bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5804: Targeting methyl donor synthesis inhibits platinum-induced enrichment of ovarian cancer stem cells
Authors: Zhang Shu , Metcalfe Tara X. , Hassel Christiane A. , O'Hagan Heather M. , Nephew Kenneth P. 
Published: April 2023

Abstract
Ovarian cancer (OC) is one of the deadliest gynecologic cancers in US. Platinum (Pt)-based chemotherapy can reprogram cancer cells to ovarian cancer stem cells (OCSCs) and contribute to incurable recurrence. We have previously shown that Pt-containing drugs, e.g., cisplatin, enrich for OCSCs and Pt-induced alterations in DNA methylation enhanced OCSC malignant properties. CSCs have been shown to be dependent on methionine (Met) in many cancers, and in the current study, we investigated the role of Met and the interplay between methylation and Met metabolism in OCSC enrichment. In high grade serous ovarian cancer cell lines (OVCAR5, OVCAR3), cisplatin treatment (IC50, 16hr) increased (p&lt;0.01) the percentage of cells that were positive for aldehyde dehydrogenase (ALDH+ cells), a known OCSCs marker. Cisplatin treatment also increased (p&lt;0.05) the whole cell level of 5-methylcytosine, indicating Pt-induced methylation changes. In addition, Met metabolism was altered by cisplatin, demonstrated by decreased (p&lt;0.01) level of Met derivative, S-adenosyl-methionine (SAM), and increased (p&lt;0.01) expression of Met utilization enzyme, methionine adenosyltransferase 2A (MAT2A). To investigate a possible role of Met metabolism in Pt-induced enrichment of OCSCs, OVCAR5 cells were cultured in complete or Met-depleted (Met-) media, treated with cisplatin or vehicle and examined for CSC properties, including ALDH+ cells and the ability to form spheroids under low-attachment conditions. Met depletion blocked (p&lt;0.01) both the Pt-induced increase of ALDH+ cells and spheroid formation. Both Met- only and Met- in combination with cisplatin activated p38, determined by increased phosphorylated p38, which may have responded to Met depletion and promoted cell cycle arrest. In addition, MAT2A expression was higher (p&lt;0.01) in ALDH+ compared to ALDH- OC cells. MAT2A inhibitor FIDAS-5 combined with cisplatin blocked the Pt-induced increase in ALDH+ cells (p&lt;0.01), demonstrating a requirement for Met utilization in Pt-induced OCSC enrichment. As MAT2A is a therapeutic target in cancer, MAT2A inhibition could represent a therapeutic approach for inhibiting CSC in ovarian cancer. We are further investigating the mechanism of MAT2A-mediated inhibition on Pt-induced OCSCs enrichment by examining the OC methylome and cell cycle arrest.
Citation Format: Shu Zhang, Tara X. Metcalfe, Christiane A. Hassel, Heather M. O'Hagan, Kenneth P. Nephew. Targeting methyl donor synthesis inhibits platinum-induced enrichment of ovarian 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 5804.
