bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2638: Developing 3d hydrogel model for patient-derived organoids of metastatic colorectal cancer
Authors: Wei He , Karelehto Eveliina , Dubbin Karen , Sebastian Aimy , Warren Robert , Moya Monica , Loots Gaby , Wheeler Elizabeth , Coleman Matthew 
Published: July 2021

Abstract
The advances in the development of preclinical models for various cancers have tremendously helped study of the biology and genetics of human cancers as well as for development of therapeutics. Recently, patient-derived organoids (PDOs) have emerged as a robust preclinical platform that can provide insight into the patient specific genetic mechanisms, cancer progression and drug susceptibility. We have developed a novel PDO platform by embedding patient-derived organoids in a 3D hydrogel suspension culture. Our previous studies have shown that, when cultured in hydrogel, spheroids derived from cancer cell lines demonstrated upregulated gene expression signatures in relation to migration and angiogenesis compared to cultures in media, suggesting a more hypoxic, nutrient deficient environment. Given that hypoxia and nutrient deficiency are important feathers of solid tumors, the hydrogel environment could provide a good platform for in vitro study of tumor development and resistance to treatment. In the current study, we embedded PDOs derived from liver metastasis of colorectal cancer into the 3D suspension hydrogel culture. The PDOs adapted well in the hydrogel gel environment. We assessed the response of PDOs in hydrogel to anticancer agents, and compared that to those cultured in media. The PDOs cultured in hydrogel showed significantly elevated resistance to the treatments. The IC50s of chemotherapeutic drugs 5-fluorouracil and oxaliplatin are increased by ~5-10 fold when cultured in hydrogel compared to those in media. Further studies through RNAseq analysis revealed differentially activated signaling pathways. In particular, the levels of the CXC ligand family chemokines are significantly up-regulated in the PDOs cultured in the hydrogel. The CXC ligand family chemokines are important immune stimulants that are known to play key role in the chemotaxis and tumor recruitment of immune cells including neutrophil, T-cell and B-cells. Interestingly, the elevated levels of CXC-ligands have been shown to relate to resistance of colorectal cancer against drug treatment such as 5-fluorouracil. Our hydrogel model could help elucidate the mechanisms behind such resistance. Future study will focus on evaluating how well the hydrogel PDO platform can recapitulate tumor microenvironment and its potential in screening for personalized medicine.
Citation Format: He Wei, Eveliina Karelehto, Karen Dubbin, Aimy Sebastian, Robert Warren, Monica Moya, Gaby Loots, Elizabeth Wheeler, Matthew Coleman. Developing 3d hydrogel model for patient-derived organoids of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2638.
Abstract 2646: Implication of different anti-angiogenic treatments on in vitro vascular tube formation in triple negative inflammatory breast cancer cell lines
Authors: Caceres Sara , Alonso-Diez Angela , Crespo Belen , ESpinosa Eduardo , Madaruiaga Beatriz , Silvan Gema , Illera Maria J. , Illera Juan Carlos 
Published: July 2021

Abstract
Introduction: Inflammatory breast cancer (IBC) is the most aggressive breast cancer in women and female dogs (IMC, Inflammatory mammary cancer) with a poor prognosis. Both IBC and IMC are highly angiogenic, lymphangiogenic and lymphangioinvasive. The aim of this study was to evaluate the effect of different anti-angiogenic treatments in the in vitro formation of vascular-like structures as well as cell secretion of different angiogenic and lymphangiogenic factors (VEGFA, VEGFC, VEGFD) and interleukin-8 (IL-8) in culture media.
Material and Methods: For in vitro tube formation assay, culture human SUM149 cells and canine IPC-366 cells were divided into a control group, treated with DMSO, and 4 experimental groups treated with 1.5 μM of VEGF, SU5416 (anti-VEGFR, VEGF B20-4.1.1 (anti-VEGF) and celecoxib (NSAID), respectively, for 4 h at 37ºC in 5% CO2 conditions. Images were taken every 2 hours. Incomplete networks were excluded, and vessel-like tube structures were counted using the Image J Angiogenesis Analyzer software. Data were represented as average percentage relative to control ± SD.
Results: VEGF and celecoxib treatment significantly augmented the formation of vascular-like tube structures respect to control group in both cell lines. However, VEGF B20-4.1.1 and SU5416 decreased the formation of vascular-like tube structures but not significantly. Conditionate media of IPC-366 and SUM149-treated cells with VEGF had significantly decreased VEGFA levels. In contrast, celecoxib treatment, reduced VEGFD levels and increased VEGFC in both cell lines. VEGF B20-4.1.1 addition increased VEGFA levels in culture media and SU5416 significantly diminished VEGFD concentrations. No significant differences in IL-8 levels were found for any treatment.
Conclusions: Increased VEGFC levels after celecoxib treatment suggest a switch from a proangiogenic state toward a lymphangiogenic state. Neutralization of VEGF by VEGF B20-4.1.1 enhances the secretion of VEGFA and VEGFC by tumor cells inhibiting angiogenesis and lymphangenesis.
Citation Format: Sara Caceres, Angela Alonso-Diez, Belen Crespo, Eduardo ESpinosa, Beatriz Madaruiaga, Gema Silvan, Maria J. Illera, Juan Carlos Illera. Implication of different anti-angiogenic treatments on in vitro vascular tube formation in triple negative inflammatory breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2646.
Abstract 2663: Determining the role of altered redox metabolism in lung tumorigenesis
Authors: Camai Alex 
Published: July 2021

