bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1466: Tobacco carcinogen impacts redox pathway to facilitate pancreatic ductal adenocarcinoma (PDAC) initiation and progression
Authors: Lin Xiaoxue , Stamp McKenna , Fowler Alexandra , Bottomley Chelsea , Okhovat Shira , Peck Kristina , Engle Dannielle 
Published: March 2024

Abstract
The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) is only 10%. PDAC is projected to soon become the second leading cause of cancer death. Tobacco is one of the main risk factors for PDAC. Incidence of PDAC increases 2-fold among tobacco users, and 20-35% of PDAC cases are attributed to smoking. However, the specific pathways activated by tobacco carcinogens remain elusive.This research project addresses the impact of carcinogens in pancreatic cancer etiology. We hypothesize that carcinogens in tobacco increase reactive oxygen species (ROS), which elevates the Nrf2 redox pathway to facilitate PDAC initiation and progression. Specifically, we focus on two major subclasses of carcinogens: the heavy metal cadmium (Cd) and the polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BaP). Using mouse pancreatic ductal organoid cultures, we found that acute carcinogen exposure increases Nrf2 activity, which is sustained after "intermediate" exposure (5 passages). Intriguingly, chronic exposure (10 passages) downregulates Nrf2 activity, which has been shown to be associated with acquired metastatic potential. Furthermore, we found an upregulation in NFkB and EGFR signaling after intermediate exposure, which are involved in microenvironment remodeling and increased proliferative potential. Overall, we demonstrate that acute carcinogen exposure elevates ROS levels and activates the Nrf2 pathway, whereas prolonged exposure upregulates NFkB and EGFR pathways. Furthermore, we have established a novel carcinogenesis model using 3D organoid culture to recapitulate each step in pancreatic tumorigenesis. Collectively, this project contributes to our understanding of tobacco-related PDAC pathogenesis.
Citation Format: Xiaoxue Lin, McKenna Stamp, Alexandra Fowler, Chelsea Bottomley, Shira Okhovat, Kristina Peck, Dannielle Engle. Tobacco carcinogen impacts redox pathway to facilitate pancreatic ductal adenocarcinoma (PDAC) initiation and progression [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 1466.
Abstract 1474: Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis
Authors: Gupta Kunj Bihari , Singh Rajendra K. , Seremak Juliette R. , Lokeshwar Vinata B. , Lokeshwar Bal L. 
Published: March 2024

Abstract
Cadmium (Cd) is a toxic heavy metal, ubiquitous in nature, and an industrial pollutant. Cadmium exposure can cause irreversible damage to lungs, liver and kidney including cancers. Alarmingly, abnormally high levels of cadmium are found in human prostate tissues. Studies on rodents have shown cadmium exposure causes liver, lung, and prostate cancers. The mechanism of carcinogenesis caused by Cd is multifactorial and specific organ carcinogenesis remains unclear. We and others have reported that the CXC-chemokine IL-8 drives cancer progression in prostate cancer (PCa). We tested a hypothesis that chronic cadmium-exposure induces upregulation of proinflammatory cytokines, such as IL-1β, IL-6, and IL-8, which individually or combined promote carcinogenesis and progression. The study used two non-transformed prostate epithelial cell lines (RWPE-1 and NHPrE1) to test whether continuous exposure to Cadmium chloride (CdCl2) perturbs cytokine expression pattern and selective silencing of elevated cytokines delays carcinogenesis and invasive potential. The CdCl2 exposed cells and culture conditioned media were analyzed regularly for changes in inflammatory milieu and for hallmarks of carcinogenesis. These studies measured changes in cell proliferation, production of cytokines (IL-8, IL-1β, IL-6, IFN-γ, TGF-β, and others), activation of Nuclear Factor-kB (NF-κB), and pro-tumorigenic factors, e.g., vascular endothelial growth factors (VEGF-A and B), cellular motility, and invasive potential, etc. Cells exposed to CdCl2 showed increased cell proliferation and clonogenic potential and specifically, increased expression of IL-8, it’s receptors (CXCR1 and CXCR2), IL-1β, and other cytokines & related genes. While un-exposed RWPE-1 cells did not express IL-8, it was the first cytokine to increase when exposed to CdCl2, followed by activation of NF-κB (p65-rel), VEGF-A, & B, CXCR1 and other markers. Gene silencing of IL-8 suppressed motility, invasion, and survival activity. These data supported that immediate-early IL-8 expression probably upregulates NF-κB mediated inflammatory signaling axis which is critical for Cd-induced carcinogenesis and may expose targets for countermeasures to prevent metal-induced toxicity & carcinogenesis.
Citation Format: Kunj Bihari Gupta, Rajendra K. Singh, Juliette R. Seremak, Vinata B. Lokeshwar, Bal L. Lokeshwar. Interleukin-8 and NF-κB mediated signaling axis: A potential driver for cadmium-induced prostate carcinogenesis [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 1474.
Abstract 1478: Chronic perfluorooctanesulfonic acid exposure promotes proliferation of colorectal cancer cells
Authors: Durham Jerika , Tessmann Josiane Weber , Hennig Bernhard , Zaytseva Yekaterina 
Published: March 2024

