bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B072: Loss of the tumor and metastasis suppressor RasGAP DAB2IP mediates therapeutic resistance in HER2+ breast cancer
Authors: Perurena Naiara , Schade Amy , Pilla Natalie , Loi Patrick , Rodriguez Carrie , Gardner Alycia , Cichowski Karen 
Published: February 2024

Abstract
Resistance to HER2 inhibitors remains a clinical challenge in HER2+ breast cancer. Therefore, there is an urgent need to 1) understand the mechanisms that underlie resistance to these current treatments and 2) develop improved, and more importantly, curative combination therapies. We previously showed that the RasGAP DAB2IP is a tumor and metastasis suppressor in breast cancer. Interestingly, we have now generated robust data demonstrating that the loss of DAB2IP also mediates therapeutic resistance in HER2+ breast cancer. First, we genetically ablated DAB2IP in multiple HER2+ breast cancer cell lines and performed manual counting experiments after 6 days of HER2 TKI treatment. In all cell lines, DAB2IP knockdown conferred resistance to HER2 inhibitors. Since HER2 inhibitors are known to induce both apoptosis and senescence, we next investigated how DAB2IP loss specifically affects these phenotypes. Interestingly, DAB2IP knockdown prevented TKI-induced caspase-3/7 activation, measured by Incucyte live cell imaging, and enabled the regrowth of cells in long-term 10-day treatment and drug washout experiments, monitored by Incucyte or crystal violet staining. Mechanistically, stable knockdown of DAB2IP reduced the suppression of the AKT and ERK pathways and the induction of the pro-apoptotic protein Bim upon HER2i treatment. In addition, cell cycle progression pathways were enriched in DAB2IP-deficient cells on lapatinib treatment and immunoblots revealed higher residual levels of pRb and low levels of p27 in these cells. Interestingly, the levels of these proteins were restored and regrowth in low density assays was inhibited with co-treatment with an NF-kB inhibitor. We next evaluated the relevance of DAB2IP loss in mediating HER2 inhibitor resistance in a SUM190 orthotopic xenograft model. Importantly, while control tumors regressed upon lapatinib treatment, DAB2IP-deficient tumors did not regress and grew with kinetics comparable to vehicle-treated tumors after few days on treatment. Further understanding the pathways deregulated by DAB2IP loss upon HER2i treatment will be essential for developing effective therapeutic strategies to combat resistance induced by DAB2IP loss.
Citation Format: Naiara Perurena, Amy Schade, Natalie Pilla, Patrick Loi, Carrie Rodriguez, Alycia Gardner, Karen Cichowski. Loss of the tumor and metastasis suppressor RasGAP DAB2IP mediates therapeutic resistance in HER2+ breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B072.
Abstract B086: Association of breast cancer-relevant DNA repair genes with postmenopausal breast cancer risk in UK Biobank
Authors: Smotherman Carmen , Sprague Brian , Braithwaite Dejana , Qin Huaizhen , Yaghjyan Lusine 
Published: February 2024

Abstract
Purpose. Several polymorphisms have been described in DNA damage signaling and repair genes and some of the polymorphisms have been implicated in genetic susceptibility to breast cancer. However, there is no consensus result yet for most of these polymorphisms. In this study, we focused on evaluating selected SNPs in BRCA1, BRCA2, ATM, XRCC1, XRCC2, XRCC3, and XPD (ERCC2) genes that have been previously reported to be associated with breast cancer risk and are available in the UK Biobank. Methods. This study included 150,929 postmenopausal women (5,969 with BCa) from UK Biobank, a population-based prospective cohort. Cancer diagnoses were ascertained through the linkage to the UK National Health Service Central Registers. DNA was extracted from blood samples collected from participants at enrollment in UK Biobank. Samples were genotyped using the Applied Biosystems UK BiLEVE Axiom Array or the Applied Biosystems UK Biobank Axiom Array. The positions of markers in the data are in GRCh37 coordinates. SNPs with frequency &lt; 1% in the study population were excluded from analyses. We included the following SNPs in the final analyses: XRCC3-rs861539, BRCA1-rs16942, BRCA1-rs4986852, XRCC1-rs25487, XRCC1-rs25489, XRCC1-rs1799782, XPD (ERCC2)-rs13181, XPD (ERCC2)-rs1799793, XRCC2-rs3218536, ATM-rs1800056, ATM-rs1800057, BRCA2-rs144848, BRCA2-rs4987117, and BRCA2-rs11571833. Information on breast cancer risk factors was collected at baseline. Cox proportional hazards regression models were used to analyze the association between each SNP and breast cancer risk while adjusting for known breast cancer risk factors. The risk estimates were presented as hazard rations (HRs) and their corresponding 95% confidence intervals (CIs). Results. The mean age of the study population at enrollment was 60.1 years (range 40-71 years). Heterozygous carriers of BRCA2-rs11571833 T allele were found to have an increased risk of breast cancer (HR=1.22, 95% CI 1.02, 1.46, p-trend = 0.033) compared to the homozygous carriers of the BRCA2-rs11571833 A allele. No other significant associations between other SNPs and breast cancer risk were found. Conclusions. We found a significant association between SNP BRCA2-rs11571833 and postmenopausal breast cancer risk. Our findings contribute to the existing evidence on the association of high-risk polymorphisms in DNA damage signaling and repair genes with postmenopausal breast cancer risk.
Citation Format: Carmen Smotherman, Brian Sprague, Dejana Braithwaite, Huaizhen Qin, Lusine Yaghjyan. Association of breast cancer-relevant DNA repair genes with postmenopausal breast cancer risk in UK Biobank [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B086.
Abstract IA20: Hormonal action in breast cancer: Common features and unique properties that drive tumor development and outcome
Authors: Zwart Wilbert 
Published: February 2024