Abstract
The purpose of this study is to determine the pathways by which short-term cigarette smoke exposure induces expression of the cystine-glutamate antiporter xCT (SLC7A11) and its downstream implications in carcinogenesis. BEAS-2B lung epithelial cells and their tumorigenic counterpart, B39-TL cells, were exposed to cigarette smoke condensate (CSC) for 3-15 days. Cells were also exposed to a range of inhibitors. Erastin and buthionine sulfoximine (BSO) are inhibitors of various steps in the glutathione synthesis pathway, found to be hyperactive in xCT-overexpressing cells. Cells were also exposed to the drug mito-2-hydroxybenzoic acid (mito-2-HOBA), which scavenges isolevuglandins, reactive γ-ketoaldehydes implicated in oxidative stress and carcinogenesis. Expression of xCT and related proteins was measured using Western blotting. Glutathione levels were detected using the luciferase-based GSH-Glo assay (Promega). Oxidative stress was detected using dihydroethidium (DHE) fluorescence. It was found that CSC exposure significantly increased the expression of xCT and SLC1A5, a transporter that potentially works in synergy with xCT, and that tumorigenic B39-TL cells had significantly increased xCT and SLC1A5 expression compared to BEAS-2B cells. In addition, BEAS-2B cells exposed to CSC and a glutathione synthesis inhibitor such as erastin or BSO showed faster depletion of glutathione than cells treated with only inhibitor. Finally, it was found that BEAS-2B cells treated for 3 days with CSC did not show increased levels of superoxide compared to control cells. However, cells treated with CSC and mito-2-HOBA together showed significantly increased superoxide. These data suggest that CSC induces an antioxidant response which is ablated by mito-2-HOBA. This antioxidant response seems to at least partially rely on glutathione synthesis fueled by xCT, as evidenced by inhibitor studies. The response also seems to be activated by isolevuglandins, because removing these molecules significantly raises oxidative stress. The mechanistic link between CSC exposure, isolevuglandin generation, and xCT/glutathione induction will be clarified in further experiments.
Citation Format: Alex Camai. Determining the role of altered redox metabolism in lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2663.
Abstract 2672: Semaphorin 7a promotes cellular transformation via activation of pro-survival signaling
Authors: Rutherford Taylor R. , Lyons Traci R. 
Published: July 2021

Abstract
We seek to further our understanding of normal mammary gland biology and determine how pregnancy associated changes in the mammary gland contribute to development of breast cancers. Though pregnancy is well-known to provide a protective effect against breast cancer risk, all women who give birth experience a transient increase in breast cancer risk following each pregnancy. The magnitude and length of this elevated risk is largely determined by a woman's age at first birth and for women over 30 at the time of first pregnancy the protective effect likely never occurs. Postpartum breast cancers (PPBC), defined as breast cancers diagnosed within 10 years of last childbirth, are more than twice as likely to become metastatic and result in death. This devastating diagnosis affects ~12,000 women annually. In 2006, for the first time, the number of women having children in their 30s was greater than the number under 25. Thus, PPBC cases are rising. We have shown that tumor cells and normal adjacent mammary epithelial cells (MECs) in PPBC patients exhibit high levels of semaphorin 7a (SEMA7A) protein expression, and SEMA7A expressing tumors are more metastatic. Thus, we believe that understanding the mechanisms underlying SEMA7A signaling in the mammary gland will lead to novel insights into aggressive PPBC. Our recent data reveal that SEMA7A+ MECs are evident during lactation, decreased during the reversible phase of postpartum mammary gland involution, and peak at involution day three, suggesting that SEMA7A promotes survival cell survival during postpartum glandular regression. Consistent with our hypothesis, we reveal that mammary luminal progenitor cells are decreased in SEMA7A knockout mice and SEMA7A promotes cell survival in cultured MECs. Interestingly, a portion of our SEMA7A KO dams exhibit evidence of lactation failure, suggestive of precocious involution. Thus, we propose that SEMA7A activates pro-survival signaling in MECs during lactation and involution. In support of this we show that exogenous SEMA7A activates pro-survival kinase AKT in a β1-integrin dependent manner. Additionally, we show that sustained signaling by SEMA7A leads to cellular transformation in vivo and in vitro and that SEMA7A KO mice crossed to MMTV-PyMT mice exhibit longer latency, ~250 days compared to 50-100 in controls. Since we also observe that SEMA7A levels in blood correlate with SEMA7A levels in breast cancer patient tumors, our results suggest that SEMA7A is a driver of tumorigenesis that could be safely monitored in postpartum women.
Citation Format: Taylor R. Rutherford, Traci R. Lyons. Semaphorin 7a promotes cellular transformation via activation of pro-survival signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2672.
Abstract 2682: STK11-loss-dependent YAP1-mediated transcriptional activation promotes immune evasion in KRAS-driven lung adenocarcinoma
Authors: Seward David Joseph 
Published: July 2021

