bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2372: Does the ubiquitin E3 ligase glycoprotein 78 (gp78/amfr) link socioeconomic factors, race, and biology in breast cancer?
Authors: Ellis Myles A. 
Published: April 2023

Abstract
This year there will be 260,00 new cases of breast cancer in the United States. Close to 40,000 women living with breast cancer, will die from the disease by the years end. However, these statistics are not evenly distributed across our citizens. Women of Western African descent are 40% more likely to die from breast cancer than their European counterparts.  Although socioeconomic factors along with racism, including affordable quality health care, availability of healthy foods, wage gaps, and trustworthiness of our physicians, have a considerable role in the difference in survival, there still is a significant gap in our understanding of the contribution of biology.  Therefore, biomarkers, mechanisms, and pathways connected with more aggressive biology that differ by race and genetic ancestry must be examined.  The ubiquitin E3 ligase, glycoprotein 78 (GP78/AMFR) is an endoplasmic reticulum-resident protein that degrades unfolded proteins found in the cell. It also supports lipid synthesis, autophagy and targets certain proteins that cause endoplasmic reticulum stress that could result in apoptosis. We have found that GP78 is a functional biomarker for breast cancer in women. Higher levels of this gp78, detected by validated antibody, is associated with more aggressive subtypes of breast cancer (e.g., luminal B, HER2 and triple-negative breast cancer, TNBC) and is expressed at notably elevated levels in breast cancer compared to normal glands. In addition, its expression is associated with poor survival, regardless of subtype, specifically in women of Western African descent. In vivo experiments using murine syngeneic allograft models, comparing wild type and gp78 knock breast cancer cells show the gp78 is required for tumor growth. Further analysis reveals a role for gp78 lipogenesis linked to immune suppression in the tumor microenvironment. Conclusion: These observations suggest a role for gp78 in 1) tumor growth and 2) immune suppression, and implies a role for race and genetic ancestry in the association between gp78 and breast cancer survival.  Therefore, corroborating a role for gp78 in both tumor growth and suppression of the tumor immune microenvironment will be an important future goal. We will validate and extend these findings in additional diverse patient populations to define the association between GP78, patient tumor biology, clinical feature, patient exposures, and other social determinants of health.
Citation Format: Myles A. Ellis. Does the ubiquitin E3 ligase glycoprotein 78 (gp78/amfr) link socioeconomic factors, race, and biology in breast 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 2372.
Abstract 2431: The role and regulation of YAP1 in paligenosis, the cell program converting mature cells into precancerous metaplasia
Authors: Zeng Yongji , Willet Spencer G. , Huang Yangzhe , Bark Steven , Mills Jason C. 
Published: April 2023

Abstract
To advance gastric cancer prevention, diagnosis, and treatment, and understand its origins, we aim to understand why precursor metaplasias form and how they progress to cancer. Paligenosis is a recently characterized conserved molecular process which cells use to convert from normal, differentiated, mature cells into proliferative, progenitor-type cells; in the stomach, paligenosis converts digestive-enzyme-secreting chief cells into Spasmolytic Polypeptide Expressing Metaplasia cells (SPEM). Paligenosis occurs by stepwise series of cellular-molecular events characterized by dynamic regulation of mTORC1: Stage 1, mTORC1 decreases, chief cells scale down their secretory apparatus. Stage 2, SPEM genes are induced. Stage 3, mTORc1 increases and the previously mitotically quiescent cells re-enter the cell cycle. Unregulated or “unlicensed” paligenosis imparts nondividing mature differentiated cells the ability to re-enter the cell cycle despite mutations and other genomic abnormalities, making paligenosis a likely initiating process for gastric cancer. The Hippo pathway regulates cell proliferation and differentiation by phosphorylating the transcriptional co-activator YAP1. YAP1 can also act as an oncogene during tumorigenesis, but the regulation of the Hippo pathway and YAP1 in metaplasia and in paligenosis are still unclear. Here we show that YAP1 accumulates in Stage 2 leading to increased expression of many canonical transcriptional targets including cell cycle genes. Overexpression of YAP-S127A in low-dose-tamoxifen-treated Mist1CreERT2/+; ROSA26LSL-rtTA.IRES.EGFP/+; tetOYap1S127A mice induced by doxycycline is sufficient to induce chief cells to enter mitosis while the deletion of YAP1 in Mist1CreERT2/+; ROSA26LSL-Ai9/+; YAP1flox/flox ; TAZflox/flox mice leads to the failure of chief cells to go through paligenosis. Yap1 mRNA was changed by single-cell RNA sequencing, whereas proteomics with western blot validation showed unchanged total YAP1 protein, suggesting YAP1 may be regulated by subcellular localization. Multi-omic data with western blot and immunohistochemistry validation indicated YAP1 localization is regulated in a Hippo pathway kinase-dependent way and SMAD2/3, key effectors of TGF-β signaling, being potential downstream targets. In summary, our study indicates that YAP1 activity is required for paligenosis, working independently of Hippo and interacting with TGF-β signaling.
