bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6997: Elucidating the tumorigenic properties of alveolar epithelial type 1 cells in EGFR-mediated LUAD tumorigenesis
Authors: Neely Aaron M. , Lanz Andrea , Wallace William Dean , Kim Anthony W. , Borok Zea , Marconett Crystal N. 
Published: March 2024

Abstract
Originating from within the distal lung, lung adenocarcinoma (LUAD) is the most common pathologic subtype of non-small cell lung carcinoma (NSCLC) and encompasses an assortment of histologic presentations. Colocalized within the distal alveolar epithelium are two alveolar epithelial cell (AEC) subpopulations: alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cells. We previously demonstrated that signatures unique to each AEC subpopulation were detected in LUAD tumors formed by oncogenic KRASG12D activation in mice and were associated with disparate survival outcomes, transcriptomic patterning, and histologic presentation. Epithelial growth factor receptor (EGFR) mutations are among the most frequent oncogenic drivers in thoracic oncology. Therefore, we set out to determine if EGFR oncogenic activation resulted in differential LUAD presentation and outcomes based on the cell of origin in which it was activated. To activate EGFR oncogenic mutations in AT1 or AT2 cells, we employed triple transgenic mouse models (AT1: Gramd2-CreERT2:EF1-LSL-tTA:TetO-EGFRdel20/T790 and AT2: Sftpc-CreERT2:EF1-LSL-tTA:TetO-EGFRdel20/T790), which allowed for EGFR activation in either Gramd2+ AT1 or Sftpc+ AT2 cells. Longitudinal analysis of hematoxylin and eosin-stained lungs over the course of 20 weeks was performed. Blinded pathology review demonstrated that EGFR oncogenic activation in Gramd2+ AT1 cells resulted in histologically defined LUAD with lepidic properties at early time points and solid adenocarcinoma properties at later time points. This differed from EGFR activation in Sftpc+ AT2 cells, which resulted in pre-carcinogenic atypical adenomatous hyperplasia (AAH) formation that did not progress to adenocarcinoma. While preliminary, our results suggest that cell of origin strongly influences EGFR-mediated lung oncogenesis and concomitant pathology and histologic presentation. This work may advance our understanding while informing patient stratification and treatment strategies for LUAD patients.
Citation Format: Aaron M. Neely, Andrea Lanz, William Dean Wallace, Anthony W. Kim, Zea Borok, Crystal N. Marconett. Elucidating the tumorigenic properties of alveolar epithelial type 1 cells in EGFR-mediated LUAD tumorigenesis [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 6997.
Abstract 704: Targeting hypoxic survival pathways to overcome radiotherapy-related treatment resistance
Authors: Beckers Claire , Vasilikos Lazaros , Sanchez-Fernandez Alba , Moor Lorena , Pruschy Martin 
Published: March 2024