Abstract 5806: Kinase library screening identifies IGF-1R/PI3K/AKT axis as a crucial pathway for survival of intrahepatic cholangiocarcinoma cells with stemness characteristics
Authors: Rattanasinchai Chotirat , Chornkrathok Chidchanok , Sriphan Donlaporn , Navasumrit Panida , Ruchirawat Mathuros 
Published: April 2023

Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a subtype of biliary malignancy that arises along the peripheral bile duct epithelium. Given its limited and inefficacious treatment options, the mortality rate of iCCA remains high and thus a novel therapeutic strategy is urgently needed. The concept of cancer stem cells (CSCs) explains a subpopulation of cancer cells that possesses self-renewal and differentiation capacities. These CSCs become the culprit for cancer metastasis, cancer recurrence and chemotherapeutic resistance, making them promising targets for cancer treatment. The propose of this study is to identify the signaling pathways crucial for the survival of iCCA with stemness characteristics. Gene expression analysis on a dataset of Thai iCCA patients (n=91) showed that iCCA tumors are enriched in the Adult Stem Cell (ASC) signature which are the shared characteristics among the epithelial-derived cancer with stemness characteristics. Although iCCA cells exhibit some degree of enrichment in stem cells markers when compared with cholangiocyte cells, further upregulation of stem cell-related genes, e.g. Nanog, Oct3/4, Sox2, and Sox9, were found in iCCA cells grown as 3D tumorspheres. A kinase inhibitor screening library was then performed on iCCA tumorspheres. Our initial screening demonstrated that 11 out of the top 50 kinase inhibitors that effectively decrease viability of iCCA tumorspheres belongs to the insulin-like growth factor-1 receptor (IGF-1R)/phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/AKT) axis. Additionally, these inhibitors increase cell apoptosis, judged by the caspase 3/7 activity, within iCCA tumorspheres. Conversely, IGF-1 treatment which is sufficient to induce activation of IGF-1R and AKT also enhances cell viability and decrease cell apoptosis in iCCA. Taken together, our data demonstrate that IGF-1R/PI3K/AKT axis is crucial for survival of iCCA cells with stemness characteristics and this pathway could be a potential therapeutic target in iCCA.
Citation Format: Chotirat Rattanasinchai, Chidchanok Chornkrathok, Donlaporn Sriphan, Panida Navasumrit, Mathuros Ruchirawat. Kinase library screening identifies IGF-1R/PI3K/AKT axis as a crucial pathway for survival of intrahepatic cholangiocarcinoma cells with stemness characteristics. [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 5806.
Abstract 5808: Integrin-linked kinase regulates Wnt transcriptional activity in platinum resistant ovarian cancer stem cells
Authors: Atwani Rula , Lazar Virginie , Sandusky George Earl , Condello Salvatore 
Published: April 2023

Abstract
Ovarian cancer (OC) is the most lethal gynecological cancer, characterized by chemo-resistance and fatal tumor recurrence after primary treatment. The metastatic progression is mediated by exfoliation of tumor cells into the peritoneal cavity, the formation of compact OC spheroids, and their implantation onto the overlying peritoneal surface. Spheroid formation is promoted by a change of cell adhesion properties, enhanced secretion of extracellular matrix (ECM) components, such as fibronectin (FN), that stiffen the tumor stroma, promote the aberrant activation of integrins, and recruit the adaptor protein integrin-linked kinase (ILK). ILK drives cytoskeletal assembly and modulates key processes, including survival, invasion, and stemness. However, the functional role of ILK in chemoresistance of ovarian cancer stem cells (OCSCs) remains incompletely understood. We tested the hypothesis that the formation of FN-integrin complexes at the cell membrane promotes survival of OCSCs and supports OC spheroid formation by activating ILK and downstream oncogenic signaling. In OCSCs compared with non-CSC, ILK, FN, and integrin β1 mRNA expression levels were increased (P&lt;0.001) and further enriched in OC spheroids compared with monolayers (P&lt;0.01). ILK blockade with the specific inhibitor cpd-22 suppressed spheroid proliferation and tumor initiating capacity in xenograft mouse model. Furthermore, key oncogenic signaling pathways, in particular decreased β-catenin signaling essential to sustaining cancer cell stemness, were altered in OC spheroids treated with cpd-22. Of the genes examined, expression of Wnt receptor Frizzled 7 (Fzd7) was the mostly highly downregulated in OC spheroids treated with cpd-22, indicating a direct correlation between ILK activation and Wnt signaling. By using co-immunoprecipitation and proximity ligation assay, we demonstrated that ILK co-localizes with Fzd7 in OC spheroids. Mechanistically, treatment of OC spheroids with the combination of carboplatin and ILK-Fzd7 blockade decreased β-catenin signaling, inhibited phospho-Akt at Ser473 and increased levels of cleaved-caspase-3 compared to single agent alone, resulting in apoptosis. By regulating β-catenin signaling, Fzd7 expression and ILK activation are essential for OCSCs survival. Targeting Fzd7-ILK clusters may represent a new therapeutic approach to eradicate OCSC and ultimately improve patient outcomes.