Citation Format: Yongji Zeng, Spencer G. Willet, Yangzhe Huang, Steven Bark, Jason C. Mills. The role and regulation of YAP1 in paligenosis, the cell program converting mature cells into precancerous metaplasia [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 2431.
Abstract 2446: An investigation of HOX-regulatory mechanisms and their role in the SC origin of human CRC
Authors: Osmond Brian , Facey Caroline O. , Opdenaker Lynn M. , Zhang Chi , Boman Bruce M. 
Published: April 2023

Abstract
HOX genes are a highly conserved subset of genes that encode for transcription factors critical for stem cell (SC) function and embryonic development. Several HOX genes have also been implicated in a myriad of cancers, including colorectal cancer (CRC). However, the mechanisms by which HOX genes contribute to cancer development are still not fully understood. Specifically, the mechanisms by which HOX genes regulate SC populations and how SC dysregulation leads to tumorigenesis needs to be clarified. Current research indicates that HOX genes are regulated by WNT and retinoic acid (RA) signaling.
Goal: To ascertain how HOX-regulatory mechanisms play a role in the SC origin of human CRC.
Hypotheses: (1) HOX genes regulated by RA and WNT signaling control SC differentiation along various lineages in normal human colonic epithelium. (2) Aberrant expression of HOX genes leads to decreased differentiation and CSC overpopulation in CRC. Preliminary data shows that RA signaling occurs in ALDH+ SCs and HOXA4, HOXA9 & HOXD10 are selectively expressed in ALDH+ SCs. Moreover, treatment of CRC cells with all-trans retinoic acid (ATRA) modulates expression of HOXA4, HOXA9, HOXC8, HOXC9, & HOXD10 while also reducing cell count. Nanostring profiling also shows that expression of select HOX genes (HOXA3, HOXA4, HOXA5, HOXA10, HOXB6, HOXB8, HOXB9, & HOXD9) significantly changes in response to ATRA. Bioinformatics analysis has identified RA response elements (RAREs) within the promoters of all mentioned HOX genes. Understanding how HOX genes control normal colonic SCs, and, how they become dysregulated in CSCs will identify mechanisms that help explain how HOX genes contribute to SC overpopulation that drives colorectal cancer (CRC) growth.
Citation Format: Brian Osmond, Caroline O. Facey, Lynn M. Opdenaker, Chi Zhang, Bruce M. Boman. An investigation of HOX-regulatory mechanisms and their role in the SC origin of human CRC [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 2446.
