bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2486: Dissecting the lineage specific roles of BCL-XL in breast cancer metastasis
Authors: Carelock Madison E. , Jiao Mo , Zhang Weizhou 
Published: April 2023

Abstract
B-cell lymphoma X-large (BCL-XL) is a member of the BCL-2 protein family and has been known as an anti-apoptotic protein. As a viable target for cancer therapy, we recently found that proteolysis-targeting chimeras (PROTAC, currently under phase I clinical investigation) against BCL-XL kill cancer cells as well as tumor-induced regulatory T cells (TI-Tregs). Interestingly, BCL-XL has been shown to promote breast cancer metastasis via a function independent of its anti-apoptotic function. We reason that BCL-XL-targeting PROTACs can be potentially used to treat metastatic breast cancer - by direct killing of circulating tumor cells at their vulnerable stages and/or by eliciting anti-cancer immunity via T-reg cell depletion. To our surprise, our pilot experiments using two syngeneic breast cancer models showed opposite results with one model showing reduced metastasis by BCL-XL PROTAC treatment and the other model showing increased metastasis. Genetic deletion of BCL-XL (KO) in those two cell lines reproduces the effect of PROTAC on metastasis, suggesting the on-targeting but contrasting function of BCL-XL in breast cancer metastasis. Our central hypothesis is that BCL-XL may play different roles in breast cancer metastasis depending on the genetics/proteomics of cellular cues from different cancer cells. To confirm the function of BCL-XL in different breast cancer cell lines, we generated BCL-XL KO lines from 4 other syngeneic mouse breast cancers. We confirmed that the majority of breast cancer cells depend on BCL-XL for metastasis, including 4T1, AT-3, E0771.lmb etc; whereas only the Py8119 model exhibits an opposite phenotype. For primary tumor growth, AT-3 and E0771.lmb cells grow bigger tumors in the WT group than in the BCL-XL KO group; and 4T1 and Py8119 cells exhibit similar tumor growth rate between WT and KO cells. For metastatic breast cancer therapy, we treated 4T1-tumor bearing mice with BCL-XL-targeting PROTAC that nearly significantly reduces metastatic spread in the lung without significant change in primary tumor growth. In addition, we found a systematic inhibition of TI-Tregs by PROTACs indicating a lineage-specific function of BCL-XL in breast cancer metastasis. We conclude that BCL-XL is a viable therapeutic target for treating breast cancer metastasis, but caution is required as BCL-XL inhibition may be detrimental for certain cancers. Our future effort will focus on the mechanisms explaining why BCL-XL inhibits metastasis in some cancer types, which can be used as an exclusion criterion for BCL-XL-targeting therapy.
Citation Format: Madison E. Carelock, Mo Jiao, Weizhou Zhang. Dissecting the lineage specific roles of BCL-XL in breast cancer metastasis [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 2486.
Abstract 25: MIF and NR3C2 interactively regulate glucose metabolism in pancreatic cancer
Authors: Yang Shouhui , Tang Wei , Azizian Azadeh , Ströbel Philipp , Ohara Yuuki , Cawley Helen , Hanna Nader , Ghadimi B. Michael , Putluri Nagireddy , Hussain S. Perwez 
Published: April 2023

Abstract
Inflammation and altered cellular metabolism are described as hallmarks of cancer. Although inflammatory signaling and metabolic reprogramming are highly integrated and play critical role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The role of inflammatory mediators in the regulation of metabolic reprogramming is not adequately studied in pancreatic cancer and remains to be explored. Here we show that macrophage migration inhibitory factor (MIF) collaborates with its downstream transcriptional factor nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2) regulate metabolic reprogramming to support cancer growth and progression in PDAC. MIF enhances glucose uptake and lactate efflux through enhancing HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression in pancreatic cancer cell in vitro and in an orthotopic mouse model. Furthermore, a decreased HK1, HK2, LDHA expression, pyruvate and lactate production are found in patient tumors with lower MIF expression and MIF-deficiency tumors from genetically engineered KPC mouse model. Conversely, NR3C2 suppresses HK1, HK2, and LDHA expression and decreases glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves MAPK-ERK Kinase pathway while NR3C2 interacts with AP-1 transcriptional factor in regulation of glycolysis metabolism. Taken together, our result demonstrates an interactive role of MIF and NR3C2 signaling in regulation cancer metabolism and therapeutic approaches target this axis may improve disease outcome in patients with PDAC.
Citation Format: Shouhui Yang, Wei Tang, Azadeh Azizian, Philipp Ströbel, Yuuki Ohara, Helen Cawley, Nader Hanna, B. Michael Ghadimi, Nagireddy Putluri, S. Perwez Hussain. MIF and NR3C2 interactively regulate glucose metabolism in pancreatic 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 25.
Abstract 2502: The role of high mobility group box-1 protein (HMGB1) in the microenvironment of non-small cell lung cancer
Authors: Habu Tomohiro , Date Keiichi , Suzawa Ken , Yoshikawa Mao , Ohki Masayoshi , Iwata Kazuma , Matsuda Naoki , Thu Yin Min , Shien Kazuhiko , Yamamoto Hiromasa , Toyooka Shinichi 
Published: April 2023