Citation Format: Rula Atwani, Virginie Lazar, George Earl Sandusky, Salvatore Condello. Integrin-linked kinase regulates Wnt transcriptional activity in platinum resistant ovarian 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 5808.
Abstract 5817: LKB1 overcomes RAS pathway-mediated loss of epithelial integrity
Authors: Tervonen Topi A. , Pant Shishir M. , Englund Johanna , Klefström Juha 
Published: April 2023

Abstract
Oncogenic RAS pathway disassembles cell-cell and cell-basement membrane junctions, thus promoting epithelial cell motility and invasion. To find tumor proteomic changes responsible for the disrupting effects of RAS on epithelial integrity, we explored cBioportal cell line proteomics data across all cancer types for correlations between oncogenic KRAS or HRAS mutations and possible regulators of epithelial integrity. We found inverse correlation between these RAS mutations and tumor suppressor LKB1 protein levels in a cohort where LKB1 was not inactivated by a mutation. Furthermore, LKB1 protein levels were also positively correlated with NF2 protein (a negative regulator of RAS) in human breast tumors and inversely correlated with c-RAF (RAS effector) activating phosphorylation at serine 338 in breast cancer cell lines. We sought to functionally clarify the relationship between RAS pathway and LKB1, finding that an ectopic constitutive or inducible expression of HRASV12 downregulates LKB1 protein in mammary epithelial MCF10A cells and HMEC-hTERT cells. Furthermore, RAS-mutant MCF10A cells regained LKB1 protein levels upon treatment with MEK/ERK inhibitors. We establish that the RAS-mediated downregulation of LKB1 protein occurs through proteasomal activity. LKB1 reconstituted MCF10A-HRASV12 (RAS-LKB1) cells displayed restored desmoplakin, γ-catenin and E-cadherin pericellular immunostaining pattern in monolayer cultures, suggesting restoration of desmosomes and adherence junctions. We also cultured RAS-LKB1 cells in 3D egg-white and observe restoration of E-cadherin, γ-catenin, α6-integrin, and laminin-332, indicating a rescue of epithelial integrity in 3D context. Our findings suggest that LKB1 rescues mutant RAS-mediated disruption of cell-cell and cell-basement membrane junctions and general epithelial integrity. Our current aim is to define how LKB1 suppresses RAS mediated disruption of breast epithelial integrity, that is expected to shed new light into early stages of tumor invasion and uncover novel therapeutic opportunities via restoration of LKB1.
Citation Format: Topi A. Tervonen, Shishir M. Pant, Johanna Englund, Juha Klefström. LKB1 overcomes RAS pathway-mediated loss of epithelial integrity [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 5817.
Abstract 5906: Gut microbiota signatures are associated with immunotherapy induced cognitive decline and neurotoxicity
Authors: Banerjee Anik , Roland Christina , Johnson Sarah , Ajami Nadim , Wargo Jennifer 
Published: April 2023

Abstract
Studies have demonstrated promising outcomes of combined immune checkpoint blockade (CICB) modulating tumor cytotoxicity via targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1). The emergence of long-term patient management has been transformed among health care professionals as patient survival rates are increasing significantly. Despite promising advances, patient outcomes are heterogenic and are correlative to host intrinsic and extrinsic factors. Multiple reports have highlighted the negative effects of cancer treatments towards inducing cognitive impairment and neurotoxicity often referred to as “chemofog”. More recently, the gut microbiome has been increasingly recognized to regulate antitumor immunity and further distinct microbiome signatures can confer favorable outcomes in the context of CICB. Interestingly, specific microbes within the gut microbiome have been shown to regulate social behavior and cognition via the bidirectional communication along the gut-brain axis though changes in microbiota-derived metabolites and vagal afferent fibers. Insights into mechanisms of immunotherapy induced cognitive decline are warranted. Thus, we hypothesize CICB exacerbates cognitive impairment and neurotoxicity via the detrimental alterations to the gut microbiome. To address this, we profiled the gut microbiome, through 16S rRNA gene and metagenomic sequencing of fecal samples from patients (n=146) with advanced melanoma treated with CICB stratified based on severity of cognitive dissonance. Beta-diversity, incorporating weighted UniFrac distances by principal coordinate analysis (PCoA), revealed a cluster of samples from patients with cognitive impairment as compared to samples from those with minimal to absent cognitive decline. Further, taxonomical analysis showed significant alterations in relative abundances of microbial candidates (e.g., L. intestinalis, A. muciniphila, F. prausnitizii, and R. hominis). These results suggests that CICB patients with cognitive impairments and neurotoxicity have altered microbiome signatures which may potentially exacerbate downstream neuroinflammatory signaling. Further studies investigating specific host-microbe pathways and profiling microbiota-derived metabolites which are implicated in these detrimental effects are essential for biomarker discovery and mechanistic insight.