Abstract
Tumor cells undergo biological adaptations in order to survive stress conditions, such as hypoxia and nutrient deprivation. These biological adaptations include the activation of hypoxic survival pathways that play an important role in acquiring radioresistance which becomes most challenging with treatment regimens using high doses of radiation/fraction (e.g., hypofractionated radiotherapy). Therefore, inhibiting key regulators within these pathways and thereby exploiting these survival mechanisms, gives rise to new potential drug targets for combined treatment modalities. This novel strategy investigated in our laboratory relies on the concept of biological cooperation: while ionizing radiation kills primarily well-oxygenated cells, such inhibitors of survival kinases will drive quiescent tumor cells under hypoxia and/or nutrient deprivation either directly into cell death or into re-entry into a proliferative and thereby more ionizing radiation-sensitive state. One of the survival kinases we are investigating in combination with ionizing radiation (IR) is DYRK1B (dual-specificity tyrosine regulated kinase 1B). We demonstrated that the expression of DYRK1B was upregulated under serum-starvation and hypoxia, but not in response to IR. The small molecule DYRK1B inhibitor AZ191 and shRNA-mediated DYRK1B knockdown significantly reduced proliferative activity and clonogenicity of SW620 tumor cells alone and in combination with IR under serum-starved conditions, which correlated with increased ROS levels and DNA damage. Furthermore, AZ191 successfully targeted the hypoxic core of tumor spheroids while IR preferentially targeted normoxic cells in the rim of the spheroids. A combined treatment effect was also observed in patient-derived colorectal carcinoma organoids but not in healthy tissue organoids. This data shows that inhibition of DYRK1B in quiescent tumor cells could drive tumor cells on their own into crisis or into a more radiosensitive cell cycle phase and thus supports our strategy of biological cooperation. In the continuation of this project, we have performed a drug-screen with approx. 3’000 clinically relevant compounds in colorectal tumor cells lines under normoxic and hypoxic conditions in order to explore additional hypoxia-mediated survival pathways contributing to radioresistance. Thereby we aim to identify novel combined treatment modalities to overcome radiotherapy-induced hypoxia and hypoxia-related resistance mechanisms.
Citation Format: Claire Beckers, Lazaros Vasilikos, Alba Sanchez-Fernandez, Lorena Moor, Martin Pruschy. Targeting hypoxic survival pathways to overcome radiotherapy-related treatment resistance [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 704.
Abstract 7043: Genomic profiling of DLL3-positive and negative CTCs in small cell lung cancer
Authors: Simandi Zoltan , Bui Thai , Ferrarini Alberto , Hepburn Steven , Del Mastro Richard G. 
Published: March 2024

Abstract
BACKGROUND: Delta-like ligand 3 (DLL3), an atypical Notch family protein implicated in neuroendocrine tumorigenesis, has emerged as a promising therapeutic target in small cell lung cancer (SCLC), prompting numerous clinical trials investigating DLL3-targeted treatments. Exploring DLL3 in circulating tumor cells (CTCs) through liquid biopsy, coupled with comprehensive genomic analysis, presents an invaluable and minimally-invasive avenue for monitoring disease progression. This approach holds the potential to tailor personalized treatment strategies, emphasizing the critical need for in-depth investigations into both DLL3-positive and negative cell genomic compositions.
METHODS: This study examined blood collected in CellSave preservative tubes from stage I (n=17) and stage IV (n=12) SCLC patients, as well as healthy donors (n=10). The CELLSEARCH® platform was employed to count EpCAM-enriched CTCs and evaluate DLL3 protein expression. Subsequently, individual CTCs were isolated based on the presence and absence of DLL3 expression using the DEPArray™ PLUS. The isolated DLL3-negative and positive CTCs were subjected to low-pass sequencing using the Ampli1™ LowPass Kit to uncover genomic aberrations.
RESULTS: CTCs were absent in the healthy control group. In stage I patients, CTCs were identified in 5.8% of blood samples, while in stage IV patients, they were present in 50% of samples, with an average CTC count of 148 in stage IV. Among a total of 2074 detected CTCs, 460 were DLL3-positive, accounting for 6-28% of EpCAM-enriched CTCs in individual patients. Analysis of &gt;300 copy number alteration (CNA) profiles of sorted single cells revealed considerable inter-patient and intra-patient heterogeneity, delineating recurrent clonality and specific genomic alterations in DLL3-negative CTCs. In contrast, DLL3-positive cells showed more stochastic CNA profiles, suggestive of apoptosis-related DNA fragmentation.
CONCLUSIONS: Integrating CellSearch, DEPArray, and low-pass sequencing provides a minimally-invasive approach to compare genomic characteristics in DLL3-positive and negative CTCs from SCLC patients. Extension of this approach to a larger patient cohort and employing machine learning algorithms will facilitate identification of patterns within diverse CNA profiles, improving patient stratification and predicting treatment responses for personalized therapeutic strategies in SCLC.
Citation Format: Zoltan Simandi, Thai Bui, Alberto Ferrarini, Steven Hepburn, Richard G. Del Mastro. Genomic profiling of DLL3-positive and negative CTCs in small cell lung 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 7043.
Abstract 7062: CIP2A enhances mitochondrial respiratory electron transport chain complexes and induces lung cancer in vivo
Authors: Yang Fu-Ying , Wang Di , liang Li-Jun , Wang Gui-Zhen , Zhou Guang-Biao 
Published: March 2024