Abstract
Why Serine Threonine Kinase 11 (STK11) loss of function (LoF) correlates with anti-PD1 therapy resistance in the context of KRAS-driven lung adenocarcinomas remains unclear and represents a critical outstanding question in the field. To address this, we knocked out STK11 in KRAS-driven human lung adenocarcinoma cell lines and performed RNAseq to identify STK11-loss-dependent differentially expressed genes. Subsequent pathway enrichment analyses implied activation of the HIPPO/YAP1 signaling network occurs in the absence of STK11. Based on work linking YAP1 with transcriptional regulation of cytokine-mediated inflammation and immune-evasion in colorectal cancer and gastric cancer, we wondered whether YAP1 activation might impact anti-PD1 therapy response in KRAS-driven lung cancers lacking STK11. To evaluate this possibility, we applied a YAP1 transcriptional signature to the differentially expressed genes and performed gene set enrichment analysis (GSEA) revealing a strong positive correlation between STK11 LoF and upregulation of YAP1 target genes, most notably induction of IL-6, IL-8 and IL-32. To validate YAP1-mediated transcriptional activation is downstream of STK11 loss, we reasoned we could rescue STK11-loss-dependent YAP1-mediated cytokine induction by genetic disruption of YAP1, or pharmacologic inhibition of YAP1 with verteporfin. STK11/YAP1 double knock-out cell lines express significantly less IL-6, IL-8 and IL-32 compared with STK11 KO lines. Further, inhibition of YAP1 with verteporfin phenocopied YAP1 genetic disruption in these cell lines, changes mirrored at the level of secreted protein. Finally, we demonstrate YAP1 chromatin occupancy is STK11-dependent. Together these data link STK11 LoF with YAP1-mediated transcriptional activation, specifically the upregulation of immune-evasion promoting cytokines including IL-6, IL-8 and IL-32. We posit these STK11-loss-dependent YAP1-mediated tumor-intrinsic changes could result in anti-PD1 therapy resistance and immune-evasion by promoting recruitment of myeloid-derived suppressor cells, neutrophils and T-regulatory cells to the tumor microenvironment. Further, our results indicate that YAP1 antagonism may represent a valid therapeutic approach to circumvent STK11-loss-dependent transcriptional changes and potentially restore sensitivity to anti-PD1 therapy. Elucidating the mechanism(s) linking STK11 with YAP1 transcriptional activation and evaluating the potential for beneficial therapeutic intervention remains the focus of our continuing work.
Citation Format: David Joseph Seward. STK11-loss-dependent YAP1-mediated transcriptional activation promotes immune evasion in KRAS-driven lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2682.
Abstract 2738: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates tumor immune evasion in cholangiocarcinoma
Authors: Loeuillard Emilien , Yang Jingchun , Dong Haidong , Gores Gregory J. , Ilyas Sumera 
Published: July 2021