Abstract
Introduction: The tumor microenvironment (TME) is critical in determining tumor development and progression. Among stromal cells in TME, cancer associated fibroblasts (CAFs) play a central role and are involved in various signals through their interaction with cancer cells in most solid tumors, leading to cancer progression and acquisition of drug resistance. Under these TME conditions, tumor cell death such as necrosis occurs, which in turn, results in the ectopic release of bioactive molecules collectively termed as damage-associated molecular patterns (DAMPs), which has been reported to play an important role in cancer progression. The purpose of this study is to clarify the effects of cancer cell-derived HMGB1, a representative DAMPs, on CAFs and to investigate whether it could be a potential therapeutic target.
Methods: We established CAFs from resected non-small cell lung cancer (NSCLC) specimens and investigated the biological activity of HMGB1 on CAFs using in vitro co-culture models with NSCLC cell lines. Furthermore, we assessed the therapeutic efficacy of targeting cancer cell-derived HMGB1 using anti-HMGB1 neutralizing antibody.
Results: Intracellular HMGB1 was expressed more in NSCLC cells than in normal bronchial epithelial cells and CAFs, and released from cancer cells extracellularly upon treatment with anticancer drugs. The stimulation with recombinant HMGB1 promoted the proliferation of CAFs in a dose-dependent manner, but not lung cancer cells. Co-culture with CAFs promoted cancer cells’ migratory ability and drug resistance, and stimulation with recombinant HMGB1 further enhanced these promoting effects, while administration of anti-HMGB1 neutralizing antibody suppressed these effects. On the other hand, these inhibitory effects were not observed in the absence of CAFs, suggestingHMGB1 has effect on CAFs, but not direct on cancer cells.
Conclusion: HMGB1 plays an important role in cancer progression and acquisition of therapeutic resistance by upregulating the CAFs’ proliferation and activity and could be a therapeutic target in NSCLC.
Citation Format: Tomohiro Habu, Keiichi Date, Ken Suzawa, Mao Yoshikawa, Masayoshi Ohki, Kazuma Iwata, Naoki Matsuda, Yin Min Thu, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka. The role of high mobility group box-1 protein (HMGB1) in the microenvironment of non-small cell lung 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 2502.
Abstract 2506: The influence of sex on the immune microenvironment in male and female breast cancer
Authors: Hargrove-Wiley Ebony , Fingleton Barbara 
Published: April 2023

Abstract
Even when accounting for multiple clinical parameters, male breast cancer patients have significantly lower survival rates than females. Males and females differ in their levels of sex hormones androgens and estrogens. These sex hormones have varying influences on immune cell populations, which in turn may affect disease progression. Thus, the sex of the patient and the levels of sex hormones are likely important for anticancer immunity. Here, we assessed the importance of sex hormone signaling in the immune cells (host) versus the tumor cells for defining the immune landscape associated with primary and metastatic tumors. We used flow cytometry to determine the immune profile of mammary tumors, spleens, and lungs, and histochemistry to evaluate metastasis in transgenic MMTV-PyMT and in mice orthotopically injected with sex-specific MMTV-PyMT-derived cell lines in male and female cohorts. In transgenic mice, males had greater proportions of CD4+ T-helper and total myeloid cells in all organs analyzed. The splenic and pulmonary immune profiles of tumor-bearing males were more similar to cancer-free littermates than in females. Interestingly, males trended towards increased metastatic colonization in the lungs. Sex-associated immune profiles differed between transgenic and orthotopic mice. In mice bearing male-derived R221a PyMT tumors, females had decreased intratumoral neutrophils and elevated natural killer cells with increased splenic B-cells in comparison to males. Overall, our data supports a sex-dependent immune response in mammary carcinoma that is, in part, regulated by the hormonal environment of the host. With emerging therapeutics targeting the tumor immune microenvironment, characterization of immune profiles is critical for optimizing their use in all breast cancer patients.
Citation Format: Ebony Hargrove-Wiley, Barbara Fingleton. The influence of sex on the immune microenvironment in male and female 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 2506.
Abstract 2555: 14-3-3 and Smad2/3 are key mediators of atypical-PKCs in neuroblastoma progression
Authors: Breedy Sloan , Ratnayake Wishrawana S. , Lajmi Luke , Hill Robert , Acevedo-Duncan Mildred 
Published: April 2023