Abstract
Identification of oncogenes that can induce cancer in vivo is critical to elucidation of tumorigenesis and development of targeted therapies. Here, we reported for the first time that forced ectopic expression of CIP2A, the cancerous inhibitor of protein phosphatase 2A (PP2A), in lung tissues induced lung adenocarcinoma in mice. CIP2A upregulated the transcription and translation of mitochondrial DNA (mtDNA), and increases the enzymatic activity of mitochondrial electron transport chain (ETC) complex IV and V, thus enhancing the function of mitochondria and promoting the level of oxidative phosphorylation in tumors. CIP2A inhibited the binding of PP2A-B56α to FOXO3a, leading to the enhancement of the phosphorylation level of FOXO3a. The phosphorylated FOXO3a then translocated into the mitochondrion, and acted as a transcription factor to regulate CIP2A-mediated metabolic reprogramming in cancer cells. We found that oxidative phosphorylation inhibitors effectively inhibited CIP2A-induced cell proliferation. In non-small cell lung cancer, CIP2A level in tumor tissues was positively associated with the level of mtDNA. Our results indicated that CIP2A is able to induce lung adenocarcinoma in mice and has a critical role in mitochondrial oxidative phosphorylation, and represents a promising therapeutic target for non-small cell lung cancer.
Competing interests: The authors declare no competing interests.
Citation Format: Fu-Ying Yang, Di Wang, Li-Jun liang, Gui-Zhen Wang, Guang-Biao Zhou. CIP2A enhances mitochondrial respiratory electron transport chain complexes and induces lung cancer 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 7062.
Abstract 7064: BRCA 1/2 haploinsufficiency-associated metabolic dysfunction in benign fallopian tube epithelia
Authors: Ravix Jovanka , Paudel Iru , Pulivendala Gauthami , Sowamber Ramlogan , Smith Elizabeth , Schlumbrecht Matthew , Lombard David , George Sophia 
Published: March 2024

Abstract
In 3-17% of women with BRCA1/2 mutations who undergo risk-reducing surgery, pre-neoplastic and neoplastic lesions are found in their fallopian tubes that display differential loss of heterozygosity of BRCA1/2. Precisely how mutations in BRCA1/2 predispose women to develop high grade serous ovarian carcinoma (HGSC) is not completely understood. Although linked to various processes localized in the nucleus, BRCA1/2 may also have essential roles in the cytoplasm, specifically in the regulation of key processes associated with mitochondrial homeostasis and metabolism. Understanding how haploinsufficiency of BRCA1/2 contributes to the potential neoplastic transformation of fallopian tube epithelial cells should reveal new insights into BRCA1/2 function, and ultimately provide novel opportunities for preventative interventions in individuals with this mutation and new treatment opportunities for HGSC associated with BRCA1/2 heterozygosity. We have identified distinct metabolic and mitochondrial deficits in BRCA2 mutation carriers compared to BRCA1 carriers and non-carriers. Fallopian tube epithelial cell lines derived from BRCA2 mutation carriers showed increased levels of mitochondrial respiration and activity followed by BRCA1 mutation carriers and non-carriers. Western blot analysis of mitochondrial proteins regulating glycolysis and oxidative phosphorylation showed differential expression based on mutation status. Transmission electron microscopy of BRCA2 mutation carriers showed increased disrupted mitochondrial networks when compared to wild type, suggesting that mutation status may contribute to increased mitochondrial fission. These observations reveal an entirely new aspect of BRCA1 and BRCA2 biology and further studies will disaggregate the effects of BRCA1 and BRCA2 on mitochondrial function, versus DNA damage repair. Ultimately, this work will provide new insight into the adaptive changes within FT cells which promote neoplastic transformation and inform how high-grade serous carcinoma (HGSC) cells distinctively respond to microenvironmental stimuli.
Citation Format: Jovanka Ravix, Iru Paudel, Gauthami Pulivendala, Ramlogan Sowamber, Elizabeth Smith, Matthew Schlumbrecht, David Lombard, Sophia George. BRCA 1/2 haploinsufficiency-associated metabolic dysfunction in benign fallopian tube epithelia [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 7064.
Abstract 7070: MEK-ERK signaling maintains epidermal proliferation through H2A.Z deposition
Authors: Droll Stephenie , Zhang Benny , Xue Celia , Levine Maxwell , Bao Xiaomin 
Published: March 2024