Abstract
Background: Chronic exposure to long-term exposures to per- and polyfluoroalkyl substances (PFAS), widely known as “forever chemicals”, has been associated with multiple negative health outcomes including increased risk of cancer. Perfluorooctanesulfonic acid (PFOS), a “long-chain” subtype of PFAS, has high bioaccumulation potential with a long elimination half-life. PFOS is frequently detected in drinking water leading to its high absorption through the gastrointestinal tract. Recent studies demonstrate that PFAS exposures promote intestinal inflammation and gut barrier dysfunction. However, how a long-term PFOS exposure affects colorectal cancer (CRC) progression is not known. Therefore, the purpose of this study is to delineate the effect of PFOS exposure on CRC cell proliferation and test the potential mitigation strategy for the harmful effects of PFOS.
Methods: SW480 and HCT116 cells have been treated with 1 ug/mL PFOS and proliferation was measured at 1, 2, and 3 months using the Presto Blue Cell Viability Reagent fluorescence assay. Proliferation markers were assessed by qPCR and Western blot. Control and PFOS exposed cells were treated with sulforaphane, a nuclear factor erythroid 2-related factor 2 (Nrf-2) inducer, at concentration 5, 10 and 20 uM for 72 hours.
Results: We show that chronic, low-dose PFOS exposure promotes proliferation of SW480 and HCT116 cell lines starting at 3 months since the first exposure. The increase in proliferation is associated with upregulation of Cyclin D, pAkt and FASN. We also show that sulforaphane significantly decreases proliferation of HCT116 and SW480 cells, and its efficacy is significantly higher in PFOS exposed CRC cells. The current studies show no effect on sulforaphane on normal colon epithelium cells.
Conclusion: Our studies suggest that chronic PFOS exposure promotes proliferation of CRC cells by increasing pro-carcinogenic gene expression and signaling. Furthermore, our findings suggest that supplementation of diet sulforaphane can potentially mitigate the harmful effects from PFOS exposure. Our studies warrant further investigation of the mechanisms behind the effect of PFOS exposure on cancer progression that would guide development of effective intervention strategies to mitigate the harmful effects of the exposure to “forever chemicals”.
Citation Format: Jerika Durham, Josiane Weber Tessmann, Bernhard Hennig, Yekaterina Zaytseva. Chronic perfluorooctanesulfonic acid exposure promotes proliferation of colorectal 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 1478.
Abstract 1528: Flowcytometric based approach to investigate prostate tumor microenvironment
Authors: sajnani karishma , Eerola Sini , Kukkonen Konsta , Rauhala Hanna , Visakorpi Tapio , Urbanucci Alfonso 
Published: March 2024