Citation Format: Anik Banerjee, Christina Roland, Sarah Johnson, Nadim Ajami, Jennifer Wargo. Gut microbiota signatures are associated with immunotherapy induced cognitive decline and neurotoxicity. [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 5906.
Abstract 5942: Mechanism and role of neutrophil recruitment in head and neck squamous cell carcinoma
Authors: Ghias Kulsoom , Shakeel Hina , Sheikh Alisalman , Abidi Syed Hani , Masood Kiran I. , Fatima Saira , Bilwani Fareena 
Published: April 2023

Abstract
The immune system plays a pivotal role in identification and clearance of tumor cells, but can also be counterproductive and enhance tumor progression. Presence of neutrophils in solid tumors, including the sixth most common cancer globally - head and neck squamous cell carcinomas (HNSCC), is associated with poor prognosis. Pro-inflammatory cytokines regulated by NF-κB promote extravasation of neutrophils into tissue; neutrophils are polarized to anti-tumor (N1) or pro-tumor (N2) phenotype through the action of various pathways, including TGF-β. The mechanism and role of neutrophil recruitment in HNSCC were explored this study.
Neutrophils isolated from adult donors were co-cultured for 5 hours with conditioned media (CM) from HNSCC cells SCC-9 and Cal-27, and stained with TNF-α, ICAM-1, CCL2, CCL5 for analysis of neutrophil phenotype by flow cytometry. TGF-β blocking antibody was used to explore the role of TGF-β in polarization of neutrophils. Canonical and non-canonical TGF-β signaling pathway activation was also investigated in these neutrophils through western blots. Using HNSCC patient samples, qPCR was performed for expression of genes involved in apoptosis, epithelial-to-mesenchymal transition, metastasis, and neutrophil function.
Following co-culture with 24-hour HNSCC CM, neutrophils begin to exhibit cell surface markers indicative of N2 phenotype, which is impacted by TGF-β blocking antibody. Neutrophils co-cultured with HNSCC CM exhibited altered expression of TGF-β mediators Smad2/3, p38 and Akt, which was abrogated with the addition of TGF-β blocking antibody indicating specificity of a TGF-β induced signaling. Gene expression analysis exhibited significantly higher expression of anti-apoptotic BCL2 and neutrophil function marker alpha defensin 1 in HNSCC patient samples with greater neutrophil infiltration, while caspase 3 was expressed at significantly higher levels in HNSCC patient samples with low neutrophil infiltration.
HNSCC cells recruit neutrophils; evidence suggests that TGF-β pathway, which typically promotes N2 phenotype in neutrophils, is involved via canonical and non-canonical mediators including p38 and Akt. Further, HNSCC patient samples have varying levels of neutrophil infiltration and differentially express genes involved in apoptosis, EMT, metastasis and invasion, inflammation.
Citation Format: Kulsoom Ghias, Hina Shakeel, Alisalman Sheikh, Syed Hani Abidi, Kiran I. Masood, Saira Fatima, Fareena Bilwani. Mechanism and role of neutrophil recruitment in head and neck squamous cell carcinoma [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 5942.