Abstract
Recent studies have connected dysregulation of H2A.Z deposition to glioblastoma as well as lung, pancreatic, and metastatic breast cancers. The H2AZ1 and H2AZ2 isoforms, collectively known as H2A.Z, are histone variants that regulate gene expression, stem cell identity, and differentiation during development and in homeostatic tissue. Most tumors originate from epithelial tissues. We utilize skin epidermis, an accessible model of epithelial tissue, to understand the regulatory mechanisms controlling proliferation and differentiation. Primary human epidermal keratinocytes retain their abilities to proliferate, differentiate, and stratify in vitro. First, we observed that progenitor keratinocytes express high levels of H2A.Z mRNA and protein, and that H2A.Z levels significantly and progressively decrease during four days of calcium-induced differentiation. Using ChIP-sequencing, we find a significant, genome-wide decrease in H2A.Z chromatin occupancy in differentiated keratinocytes. Therefore, we hypothesized that H2A.Z is critical for progenitor function. Knock down of either H2AZ1 or H2AZ2 significantly impaired keratinocyte proliferation in holoclone assays. Furthermore, H2AZ1 or H2AZ2 knockdown inhibited epidermal stratification in organotypic culture. Canonically, two chromatin remodeling complexes, SRCAP and EP400, deposit H2A.Z into nucleosomes. While both SRCAP and EP400 knockdown diminish keratinocyte proliferation, only SRCAP knockdown decreases H2A.Z deposition in epidermal keratinocytes. Finally, we find that MEK and ERK signaling is required to sustain expression of SRCAP, H2AZ1, and H2AZ2. MEK or ERK inhibition is sufficient to significantly decrease H2A.Z occupancy genome-wide in progenitor keratinocytes.
Citation Format: Stephenie Droll, Benny Zhang, Celia Xue, Maxwell Levine, Xiaomin Bao. MEK-ERK signaling maintains epidermal proliferation through H2A.Z deposition [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 7070.
Abstract 7080: Regulation of caveolin-1 by RAS/RAF oncogenic signaling in cancer cells
Authors: Aceituno Veronica Castro , Cui Tiantian , Feng Haihua , Yang Linlin , Nair Sindhu , Williams Terence M. 
Published: March 2024