Abstract
Prostate cancer (PC) and its tumor microenvironment (TME) are heterogenous and evolving along with the treatment patients are exposed to. Modelling of the TME represents an attractive approach to understand how PC evolves and spreads. Flow cytometry is a technique for quantitative measurement of single cell profiling based on the cell surface as well as intracellular markers. We designed a flowcytometric based approach to investigate the interplay between the PC cells and immune cells in a direct coculture. Cells are fluorescently tagged with a cell tracer and the analysis is performed separately on the adherent and non-adherent cells. To optimize the readout method, we investigate the interplay between Jurkat cells and PC cells (LNCaP) as well as immortalized prostate epithelial cell models modified to mimic early events in prostate carcinogenesis (RWPE-1 cells overexpressing androgen receptor, RWPE-1-AR, and having PTEN deletion, RWPE-1-AR-PTENdel).Jurkat (suspension culture) cocultured with LNCaP (adherent culture) exhibited 40% decrease in viability but only 30% of LNCaP dying cell in the floating population compared to LNcaP only which is 60%. When Jurkat were activated using Phorbol 12-myristate 13-acetate (PMA), we observed an increase in LNCaP cell death. Jurkat viability was not impacted in presence of RWPE-1 neither when exposed to RWPE1-AR-PTENdel. In summary our Flowcytometric-based approach will help to understand the interplay between immune cells and prostate cancer cells.
Citation Format: karishma sajnani, Sini Eerola, Konsta Kukkonen, Hanna Rauhala, Tapio Visakorpi, Alfonso Urbanucci. Flowcytometric based approach to investigate prostate tumor microenvironment [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 1528.
Abstract 1557: Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4
Authors: Liu Yin , Smith Margaret R. , Wang Yuezhu , D’Agostino Ralph , Ruiz Jimmy , Kucera Gregory L. , Miller Lance D. , Li Wencheng , Chan Michael D. , Farris Michael , Zhao Dawen , Xing Fei 
Published: March 2024

Abstract
Metastatic disease is the main cause of cancer death, and the brain is one of the major sites of breast tumor metastasis. The median survival of breast cancer patients who developed brain metastases (BrM) is less than a year even with the advanced treatment such as stereotactic radiosurgery (SRS). Regardless of high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. Previously, we found that loss of lncRNA XIST robustly promote metastasis and specially brain metastasis in breast cancer. However, the underlying molecular mechanism was not fully understood. In following study, we found that loss of XIST has significantly altered lipid metabolism of breast cancer cells specifically increasing lipid droplet amount and PUFA incorporation. Instead of de novo syntheses, XISTlow cancer cells acquire fatty acid by uptake from exogenous. We found that one X-linked gene, Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) which are highly upregulated after loss of XIST is responsible for the altered lipid metabolism. ACSL4 activated the free polyunsaturated fatty acids (PUFAs) and lead to increased incorporation of PUFAs into phospholipids. On one hand, elevated ACLS4 expression leads to relative low PPAR pathway activation by decreasing the cellular free PUFA level which directly binds and activate PPAR. PPAR pathway is known to inhibit the expression of inflammatory cytokines which are important for cancer cells to establish brain metastasis. On the other hand, elevated ACSL4 expression enable cancer cells to metabolize the abundant PUFAs in the brain environment, thereby gaining survival advantage. However, increased PUFA incorporation into lipids especially phospholipids produce excess lipid ROS and sensitize cells to ferroptosis inducer such as RSL3. Our study has find out that brain microenvironment not only supports the outgrowth of XIST low cells by providing PUFAs for maintaining their metastatic properties but also sensitizes those cells to ferroptosis inducers, a potential therapy for treating this devastating disease.
Citation Format: Yin Liu, Margaret R. Smith, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Gregory L. Kucera, Lance D. Miller, Wencheng Li, Michael D. Chan, Michael Farris, Dawen Zhao, Fei Xing. Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4 [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 1557.
Abstract 1611: DNA methylation co-operates with genomic alterations during non-small cell lung cancer evolution
Authors: Gimeno-Valiente Francisco , Castignani Carla , Cadieux Elizabeth Cadieux L. , Mensah Nana E. , Chervova Olga , Jamal-Hanjani Mariam , McGranahan Nicholas , Beck Stephan , Demeulemeester Jonas , Tanic Miljana , Swanton Charles , Van Loo Peter , Kanu Nnennya 
Published: March 2024