Abstract 2448: Galectin-3 regulates stemness and cellular states in glioblastoma stem cells
Authors: Akosman Bedia , Lalvani Shaan , Suita Yusuke , Karambizi David , Tapinos Nikos 
Published: April 2023

Abstract
Glioblastoma stem cells (GSCs) are a subset of cells in the Glioblastoma (GBM) tumor microenvironment that play an important role in tumor heterogeneity, aggressiveness, recurrence, and therapy resistance. Dynamic environmental, transcriptional, and epigenetic oscillations envelope GSCs in a variety of cellular states, contributing to GSC heterogeneity and carcinogenesis. The creation of effective therapies may therefore benefit from a better understanding of the factors associated with the GSC's distinct traits as well as the mechanisms affecting GSC cellular states and transformation.
Galectin-3 is a molecule that is highly expressed in GBM, and higher levels are linked to poor survival and mesenchymal subtype. Although Galectin-3 has previously been found primarily in microglia and tumor-infiltrating macrophages, our studies using patient-derived GSCs show that it is abundantly produced by GSCs and that its expression significantly decreases when they differentiate into non-stem differentiated cancer cells, which are more responsive to therapies. Our findings also show that Galectin-3 is not expressed in normal neural stem cells, leading us to believe that it could serve as a unique identifier for GSCs. Additionally, when Galectin-3 is silenced in GSCs, we see a decreased self-renewal frequency and enrichment of genes associated with pro-neural state, which has a less aggressive phenotype. Confocal imaging and single-cell RNA-seq analysis further revealed heterogeneous expression of Galectin-3 in GSCs, and the functional pathway analysis shows that Galectin-3high cell clusters have a significant overlap with cells enriched in EMT pathways. Therefore, our findings suggest that Galectin-3 may be a unique distinguishing characteristic of GSCs and may play a particular role in regulating GSC stemness and determining GSCs states, making it a potential molecular target for the treatment of glioblastoma.
Citation Format: Bedia Akosman, Shaan Lalvani, Yusuke Suita, David Karambizi, Nikos Tapinos. Galectin-3 regulates stemness and cellular states in glioblastoma 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 2448.
Abstract 2453: Olfactomedin 4 downregulation enhances MYC-signaling in human benign prostate cells and the Olfm4 mouse models
Authors: Li Hongzhen , Liu Wenli , Zhu Jianqiong , Chin Kay , Rodgers Griffin P. 
Published: April 2023

Abstract
Prostate cancer is the most diagnosed solid tumor and the second leading cause of cancer related death in American men. We have reported previously that OLFM4 gene expression was reduced or lost during prostate cancer progression due to frequent genetic deletion and hypermethylation of the OLFM4 gene promoter region. To investigate OLFM4 gene biological functions and molecular mechanisms underlying prostate cancer progression, we have established OLFM4 knock out RWPE1 cells and Olfm4 knock out mouse model. Functionally, OLFM4-knockout RWPE1 cells exhibited enhanced proliferation of the stem/progenitor-like cell population and abnormal differentiation. Bulk-cell RNA sequencing analysis pinpointed that MYC expression was enhanced in the OLFM4-knockout RWPE1 cells compared with OLFM4-wild cells. Molecular and signaling pathway studies revealed an increase in the WNT/APC/MYC signaling pathway gene signature and MYC target genes that regulate multiple biological processes in OLFM4-knockout RWPE1 cells and Olfm4-knock out mouse models. To test the function of the MYC gene in RWPE1 cells, we used (+)-JQ1, an MYC inhibitor, in both 2D and 3D culture models and found that (+)-JQ1 substantially inhibited the proliferation of OLFM4-knockout GFP reporter RWPE1 cells compared with OLFM4-W RWPE1 cells in both types of cultures. We further studied MYC inhibitors using organoid culture for Olfm4-/-/TRAMP mouse prostate tumors. These results suggest that OLFM4-negative prostate cancer is more sensitive to MYC inhibitor’s therapeutic approaches.
Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Griffin P. Rodgers. Olfactomedin 4 downregulation enhances MYC-signaling in human benign prostate cells and the Olfm4 mouse models [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 2453.
