine progression of metastatic disease, and T cell populations were quantified in metastatic lung tissue from obese and lean mice using flow cytometry. Lungs from obese mice showed a significant increase of total immune cells (CD45) and a decrease in total T cells and natural killer cells (NK) compared with controls. CD3+ cells and CD8+ T cells from obese mice expressed higher levels of programmed cell death protein-1 (PD1), a marker of T cell dysfunction. These results suggest that T cells from the lungs of obese mice may have a greater level of T cell dysfunction than controls. To further investigate how obesity alters the function of T cells, CD45+ cells were sorted from lungs from lean and obese mice with and without metastasis, and gene expression was examined using the Nanostring nCounter Immune Exhaustion panel. Immune cells from the lungs of obese non-tumor-bearing mice showed increased expression of NK exhaustion markers and increased TCR signaling. In metastatic lungs from obese mice, immune cells also showed impaired interferon and tumor necrosis factor signaling and an increase in genes associated with exhaustion in NK cells. Further analysis showed upregulated expression of genes associated with senescence in immune cells from metastatic lungs of obese mice. These data suggest that obesity may increase dysfunctional states of T cells and NK cells, leading to enhanced metastatic growth of breast cancer cells.
Citation Format: Abbey E. Williams, Lisa M. Arendt. Immune cell dysfunction is enhanced in a mouse model of obesity-associated breast cancer lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1316.
Abstract 1349: Exploring CD63 as a targetable mediator of the pro-tumorigenic tissue microenvironment in HNSCC
Authors: Dingendorf Elisabeth B. , Stoffel Michael C. , Kittel Dahlia L. , Kristiansen Glen , Lerbs Tristan 
Published: April 2023

Abstract
Introduction: Head and neck squamous cell carcinoma (HNSCC) is one of the ten most common cancer types worldwide - ranked on the sixth position with 560,000 new diagnoses and 270,000 deaths in 2020. The survival could be increased only slightly over the past decades and in addition the incidence of HNSCC continues to rise. In this study, we investigated the role of the tetraspanin CD63 during cancer progression.
Methods: First, we performed survival analyses with available statistics from data bases to correlate CD63 and survival. Then, we established a 20-marker spectral FACS panel to identify different fibroblast subpopulations in patient tissue. Upon receiving patient consent, fresh HNSCC tissue was received from surgical tumor resections at the University Hospital of Bonn. We mechanically and enzymatically digested and purified the tissue of ten patients to create single-cell suspensions. After staining, the cells were measured on a Sony ID7000 Spectral Analyzer and interpreted with FlowJo. To identify whether CD63 on fibroblasts affects the differentiation of macrophages in vitro, we isolated primary fibroblasts and monocytes from HNSCC patients and deleted CD63 in fibroblasts by CRISPR-Cas9. Thereafter, we co-incubated fibroblasts (without and with the CD63-Knockout) and macrophages over ten days in M-CSF containing medium, and measured the expression of M1 and M2 markers through flow cytometry.
Results: First, correlating CD63 gene expression with the patient outcome showed that CD63 correlated with a decreased survival. Then, analyzing fresh tumor specimens with the multicolor panel showed an increase of CD63 expression in different fibroblast subpopulations in the tumor specimens, e. g. CD9+ CD34+ CD63+ CD90+ fibroblasts increased more than eightfold. Investigating potential mechanisms, by which CD63 expression on fibroblasts affects tumor progression, deleting CD63 steered macrophages towards the pro-inflammatory M1 phenotype.
Conclusion: This study demonstrates that HNSCC increases CD63 expression in different fibroblast populations and that deleting CD63 on fibroblasts can steer macrophages towards the pro-inflammatory phenotype, thereby suggesting a rationale for testing CD63 as a therapeutic target.
Citation Format: Elisabeth B. Dingendorf, Michael C. Stoffel, Dahlia L. Kittel, Glen Kristiansen, Tristan Lerbs. Exploring CD63 as a targetable mediator of the pro-tumorigenic tissue microenvironment in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1349.
Abstract 1361: Astrocytes activate neuronal programming in melanoma brain metastases
Authors: Farnan Julia K. , Cavallo Maria R. , Hartsough Edward J. , Jackson Joshua G. 
Published: April 2023

Abstract
Melanoma Brain Metastases (MBM) pose a major challenge for treating metastatic melanoma. Up to 70% of advanced melanoma patients develop MBM, resulting in significant morbidity and mortality. Melanocytes, the originating cell type of melanomas, are derived from neural crest cells in development. Melanoma’s proclivity to metastasize to the brain has been anecdotally connected to its neural crest origins. Recently, transcriptomic analyses have demonstrated that MBM express a neuronal-like phenotype, upregulating neural crest factors such as NCAM (Neural cell adhesion molecule), L1CAM (L1 cell adhesion molecule protein), while expressing melanocytic markers like MITF (melanocyte induction transcription factor). The activation of neuronal development programming may be a key mediator in brain-metastatic growth, and thus necessitates a better understanding of how melanoma cells adapt to the brain. Astrocytes have emerged as the major host cell type that cancer cells encounter and interact with during brain metastasis formation. Typically, astrocytes regulate brain homeostasis and support neuronal function. Their response to injury, termed reactive astrocytosis, is a process defined by increased secretion of growth factors and inflammatory cytokine production. Post-mortem analyses of MBM patients reveal perilesional reactive astrocytosis. Here we demonstrate that astrocyte reactivity promotes MBM growth, using in vitro and in vivo model systems. We identify that astrocytes secrete factors that increase tumor growth and expression of neural development factors. Moreover, pharmacological inhibition of neural development pathways, like Wnt signaling, attenuate the effects of astrocyte secreted factors. We developed a brain adapted melanoma line, D4M3a BrJ, and demonstrate the time course of astrocyte reactivity in vivo in its relationship with tumor growth. Our findings provide evidence that astrocyte reactivity promotes MBM growth and activation of neural development programming, unveiling a new therapeutic avenue for targeting the brain metastatic niche.
Citation Format: Julia K. Farnan, Maria R. Cavallo, Edward J. Hartsough, Joshua G. Jackson. Astrocytes activate neuronal programming in melanoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1361.