Abstract
Background and Purpose: Caveolin-1 (Cav-1), a scaffolding protein implicated in cellular signaling and membrane dynamics, undergoes intricate regulation at multiple levels. Recent evidence has suggested a potential association between oncogenic mutations and alterations in Cav-1 expression. Our study aimed to comprehensively explore how RAS/RAF mutations influence Cav-1 expression in cancer cells, as well as the underlying molecular mechanisms, using tetracycline (tet)-inducible cell lines and cancer cell lines harboring endogenous BRAF or KRAS mutations.
Experimental Design: We assessed the regulation of Cav-1 expression using tet-inducible cell lines with BRAFV600E, KRASG12D, or KRASG12C mutations. We measured the half-life of Cav-1 at protein levels by using cycloheximide. We monitored Cav-1 localization and degradation dynamics by SNAP-based pulse-chase assay. Additionally, we performed protein and gene expression analyses by immunoblotting and qRT-PCR, luciferase reporter assay, and immunofluorescence to dissect the impact of BRAF and KRAS mutations on Cav-1 regulation at various stages of its life cycle.
Results: We found a significant downregulation of Cav-1 at both mRNA and protein levels upon induction of BRAF or KRAS mutations. The use of KRASG12C, BRAFV600E, ERK, and/or MEK inhibitors in tet-inducible cell lines rescued the effects observed upon induction. The rescue effects have also been observed in H23, MiaPaCa-2 and 8505-C cancer cell lines bearing either BRAF or KRAS mutations. Notably, BRAFV600E exhibited a more pronounced reduction in Cav-1 expression than other mutations. We observed shortened half-life of Cav-1 at protein levels after induction of RAS/RAF mutations by using cycloheximide, and SNAP-based pulse-chase. These mutations accelerated lysosomal-mediated degradation of Cav-1 as determined by immunoblotting and immunofluorescence, which was reversed by lysosomal inhibitors.
Conclusions: Our study establishes a novel regulatory paradigm wherein RAS/RAF mutations exert a multi-faceted influence on Cav-1 dynamics in cancer cells. The transcriptional and translational downregulation, coupled with accelerated lysosomal degradation, collectively contributes to the decreased half-life of Cav-1 following the induction of BRAF or KRAS mutations. These findings provide insights into the intricate molecular mechanisms underpinning the dysregulation of Cav-1 in the context of RAS/RAF mutations, offering potential avenues for therapeutic interventions.
Citation Format: Veronica Castro Aceituno, Tiantian Cui, Haihua Feng, Linlin Yang, Sindhu Nair, Terence M. Williams. Regulation of caveolin-1 by RAS/RAF oncogenic signaling in 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 7080.
Abstract 7122: A novel USP1 inhibitor coupled with a novel proteomic response biomarker for precision oncology therapy
Authors: Alchanati Iris , Morley Andrew , Hay-Koren Avital , Fierro Fabrizio , Otonin Galina , Herman Shay , Shtrikman Alon , Katzenelenbogen Yonatan , Arad Gali , Tivon Barr , Pevzner Kirill , Seger Eran 
Published: March 2024

Abstract
Ubiquitin-specific protease 1 (USP1) is a well-characterized deubiquitinating enzyme (DUB) that plays a critical role in DNA damage repair (DDR). It was shown to regulate various key repair processes, most notably proliferating cell nuclear antigen (PCNA) in the Translesion Repair (TLS) pathway and FANCD2/FANCI in the Fanconi Anemia (FA) repair pathway. Research indicates that USP1 deficiency leads to a decrease in cell survival and disruption of genomic stability, suggesting that USP1 inhibitors (USP1i) may hold promise in treating DDR deficient tumors. Through the integration of computational and medicinal chemistry approaches, we discovered a novel, potent inhibitor of USP1, showing anti-USP1 activity in both cell-free enzymatic assay and in measurement of PCNA-ubiquitination change upon USP1 inhibition in cells. We demonstrate anti tumor activity in DDR-related and other indications. By utilizing our platform to analyze the basal proteomics of resistant and sensitive cell lines treated with USP1i, we revealed a distinctive proteomic biomarker signature for USP1i response. This data demonstrates the potential of our novel USP1 inhibitor to serve as a potent therapeutic agent for DDR-deficient and other biomarker-positive cancer patients.
Citation Format: Iris Alchanati, Andrew Morley, Avital Hay-Koren, Fabrizio Fierro, Galina Otonin, Shay Herman, Alon Shtrikman, Yonatan Katzenelenbogen, Gali Arad, Barr Tivon, Kirill Pevzner, Eran Seger. A novel USP1 inhibitor coupled with a novel proteomic response biomarker for precision oncology therapy [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 7122.
Abstract 7139: Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian cancer
Authors: Lee Jeong-Won , Lee Kwangho , Koh Byumseok , Lee Yoo-Young , Bae Duk-Soo 
Published: March 2024

Abstract
Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer. With improved pharmacokinetic parameters, BNZ-111 effectively disrupts tubulin polymerization through hydrogen bonds and hydrophobic interactions. It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating β-3 tubulin expression to suppress microtubule dynamics. This study suggests that BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology
Citation Format: Jeong-Won Lee, Kwangho Lee, Byumseok Koh, Yoo-Young Lee, Duk-Soo Bae. Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian 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 7139.