Abstract
Neuroblastoma (NB) is a cancer that develops in the neuroblasts. It is the most common cancer in children under the age of 1 year, accounting for approximately 6% of all cancers. The prognosis of NB is linked to both age and degree of cell differentiation. This results in a range of survival rates for patients, with outcomes ranging from recurrence and mortality to high survival rates and tumor regression. Our previous work indicated that PKC-ι promotes cell proliferation in NB cells through the PKC-ι/Cdk7/Cdk2 cascade. We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and BE(2)-M17 cells: a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat). In the current study, we report the effects of aPKC inhibition on 14-3-3-centered signaling in NB progression. To this end we utilized various techniques such as western blotting, Flowcytometry, scratch assays and invasion assays. These assays were employed to assess the downstream implications of aPKCs and 14-3-3 attenuation on signaling pathways regulating proliferation, cell cycle regulation, apoptosis, and metastasis. Both compounds induced apoptosis and retarded the epithelial-mesenchymal transition (EMT) of NB cells. Proteins 14-3-3 and Smad2/3 acted as central regulators of aPKC-driven progression in BE(2)-C and BE(2)-M17 cells in relation to the Akt1/NF-κB and TGF-β pathways. We demonstrate the downstream effects of aPKC attenuation on aPKC phosphorylation, the Akt1/NF-κB pathway, the Cdk7/Cdk2 pathway and EMT in relation to 14-3-3 and Smad2/3. We have analyzed the expression of EMT markers including Vimentin, a mesenchymal marker that is a hallmark of cancer metastasis. Data indicates that aPKCs upregulate Akt1/NF-κB and TGF-β pathways in NB cells through an association with 14-3-3 and Smad2/3 that can be diminished by aPKC inhibitors. In summary, both inhibitors appear to be promising potential neuroblastoma therapeutics and merit further research.
Citation Format: Sloan Breedy, Wishrawana S. Ratnayake, Luke Lajmi, Robert Hill, Mildred Acevedo-Duncan. 14-3-3 and Smad2/3 are key mediators of atypical-PKCs in neuroblastoma progression [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 2555.
Abstract 2583: AKT2 as the determining factor for PTEN loss-induced liver malignancy
Authors: Tang Qi , He LIna , Chen Chien-Yu , Chopra Shefali , Stiles Bangyan L. 
Published: April 2023