Abstract
Estrogen receptor (ER) occupies many thousands of regions throughout the human genome. Interestingly, the functional implications of most of these chromatin-bound sites remain completely elusive. In two interconnected stories, I will highlight distinct genomic features that differentiate ER genomic action between patient subgroups, but also between individual patients. Between patients subgroups, we identify clearlty distinct profiles of ER action, dictated by Glucocorticoid Receptor (GR) activity. We show that the activity status of GR determines luminal subtype identity and is associated with patient outcome. GR suppresses tumor growth by engaging with ER, leading to redistribution of ER on the chromatin and upregulation of the tumor suppressor gene ZBTB16. We importantly demonstrate that clinically available epigenetic inhibitors, which mimic GR-induced gene repression, can effectively suppress the growth of highly aggressive ER-positive breast cancer cells displaying absence of GR activity. In a second study, I will elaborate on the massive inter-patient heterogeneity of ER chromatin interactions, with direct biological and clinical implications. While the vast majorty of ER/DNA binding events are poorly conserved between patients, common ER sites are most-transcriptionally active and enriched for breast cancer risk SNPs. With that, we present a natural hierarchy of ER genomic action, identifying those regiosn with the most-direct impact on breast cancer development and progresion.
Citation Format: Wilbert Zwart. Hormonal action in breast cancer: Common features and unique properties that drive tumor development and outcome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA20.
Abstract A026: EGF/EGFR signaling in priming for resistance to BRAF/MEK inhibitors in melanoma
Authors: Vander Velde Robert J. , Shaffer Sydney M. 
Published: February 2024

Abstract
Targeted therapies kill cancer cells very efficiently. However, the effectiveness of targeted therapies is limited by the eventual emergence of resistance, arising from a small subset of cells capable of surviving therapy. Our work has shown genetically homogeneous cells, in distinct transcriptomic states, are capable of surviving combination BRAF and MEK inhibition. In the presence of targeted therapies these rare cells transform into resistant cells, we therefore call these cells ‘primed’ for resistance. Our research has focused on characterizing these primed cells, however, the mechanisms of survival remain unknown. Since primed cells overexpress receptor tyrosine kinases (RTKs), which are associated with growth and survival, we tested if overexpression of the RTK EGFR could explain priming and subsequent resistance. While melanoma cells in which we artificially overexpressed EGFR had no significant increase in resistance, EGFR overexpressing cells in the presence of exogenous EGF are highly resistant to combination BRAF/MEK inhibition. While EGF is not overexpressed in primed cells, preliminary data suggests that while most cells reduce EGF expression in the presence of BRAF/MEK inhibition, primed cells maintain their baseline expression, potentially maintaining EGF/EGFR signaling in these colonies. We are therefore testing if EGF/EGFR signaling is necessary in vitro by knocking out EGF or EGFR. Furthermore, to test if EGF/EGFR signaling can create a primed state, we used flow cytometry to determine expression of the prime cell marker NT5E. In cells with confirmed EGFR overexpression we observed an increased fraction of NT5E overexpressing cells, suggesting that EGF/EGFR signaling could initiate aspects of primeness beyond simple survival. Further research will determine if EGF/EGFR signaling can initiate an overall primed transcriptional state. The heritability of any primeness as a consequence of EGF/EGFR signaling will inform us if this signaling is a potential cause of priming or a mechanism by which paracrine signaling and/or stromal protection can eventually result in independent resistance.
Citation Format: Robert J. Vander Velde, Sydney M. Shaffer. EGF/EGFR signaling in priming for resistance to BRAF/MEK inhibitors in melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A026.
Abstract A031: Investigating the mechanism and impact of frequency-dependent interactions in non-small cell lung cancer
Authors: King Eshan S. , Tadele Dagim S. , Strobl Maximillian A. R. , Scott Jacob G. 
Published: February 2024