Abstract 5948: MAGE-A3 expression with MMR-MSH6 screening suggests MAGE-A3 as a potential target for microsatellite-stable colorectal cancer
Authors: Yom Jina , Gonzalez Rachel , Zewdu Eden , Su Aubrey , Yin Patrick , Gilmore Bailey , Kong Dehe , Han Andy , Guo Zhaoying , Qu Tianli , Zhao Zoe , Christenson Eric , Ma Yan , Guo Hailey , Hu Xiaomin , Ren Qi , Wu Zhaohui , Liu Xuan , Fu Wei 
Published: April 2023

Abstract
Colorectal Cancer (CRC) is the second leading cause of death worldwide. Recent developments in cancer immunotherapy have obtained encouraging clinical responses, including PD-1/PD-L1 blockade therapy, although response rates vary depending on tumor type. For example, despite the lack of response by microsatellite-stable CRC, a subset of CRC with deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H) responds especially well to the PD-1/PD-L1 blockade therapy. For other types of CRC which do not respond to PD-L1 therapy, new targets are being investigated. One family of targets is the cancer testis antigen MAGE-A whose expression is restricted to germline cells in normal tissue but is overexpressed in many cancer cells. In this study, immunohistochemical analysis of MAGE-A3 expression in colon cancer along with IHC screening of mismatch protein MSH6 was performed. Many of the cases in this study observed a co-expression in the tissue. In the tumors, MAGE-A3 was observed to have weak cytoplasmic expression while MSH6 had strong nuclear expression in the epithelial cells. The immune cells adjacent to the epithelial cells were also positive for MAGE-A3. This result suggests that MAGE-A3 may be a promising target for microsatellite-stable colorectal cancer immunotherapy.
Citation Format: Jina Yom, Rachel Gonzalez, Eden Zewdu, Aubrey Su, Patrick Yin, Bailey Gilmore, Dehe Kong, Andy Han, Zhaoying Guo, Tianli Qu, Zoe Zhao, Eric Christenson, Yan Ma, Hailey Guo, Xiaomin Hu, Qi Ren, Zhaohui Wu, Xuan Liu, Wei Fu. MAGE-A3 expression with MMR-MSH6 screening suggests MAGE-A3 as a potential target for microsatellite-stable 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 5948.
Abstract 596: Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments
Authors: Cai Jiaqiang , Song Shuai , Zong Qing , Liu Qigang , Xu Jian 
Published: April 2023

Abstract
Antibody-drug conjugates (ADC) are one of the fastest growing anticancer drugs, which bring cytotoxic drugs into tumors while avoiding high systemic toxicities. To date, all commercial ADCs use intracellular lysosomal cleavage mechanisms for payload release to kill tumor cells which is often limited by the low tumor antigen expression. To this end, a novel systemically stable and extracellular tumor microenvironment activable linker-payload technology platform has been developed.
Preclinical assessments demonstrated that the highly hydrophilic linker-payload, which showed limited impact on the hydrophilicity of antibody, prolonged the retention time in vivo and eventually enhanced the in vivo potency of ADC. The linker-payload is stable with less than 2% payload drop-off after 28-day incubation in plasma under physiological conditions in vitro. The high stability was also illustrated by GLP cynomolgus monkey studies and preliminary clinical trial data, with the overlap of ADC and TAb PK profile. Furthermore, a battery in vitro and in vivo cell line-derived xenograft (CDX) mouse model studies showed the linker-payload is stable in normal tissues but efficiently releases the payload in tumor tissues. The ADCs using TMALIN platform elucidated significant anti-tumor activity advantages when compared with those marketed ADCs targeting the same antigen, besides showing an acceptable safety profile in pivotal NHP studies without lung/liver/kidney toxicities.
In summary, the TMALIN platform addresses the unmet need of ADCs by releasing the payload extracellularly in tumors and tumor microenvironments on top of the known intracellular lysosomal cleavage mechanisms. Continued clinical validation work is underway for several pipeline candidates as well as investigation into other target areas.
Citation Format: Jiaqiang Cai, Shuai Song, Qing Zong, Qigang Liu, Jian Xu. Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments [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 596.