Abstract 2612: Mutational pattern of SWI/SNF pathway genes in lung adenocarcinoma patients reveal uneven correlation with immunotherapy sensitivity
Authors: Tang Haimeng , Bao Hua , Wu Xue , Shao Yang 
Published: April 2023

Abstract
Background: The search for prognostic biomarkers indicating sensitivity to immunotherapy in lung adenocarcinoma patients have zeroed in on genes in the SWI/SNF pathway. However, the mutational profiles of the relevant key genes on this pathway have not been clearly defined, and no comparisons have been conducted on whether mutations in these genes provide the same predictive value in lung cancer patients.
Methods: In this study, statistical analysis of clinical factors, tumor mutation burden, chromosomal instability, and co-appearing alterations of 5 key genes on the SWI/SNF pathway was conducted for 4344 lung adenocarcinoma samples. Two independent online cohorts (N = 1661 and N = 576) were used to supplement the analysis with survival and RNA-Seq data, respectively.
Results: ARID mutations were found to be more prominent in males under the age of 60 than any other clinical group, while no significant differences exists for SMARC-mutant groups. Mutational burden and chromosomal instability analysis showed that patients with either ARID family mutations (including ARID1A, ARID1B, or ARID2 mutations) or SMARC family mutations (including SMARCA4 or SMARCB1 mutations) display different sample-level metrics than patients with wild-type samples (TMB: ARID v WT: p&lt;2.2X10-16, SMARC v WT: p&lt;2.2X10-16; CIN: ARID v WT: p=1.8X10-5, SMARC v WT: p=0.027). Additionally, both mutant groups have a higher proportion of transversions than transitions, while the ratio is more equal for wild-type samples. Survival analysis shows that patients with ARID mutations were more sensitive to immunotherapy treatment than wild-type and SMARC-mutated patients (p &lt; 0.001 and
p=0.013, respectively), and multivariate cox analysis reveals that presence of ARID mutations is likely the main cause. Furthermore, we observed higher expression of genes on the MTOR1C signaling pathway and the unfolded protein response pathway in the SMARC-mutated group in comparison to the ARID-mutated group, both of which have been reported to increase resistance to immunotherapy.
Conclusions: In summary, the mutational landscape of 5 major SWI/SNF pathway genes were classified. The research presented also shows that mutations in the ARID gene family, including ARID1A, ARID1B, and ARID2, are primarily responsible for the sensitive response to immunotherapy treatment in patients with SWI/SNF mutant lung adenocarcinoma.
Citation Format: Haimeng Tang, Hua Bao, Xue Wu, Yang Shao. Mutational pattern of SWI/SNF pathway genes in lung adenocarcinoma patients reveal uneven correlation with immunotherapy sensitivity [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 2612.
Abstract 2617: Rac and Cdc42 inhibition on macrophage function in the pancreatic tumor microenvironment
Authors: Torres-Sánchez Anamaris , Rivera-Robles Michael , Dorta-Estremera Stephanie , Dharmawardhane Suranganie 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. To date, there are few therapies that are efficient against this disease, and patients often develop therapy resistance. The homologous Rho GTPases, Rac and Cdc42, are overexpressed in pancreatic cancer and correlated with poor prognosis. Rho GTPases regulate cell migration/invasion, cell morphology/polarity, and cell survival/viability. Rac and Cdc42 are essential Rho GTPases in oncogenic transformation and invasiveness and govern invasion in both cancer cells and tumor-associated macrophages (TAMs). TAMs are immunosuppressive cells that exacerbate cancer progression via inflammatory responses and crosstalk signaling with malignant cancer cells to promote invasion and immunesuppression. Our laboratory has developed a dual Rac/Cdc42 inhibitor, MBQ-167 (IC50 100nM), as an anticancer agent that recently received IND approval from the US FDA due to its safety and efficacy in breast cancer models. The hypothesis tested in this study is that MBQ-167 will simultaneously target the migration and activity of pancreatic cancer cells and immunosuppressive cells in the tumor microenvironment (TME). To evaluate this, we performed pulldown assays for Rac and Cdc42 activation, MTT cell viability assays, wound-healing assays for cell migration, and phagocytosis assays using human and rat macrophage and human pancreatic cancer cell lines. Results show that MBQ-167 is not toxic to macrophages even at concentrations as high as 10uM. MBQ-167 inhibited Rac1activation by 75% and Cdc42 activation by 40% in THP-1 human macrophages at 500nM. MBQ-167 reduced macrophage migration by 67% at 150nM, and decreased pancreatic cancer cell migration by 60% at 250nM. In addition, MBQ-167 reduced macrophage phagocytosis by 56% at 500nM. This study demonstrates the utility of Rac/Cdc42 inhibition to reduce pancreatic cancer progression in the TME.