Abstract
Liver malignancies consist of hepatocellular carcinoma (HCC) with the highest occurrence, intrahepatic cholangiocarcinoma (iCCA), and serval rare subtypes, which is the third lethal cause among all cancer types worldwide. PTEN is a well-known tumor suppressor gene, liver-specific loss of PTEN leads to the development of liver tumors from tumor-initiating cells (TICs). A mouse model that specifically mutant PTEN in hepatocytes (PM mice, PTENloxP/loxP; Alb-Cre+) has been used to mimic the natural progression of liver malignancy and study the mechanism of liver tumorigenesis. AKT, also known as protein kinase B, is a downstream kinase that is negatively regulated by PTEN. PTEN loss will unequivocally result in AKT phosphorylation and activation of the AKT pathway. In this study, we explored the role of AKT2, the most abundant liver isoform of AKT in the PTEN loss-driven liver malignancy by generating a new double mutant mouse model (DM mice, PTENloxP/loxP; AKT2loxP/loxP; Alb-Cre+). Our data demonstrated that only PM mice developed tumors starting from a 6-month age. A moderate reactive duct/oval cell accumulation phenotype is observed in the PM livers with Von Meyenbury complex (VMC) formation. And both HCC and iCCA phenotypes are observed following steatosis development in PM mice. AKT2 loss arrested tumor development at the pre-malignant stage. The DM mice also developed VMC condition with minimum steatosis starting from 9-month age and some of them manifest an advanced stage called polycystic liver disease. No tumors are observed in these mice up to 16 months of age. Our preliminary data showed that the deletion of AKT2 attenuated the accumulation of TICs marked by Sox9 suggesting a potential role of SOX9 in the regulation of PTEN-driven tumorigenesis. In summary, our result shows that AKT2 is a determining factor in PTEN loss-induced liver malignancy.
Citation Format: Qi Tang, LIna He, Chien-Yu Chen, Shefali Chopra, Bangyan L. Stiles. AKT2 as the determining factor for PTEN loss-induced liver malignancy [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 2583.
Abstract 2591: Role of Rab25 in Melanoma and its potential targeting
Authors: Kandel Samikshya , Rao Krishna 
Published: April 2023

Abstract
Background: RAB25 is a protein that belongs to the RAB11 subfamily located in the lq22 locus of chromosome and is ubiquitously expressed in cells of the gastrointestinal mucosa, ileum, and kidney. Its role in tumorigenesis is variable but is unclear in the case of melanoma progression. Our previous studies showed that loss of RAB25 has a special role in mediating the tumorigenic transformation of human mammary epithelial cells. Its loss particularly cooperated with mutant Ras isoforms to promote transformation in vitro. We are now examining the role of RAB25 in melanomas as melanomas exhibit a high rate of N-Ras mutations. We hypothesize that the presence of NRAS types of mutation and expression of RAB25 are mutually exclusive as RAB25 functions are a tumor suppressor to inhibit this mutation. Methods: Different NRAS mutant melanoma cell lines (SKMEL-2, SKMEL-28, WM1366 and WM266-4) were examined forRab25 expression through qRT-PCR and Western Blotting. The positive control was MCF cell lines and MDA-MB-231 was considered as negative control. Immunohistochemistry was done with biopsy proven melanoma tissue samples and normal adjacent tissue to observe the trend of Rab25 expression. Keratinocytes and fibroblasts in the tissue samples were considered as internal controls.Results: We found a significant decrease in Rab25 expression in NRAS mutant melanoma cell lines compared to Raf mutants and primary melanocytes. The reduction was prominent at both the RNA and protein level. RAB25 expression was also reduced in melanoma tumors as compared to surrounding tissue. Conclusion: RAB25 loss may indeed cooperate with NRAS mutation to promote transformation in melanomas. Further studies including overexpression experiment in the cell line model followed by migration assay, invasion assay, and in vivo nude mouse experiments will provide further confirmation of our hypothesis.
Citation Format: Samikshya Kandel, Krishna Rao. Role of Rab25 in Melanoma and its potential targeting [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 2591.
Abstract 2618: IQGAP3 regulates intra-cellular Ras signaling and intra-tumoral malignant cycles via TGFβ signaling
Authors: Shimura Mitsuhiro , SHUCHIN Pang , Matsuo Junichi , Chuang Linda Shyue , Ito Yoshiaki 
Published: April 2023