Abstract
Aberrant DNA methylation patterns have been described in nearly all human cancers, yet their interplay with genomic alterations during tumor evolution is poorly understood. To explore this crosstalk, we performed reduced representation bisulfite sequencing on 217 tumor regions from 59 patients from the TRACERx study, all with matched adjacent normal tissue, to deconvolve tumor methylation rates. We combined two new metrics for integrative evolutionary analysis with DNA and RNA sequencing data. I-TMD (intra-tumoral methylation distance) quantifies intra-tumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus non-regulatory (MN) CpGs, to identify driver genes exhibiting recurrent functional hypermethylation. We observed early DNA methylation of VIPR2 and ZNF714 co-occurring with driver mutations in CDKN2A and STK11, respectively. Finally, we found DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. Our identification of hypermethylated driver genes under positive selection may open new avenues for therapeutic stratification of patients with non-small cell lung cancer.
Citation Format: Francisco Gimeno-Valiente, Carla Castignani, Elizabeth Cadieux L. Cadieux, Nana E. Mensah, Olga Chervova, Mariam Jamal-Hanjani, Nicholas McGranahan, Stephan Beck, Jonas Demeulemeester, Miljana Tanic, Charles Swanton, Peter Van Loo, Nnennya Kanu. DNA methylation co-operates with genomic alterations during non-small cell lung cancer evolution [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 1611.
Abstract 1640: The role of CDC20 in the progression of colorectal cancer
Authors: Abualsaud Nouran , Gazzaz Nada , Alhamid Amal , Alenizy Deemah , Alrfaei Bahauddeen M. , Alshehri Mana 
Published: March 2024

Abstract
Colorectal cancer (CRC) is the one of most common cancers and a major leading cause of cancer-related death worldwide. CDC20 is a key cell cycle regulator required during mitosis. Pathologically, CDC20 has been found to be overexpressed in cancer cells of various malignancies including breast, lung, brain and hepatic cancers and high level of CDC20 expression is associated with poor prognosis and disease progression in these cancers. Although it has been reported that CDC20 is associated with CRC progression and metastasis, it is still largely unknown how CDC20 regulates CRC cancer progression. Thus, the goal of this study is to identify the role of CDC20 in the progression of colorectal cancer. Our gene expression analysis revealed that CDC20 is highly expressed in colon cancer tissues compared to their adjacent normal colon in a cohort of CRC patients, suggesting the involvement of CDC20 in the CRC progression. To further understand the role of CDC20 in CRC progression, we experimentally targeted CDC20 genetically and pharmacologically. To perform CDC20 Loss of function studies, we screened various CRC cell lines for CDC20 protein levels and CDC20 highly expressing cell lines were utilized to establish CDC20-knockdown cells using shRNA targeting CDC20 and scrambled shRNA as controls. CDC20 Down-regulation levels were confirmed using both western blot and RT-PCR analysis. The effect of CDC20 knockdown/CRC cells on CRC cell proliferation was investigated using xCELLigence real-time cell analysis instrument and colony formation assay. Our results revealed that CDC20 knockdown CRC cells have lower proliferation capacity compared to the control, suggesting involvement of CDC20 in regulating tumorigenic phenotypes of CRC cells. Pharmacologically, we targeted CDC20 using a specific molecular inhibitor, Apcin and we assessed the Apcin treatment effect on cell viability and migration of CRC cells. Our results showed that Apcin significantly reduced CRC cell viability and migration in a dose-dependent manner. Taken together, our results suggest that CDC20 is a key regulator in the tumorigenic behavior of CRC and is considered a potential therapeutic target for treating patients with CRC.
Citation Format: Nouran Abualsaud, Nada Gazzaz, Amal Alhamid, Deemah Alenizy, Bahauddeen M. Alrfaei, Mana Alshehri. The role of CDC20 in the progression of colorectal 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 1640.
Abstract 1667: The role of CCN1 in mutant K-RAS addiction in pancreatic cancer
Authors: Kambhampati Anjali , De Archana , Haque Inamul , Banerjee Snigdha , Banerjee Sushanta K. 
Published: March 2024