Citation Format: Anamaris Torres-Sánchez, Michael Rivera-Robles, Stephanie Dorta-Estremera, Suranganie Dharmawardhane. Rac and Cdc42 inhibition on macrophage function in the pancreatic tumor microenvironment [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 2617.
Abstract 2723: Treatment of gastric cancer cells with tumor treating fields (TTFields) and concomitant FOLFOX
Authors: Flint-Brodsly Naama , Zeevi Einav , Wainer-Katsir Kerem , Fishman Hila , Martinez-Conde Antonia , Dor-On Eyal , Munster Mijal , Porat Yaara , Voloshin Tali , Davidi Shiri , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: April 2023

Abstract
Background: Gastric cancer, one of the most common types of cancers, is mainly treated with the FOLFOX chemotherapy regimen (oxaliplatin, fluorouracil [5-FU], and leucovorin); yet long-term survival remains poor. Tumor Treating Fields (TTFields) are electrical fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. In several tumor types, the mechanism of action of TTFields included an antimitotic effect and DNA damage induction with impaired DNA damage repair. The current study aimed to examine the efficacy of TTFields for treating gastric cancer cells, and the potential application of TTFields concomitant with FOLFOX.
Methods: Human gastric cancer cell lines, AGS and KATO III, were treated with TTFields (intensity of 1.1 and 1.7 V/cm, respectively; frequency of 150 kHz) using the inovitro system. Cell count and colony formation were examined following treatment, and the overall effect calculated by multiplication of the two. RNA sequencing was also performed on samples from control and TTFields-treated cells. Mitotic spindle defects, chromosome miss-localization, and DNA double strand breaks (DSB) formation were examined by fluorescent staining for α-tubulin, phospho-histone 3 (PH3), and phospho-histone H2AX (γH2AX), respectively. Expression of DNA repair proteins was measured using Western Blot. The impact of TTFields with FOLFOX and its individual therapeutic components, oxaliplatin and 5-FU on cell count and clonogenicity was tested.
Results: TTFields reduced cell count and the colony forming ability of the cells. Cells treated with TTFields displayed abnormal mitotic figures and increased levels of DNA damage. Expression of DNA repair proteins was downregulated following treatment with TTFields, as evident from RNA and protein levels. Furthermore, TTFields augmented the cytotoxic and clonogenic effects of FOLFOX and its individual therapeutic components, oxaliplatin and 5-FU.
Conclusions: TTFields show potential as an effective gastric cancer treatment, with a mechanism of action involving an anti-mitotic effect and DNA damage repair impairment. TTFields may be applied to enhance the efficacy of gastric cancer standard-of-care.
Citation Format: Naama Flint-Brodsly, Einav Zeevi, Kerem Wainer-Katsir, Hila Fishman, Antonia Martinez-Conde, Eyal Dor-On, Mijal Munster, Yaara Porat, Tali Voloshin, Shiri Davidi, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Treatment of gastric cancer cells with tumor treating fields (TTFields) and concomitant FOLFOX [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 2723.