Abstract
Scaffold protein IQ motif-containing GTPase-activating protein 3 (IQGAP3; IQ3) is a member of the multifunctional IQGAP family. The interaction between IQ3 and Ras-ERK signaling has been reported, but how IQ3 regulates Ras-ERK signaling in malignancies is still unclear. The purpose of this study is to elucidate the role of IQ3 in coordinating diverse pathways, such as ERK-Ras and TGFβ in gastric cancer (GC).According to Stomach Adenocarcinoma of TCGA Pan-Cancer Atlas, the frequency of gene mutations is high in TP53 (60.1%), RTK-Ras (51.8%), and TGFβ pathways (36.4%). Gene Set Enrichment Analysis (GSEA) indicated that KRAS signaling was significantly downregulated after IQ3 knockdown (KD) in three GC cell lines (AGS, NUGC3, Hs746T). Ingenuity upstream regulator analysis (IPA) of RNA sequencing data revealed that TGFβ1, the top-ranked growth factor, is significantly inhibited after IQ3 KD. Immunoblot analysis showed that IQ3 KD led to suppression of TGFβ-induced phosphorylation of MEK/ERK in three GC cell lines, particularly NUGC3. While TGFβ treatment promoted invasion and migration in transwell migration assays, IQ3 KD significantly diminished TGFβ-mediated cell migration. In vivo, the size and volume of subcutaneous tumors from IQ3 KD NUGC3 cells were significantly smaller than that from Control (Ctrl) cells. According to RNA sequencing using bulk tumors, mouse stromal cells in Ctrl tumors showed significantly higher expression of acta2, fap, pdgfa, which are the markers of cancer-associated fibroblasts, than in IQ3 KD tumors. The TGFβ1 expression levels in the NUGC3 xenograft and mouse stromal cells harvested from Ctrl were significantly higher than that from IQ3 KD, respectively. Additionally, digital spatial profiler (DSP) GeoMx evaluation of the intra-tumoral expressions from the human xenograft and mouse stromal cells showed that the mouse stromal cells from Ctrl expressed significantly higher acta2 and tgfβ1 than that from IQ3 KD. Furthermore, metastasis assays via tail vein injection in vivo showed dramatically lesser lung metastases from IQ3 KD cells than that from Ctrl cells. This study shows that IQ3 KD suppressed Ras signaling and blocked upstream regulator TGFβ1 in vitro. The stromal cells in the IQ3 KD xenografts showed a reduced population of cancer-associated fibroblasts in vivo. Consequently, tumorigenesis and metastasis were strongly suppressed after IQ3 KD. IQ3 is thus a highly relevant therapy target in GC.
Citation Format: Mitsuhiro Shimura, Pang SHUCHIN, Junichi Matsuo, Linda Shyue Chuang, Yoshiaki Ito. IQGAP3 regulates intra-cellular Ras signaling and intra-tumoral malignant cycles via TGFβ signaling [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 2618.
Abstract 262: Heat Map Analysis, a new integrated pathway scoring system for cancer genome profiling
Authors: Nakashima Chiho , Shiotsu Yukimasa , Harada Yohei , Katsuya Hiroo , Ookuma Emi , Nishi Masanori , Sato Akemi , Nakamura Hideaki , Sueoka-Aragane Naoko 
Published: April 2023

Abstract
Background: Cancer genome profiling using next-generation sequencing (NGS) has become widespread. Multiple genetic abnormalities including variant of unknown significance (VUS) have been detected in various cancer types. However, there is a lack of an integrated analysis system capable of identifying relationships among multiple genetic abnormalities and weighting them appropriately. Here, we report heat map analysis, a new integrated pathway scoring system for cancer genome profiling.
Methods: In heat map analysis, approximately 180 cancer-related genes among 324 genes evaluated by FoundationOne CDxTM are scored based on gene annotation and variant allele fraction (VAF), and classified into 16 pathways. This system provides an overall picture of genetic abnormalities and easy recognition of abnormal pathways. To examine the usefulness of the heat map analysis, a retrospective observational study was conducted on 50 patients with solid tumors who underwent cancer genome profiling test at Saga University Hospital from June 2019 to February 2022. The primary end point was the presentation rate of pathways with significantly increased scores.
Results: A total of 749 genetic abnormalities including VUS were detected in 50 patients with 15 cancer types: 571 single nucleotide variants (SNVs), 156 copy number variants (CNVs), and 22 fusions. The median number of abnormalities detected was 11 (2-20) SNVs, 2 (0-23) CNVs, and 0 (0-4) fusions, respectively. Heat map analysis presented active pathways with significant score elevation in 42 cases (84%). The TP53 pathway was the most common, followed by the Receptor Tyrosine Kinase pathway, PIK3-AKT, RAS, and DNA repair-related pathways.
Conclusion: Heat map analysis could be a promising new method for integrated analysis using cancer genome profiling tests.
Citation Format: Chiho Nakashima, Yukimasa Shiotsu, Yohei Harada, Hiroo Katsuya, Emi Ookuma, Masanori Nishi, Akemi Sato, Hideaki Nakamura, Naoko Sueoka-Aragane. Heat Map Analysis, a new integrated pathway scoring system for cancer genome profiling [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 262.