Abstract
Introduction: Pre-treatment tumor heterogeneity in cancer is a major driver of drug resistance. Given that resistance mechanisms often impose a fitness cost, the presence of drug-resistant clones prior to treatment poses a paradox—less fit drug-resistant clones should be selected out of a growing population. Recent work has identified frequency-dependent interactions (FDIs) in cancer cell lines, where different proportions of drug-sensitive and resistant cells modulate their respective fitness. FDIs may help explain pre-treatment drug resistance in cancer. Here, we sought to characterize FDIs in a drug-resistant model of non-small cell lung cancer (NSCLC). Methods: We developed a drug-resistant cell line in NSCLC by transducing PC9 cells with BRAF V600E. We then quantified the frequency-dependent interaction between sensitive and resistant cell lines across a range of gefitinib concentrations using the previously published evolutionary game assay. We also implemented an agent-based spatial model of evolution to investigate the different potential molecular mechanisms of frequency-dependent interactions. Results: We found that, despite growing slower in monoculture, low proportions of resistant cells in co-culture with sensitive cells rescued their growth rate in the absence of drug. This phenomenon may help explain pre-treatment drug-resistance and may present a future targetable pathway. Using a computational model parameterized with this data, we investigated the impact of different molecular mechanisms of FDIs on tumor evolution. We found that a mechanism driven by compound diffusion, in contrast to a cell-cell contact mechanism, facilitates drug resistance to greater extent. Through a conditioned media transfer experiment, we found that the FDI in our experimental system is most likely governed by a compound released in the cell culture media. Conclusions: Here we have identified FDIs in an engineered model of drug resistance in NSCLC. Using a computational model, we demonstrated how different mechanisms of FDIs impact tumor evolution. Our ongoing work seeks to identify the specific molecular mechanism responsible for the observed FDIs. In the future, we may leverage this approach to modulate frequency-dependent interactions, allowing us to mitigate pre-treatment drug resistance in vivo.
Citation Format: Eshan S. King, Dagim S. Tadele, Maximillian A. R. Strobl, Jacob G. Scott. Investigating the mechanism and impact of frequency-dependent interactions in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A031.
Abstract A035: Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer
Authors: Glasmacher Kira A. , Cannataro Vincent L. , Mandell Jeffrey D. , Jackson Mia , Fisk J. Nic , Townsend Jeffrey P. 
Published: February 2024

Abstract
Sequencing of tissues from histologically normal esophagus, among other organs, has revealed that normal tissues acquire somatic variants that are also found in cancers arising from the same tissue types. Our understanding of how somatic mutations that are commonly found in normal tissue can contribute to tumorigenesis is limited: common somatic mutations may or may not confer phenotypes compatible with oncogenesis. However, the strength of selection for somatic variants that appear in both normal and cancer tissues can be quantified in each context using evolutionary modeling approaches. We studied the evolutionary trajectory from normal esophageal tissue to esophageal squamous-cell carcinoma (ESCC) by analysis of sequencing data from previous studies on normal esophageal epithelium and ESCC to reveal the stepwise contributions of somatic mutations to increased cellular division and survival. We also analyzed pairwise selective epistasis between somatically mutated genes that may lead to stepwise substitution patterns. We found that NOTCH1 substitutions are at high prevalence in normal tissue, and scaled selection coefficients indicate that NOTCH1 mutations are highly selected in normal esophageal tissue. In contrast, there is little to no positive selection for NOTCH1 mutations in ESCC, suggesting that NOTCH1 substitutions do not drive tumorigenesis. Indeed, NOTCH1 mutations have recently been shown to favor clonal expansion in normal esophageal tissue. Furthermore, we calculate that mutations in NOTCH1 exhibit antagonistic epistasis with well-known cancer drivers, including TP53, reducing selection for progressive mutations in tumorigenesis. This antagonistic epistasis likely underlies the low likelihood of tumor progression in the presence of NOTCH1 mutations in the esophagus.
Citation Format: Kira A. Glasmacher, Vincent L. Cannataro, Jeffrey D. Mandell, Mia Jackson, J. Nic Fisk, Jeffrey P. Townsend. Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A035.
Abstract A039: Metabolic evolution in breast cancer predicts organ-specific metastasis
Authors: Mathur Deepti , Liao Chen , Lin Wendy , La Ferlita Alessandro , Alaimo Salvatore , Taylor Samuel , Zhong Yi , Iacobuzio-Donahue Christine , Ferro Alfredo , Xavier Joao 
Published: February 2024