Abstract
Background and Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is predominantly expressed on immune cells. Although TRAIL biology has garnered considerable interest as a potential anti-cancer strategy, TR agonists have had very limited anti-cancer activity in humans. TRAIL signaling in T cells may also potentially provide an immune checkpoint function as it can inhibit T cell activation and proliferation by interfering with T cell receptor signaling. However, this potential immune checkpoint function of TRAIL has not been examined in cancer biology. Cholangiocarcinoma (CCA), a malignancy of the bile ducts, provides a model to examine the potential immune checkpoint function of TRAIL.
Methods: Using a syngeneic, orthotopic murine model of CCA (PMID: 29464042), murine CCA cells (SB cells) that express both TRAIL and TRAIL receptor (TR) were implanted into livers of WT C57BL/6J and Tr−/− mice. Hence, in this model the host immune cells express TRAIL but not the receptor; they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to potential TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed and tumor and immune characterization (via flow cytometry) was conducted.
Results: Implantation of SB cells into Tr−/− mice result in a significant reduction in tumor volumes compared to WT mice. Tumor-bearing Tr−/− mice had a significant infiltration of cytotoxic T lymphocytes (CTLs) (CD45+CD3+CD8+CD11a+) and enhanced CTL effector function. Moreover, Tr−/− mice tumors had a significant decrease in granulocytic and monocytic myeloid-derived suppressor cell (MDSCs) as well as tumor-associated macrophages (TAMs) (CD45+F4/80+CD11b+CD206+) compared to WT mice tumors.
Conclusion: Using a unique syngeneic orthotopic implantation model of murine CCA, we demonstrate that CCA cells expressing TRAIL in a mouse genetically deficient for TR exhibit reduced tumor volumes enhanced CTL infiltration and function, and reduced MDSC and TAM infiltration into the tumors. These data suggest that TRAIL has a potential immune checkpoint function, and targeting TRAIL signaling with consequent augmentation of CTL function maybe a promising therapeutic approach in human cancers.
Citation Format: Emilien Loeuillard, Jingchun Yang, Haidong Dong, Gregory J. Gores, Sumera Ilyas. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates tumor immune evasion in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2738.
Abstract 2774: Establishment of in vitro human T cell exhaustion model to enable high throughput target validation for T cell phenotype restoring
Authors: Wang Tienan , Zhang Jie , Wang Zhijun , Li Yingnian , Shi Linghong , Lin Qing 
Published: July 2021

Abstract
Immune surveillance was defined as three phases during tumorigenesis: elimination, equilibrium and escape. During the escape phase, cancer cell acquire a series of mechanism to evade the recognition by immune system, including reduce the function of antigen presenting cells, recruitment of suppressive cells, induce T cell exhaustion etc. The exhaustion phenotype of T cells were frequently observed in various cancer types and exhibit as reduced effector cytokine production, decrease in proliferation and cytolytic activity and overexpression of inhibitory receptors. Restoring T cell exhaustion phenotype become the inspiring filed for cancer therapy and PD1 blocking antibody further encouraging the concept of intervention on T cell exhausted phenotype in tumor microenvironment. In this study, we utilize human primary T cell to establish the in vitro model of T cell exhaustion. Subsequent functional study reveal that the induced exhausted T cell (Tex) display significantly weak response towards dendritic cell activation compare to normal T cell (Tnorm). We take advantage of the model to validate the function of PD1 antibody and demonstrate that blocking of PD1 could partially restore the function of Tex, which suggesting there are still other regulators involved in mediating T cell exhaustion beyond PD1.
Citation Format: Tienan Wang, Jie Zhang, Zhijun Wang, Yingnian Li, Linghong Shi, Qing Lin. Establishment of in vitro human T cell exhaustion model to enable high throughput target validation for T cell phenotype restoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2774.
Abstract 2890: Mitotic inhibitors suppresses tumor formation and metastasis of triple negative breast cancer (TNBC)
Authors: Song Chaeun , Lee SeungBaek 
Published: July 2021

Abstract
Cell division cycle 20 (Cdc20) is the main activator of the anaphase-promoting complex (APC/C) and is essential in mitosis regulation. Recently, several papers reported that Cdc20 is highly conserved in various human cancers such as pancreatic, prostate, and lung cancers yet its relation to breast cancer is unclear. Here, we found that Cdc20 gene was highly expressed in three different TNBC cell lines among the mitosis regulator genes through the National Center for Biotechnology Information (NCBI). High Cdc20 level is positively correlated with metastasis-free patient survival and relapse-free patient survival in breast cancer patient database. We also checked that Cdc20 is highly conserved in all TNBC cell lines compared to other subtypes of breast cancer cell lines and the knockdown of this gene decreased cell growth and invasion in TNBC. Furthermore, we investigated that the mitosis-related small molecule protein kinase inhibitors such as VX-680, ZM447439, BI2536, and apcin also inhibit tumor cell proliferation, migration, and invasion. In conclusion, Cdc20 has an important role in TNBC cell growth and metastasis. Cdc20 might serve as a potential marker of disease progression and as a principal potential therapeutic target. Also, mitosis-related protein kinase inhibitors are additional potential therapy to suppress cancer cell progression and invasion in TNBC effectively.
Citation Format: Chaeun Song, SeungBaek Lee. Mitotic inhibitors suppresses tumor formation and metastasis of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2890.