Abstract
Mutant K-RAS addiction of pancreatic ductal adenocarcinoma cells (PDAC) coordinates their transformation, proliferation, and survival. Therefore, initially, it had an impression that targeting mutant K-RAS could be an ideal strategy to treat PDAC. However, after decades of studies, no effective RAS inhibitors reached the clinic, indicating that RAS-oncoprotein is an undruggable target in PDAC. Thus, identifying a new target linked with K-RAS signaling was most needed. Using genetically engineered cell lines and K-RAS-driven genetically engineered mouse models (KC or KPC) with or without pancreas-specific CCN1 conditional knockout background, we identified a positive feedback circuit between CCN1 and mutant K-RAS expression. Moreover, blocking this feedback via conditional knockout of CCN1 in the pancreas significantly reduced invasive phenotypes, PDAC growth, and metastasis in the lung in KC and KPC mice. Mechanistically, we found that the K-RAS-CCN1 feedback circuit is regulated by microRNA miR-145 via a feedforward mechanism. Collectively, these studies highlight the clinical potential of targeting CCN1 in PDAC. (VA Merit Grant supports this work)
Citation Format: Anjali Kambhampati, Archana De, Inamul Haque, Snigdha Banerjee, Sushanta K. Banerjee. The role of CCN1 in mutant K-RAS addiction in pancreatic 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 1667.
Abstract 1673: KRAS dependency, a gene editing approach
Authors: Marcireau Christophe , Lacroix Fréderic , Hoffmann Dietmar , Cindhuchao May , Calvet Loreley , Ruffin Yvette , Debussche Laurent 
Published: March 2024

Abstract
The RAS family genes encode small GTP-binding cytoplasmic proteins that are important signaling molecules. They regulate cell growth, survival and differentiation by coupling receptor activation to downstream effector pathways. Activating mutations of oncogenic RAS pathway genes are frequently detected in human cancers. The role of KRAS in tumor formation is not questionable. It’s implication in tumor maintenance is less well validated. The KRAS dependency is a key question to answer before to develop KRAS inhibitor. Targeted genome editing using CRISPR/Cas9 is a relatively new, revolutionary technology allowing for efficient and directed alterations of the genome. CRISPR is a genome-editing platform that makes use of the bacterially-derived endonuclease Cas9 to introduce DNA double-strand breaks at precise locations in the genome using complementary guide RNAs. These double strand breaks can be repaired by homologous recombination DNA repair mechanisms thank to a donor DNA template. By this way mutations can be introduced at desired loci, DNA fragment can be deleted or introduce at the desired location. We aimed at investigating the KRAS dependence and we applied the CRISPR-Cas9 technology to engineer isogenic cancer cells harboring a “conditional KRAS gene knockout" by exchanging the KRAS endogenous promoter. This promoter replacement approach can be used also to validate new targets.
Citation Format: Christophe Marcireau, Fréderic Lacroix, Dietmar Hoffmann, May Cindhuchao, Loreley Calvet, Yvette Ruffin, Laurent Debussche. KRAS dependency, a gene editing approach [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 1673.