Abstract
The metastatic cascade is a critical component of cancer evolution. Understanding the rewired metabolism in organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to assess the evolution of metabolic fluxes from parental breast cancer cells to their brain- and lung-homing metastatic derivatives. We found that divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained adaptations for high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This exacerbated Warburg effect –– stronger than the Warburg effect in the primary tumor –– was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, a signature which correlated with lung metastasis in patients with breast cancer. While feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of a patient's future metastasis to the lung but not to other organs, independent of other transcriptomic signatures. Lung- and brain-homing lineages had differential selection patterns in acidic metabolic microenvironments. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolic evolution plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in breast cancer patients.
Citation Format: Deepti Mathur, Chen Liao, Wendy Lin, Alessandro La Ferlita, Salvatore Alaimo, Samuel Taylor, Yi Zhong, Christine Iacobuzio-Donahue, Alfredo Ferro, Joao Xavier. Metabolic evolution in breast cancer predicts organ-specific metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A039.
Abstract B007: Reconstruction of cellular phylogenies and analysis of gene expression variation in single cells
Authors: Miura Sayaka , Kumar Sudhir 
Published: February 2024

Abstract
In cancer, somatic mutations occur continuously, causing cell populations to evolve. These somatic mutations result in the evolution of cellular gene expression patterns that can also change due to epigenetic modifications and environmental changes. By exploring the concordance of gene expression changes with molecular evolutionary trajectories of cells, we can examine the role of somatic variation on the evolution of gene expression patterns. In these endeavors, reliable inference of the evolutionary relationship of single cells is a key step. However, single-cell sequences contain many errors and missing bases, which necessitate advancing standard molecular phylogenetics approaches for applications in analyzing these datasets. We first show our new computational approach (TopHap+) that integratively applies standard phylogenetic optimality principles and patterns of co-occurrence of sequence variations to produce more expansive and accurate cellular phylogenies from single-cell sequence datasets. We then present Multi-Omics Concordance Analysis (MOCA) software to jointly analyze gene expressions and genetic variations from single-cell RNA sequencing profiles. MOCA outputs cells and genes showing convergent and divergent gene expression patterns in functional genomics.
Citation Format: Sayaka Miura, Sudhir Kumar. Reconstruction of cellular phylogenies and analysis of gene expression variation in single cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B007.
Abstract B015: Tobacco-derived miRNAs and their crosstalk with human transcripts towards carcinogenesis: A cross kingdom approach
Authors: Patel Saumya , Bhavsar Manasi , Rawal Rakesh 
Published: February 2024

Abstract
There are more than 70 different species of Nicotiana reported around the world; however, Nicotiana tabacum (common tobacco) and Nicotiana rustica (aztec tobacco) are widely used for snuffing, chewing, smoking, etc., worldwide. Early reports have described that tobacco causes cancer and is associated with many neurological and cardiac disorders. The current study was an effort to understand the paradoxical regulatory mechanism of tobacco-derived miRNAs on human transcripts at 3’ untranslated regions (UTRs) through a computational and experimental genomics approach. This is the first attempt at cross-kingdom analysis where tobacco-specific miRNAs were predicted from different available sources like express sequence tags (EST), genome-wide approaches, and deep sequencing. The miRNA-derived plant targets were identified using stringent bioinformatics methods. A total of 164 mature reported miRNAs, 38 miRNAs from EST datasets, and 21 miRNAs from the genome were studied in detail for cross-kingdom regulation. The potential predicted and reported tobacco-derived miRNAs were analysed against human transcripts. Interestingly, we found tobacco-derived miRNAs such as miR156, miR403, miR7997, miR8011, and miR8036 target tumour suppressor genes and have a putative role in pathways in cancer. Collectively, we have identified a comprehensive set of miRNAs from small RNA sequencing of N. rustica and revealed 842 new miRNAs that have not been reported yet and have putative targets in cancer pathways like AMPK and WNT signalling pathways. Conclusively, this study is the first report of intra- and interspecies relationships using N. tabacum miRNAs with Human and has created a clear road map to focus on specific cancer targets that are modulated by tobacco-derived miRNAs for future studies.
Citation Format: Saumya Patel, Manasi Bhavsar, Rakesh Rawal. Tobacco-derived miRNAs and their crosstalk with human transcripts towards carcinogenesis: A cross kingdom approach [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B015.