bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1323: Peristalsis based modulation of colorectal cancer cells leads to changes in stemness and invasiveness in an organ on chip model
Authors: Shah Curran A. , Strelez Carly , Amzaleg Yonatan , Gunnarsson Einar B. , Foo Jasmine , Yu Min , Mumenthaler Shannon M. 
Published: April 2023

Abstract
Colorectal cancer (CRC) remains one of the deadliest cancers worldwide due to poor outcomes upon metastatic spread. Given the drastic impact on mortality, a better understanding of the CRC metastatic process could yield significant improvements to overall survival. Here, we investigate the influences of biomechanical forces on early metastatic spread (i.e., tumor cell intravasation events) in an organ-on-chip (OOC) model. Our microfluidic CRC OOC model consists of two channels separated by a porous membrane: a top channel representing normal and cancerous colon epithelial tissue, and a bottom channel consisting of endothelial cells in a tube-like structure representing the vasculature. Vacuum channels flank the sides of the model to apply forces in a cyclic manner to mimic peristalsis-like motions and provide further in vivo resemblance. In our prior work, we demonstrated that peristaltic forces promoted tumor cell invasion within the CRC OOC. Specifically using on-chip confocal imaging, we revealed that cyclic strain leads to an increase in the number of tumor cells capable of intravasating from the epithelial channel into the vascular channel. Additionally, we showed dynamic sensitivity of tumor cell invasion in response to intermittent stretching conditions, leading us to hypothesize mechanical stress-induced phenotypic switching. Therefore, using single-cell RNA sequencing, we investigated gene expression changes of tumor cells in the presence or absence of peristaltic forces and found alterations in stemness, adhesion and metabolism-related genes. Using median fluorescence intensity (MFI) from flow cytometry data, we have revealed differences in stem-like properties (e.g., CD44, CD133, LGR5) of tumor cells with and without the influence of peristaltic forces both prior to and after intravasation. Additionally, effluent-based analysis of the OOC has shown cytokine and metabolism changes due to peristaltic forces. Ongoing work involves using flow cytometry to further quantify changes in adhesion and metabolism as well further validation in patient derived organoids-on-a-chip. Taken together, OOCs provide a physiologically relevant model to study early CRC intravasation events, revealing phenotypic changes in response to mechanical stimuli that influence tumor cell stemness and invasiveness.
Citation Format: Curran A. Shah, Carly Strelez, Yonatan Amzaleg, Einar B. Gunnarsson, Jasmine Foo, Min Yu, Shannon M. Mumenthaler. Peristalsis based modulation of colorectal cancer cells leads to changes in stemness and invasiveness in an organ on chip model [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 1323.
Abstract 1345: p21 (WAF1/CIP1) drives a secretory phenotype in senescent fibroblasts and promotes bystander cancer cell growth in the tumor microenvironment
Authors: Zhang Shengliang , Huntington Kelsey E. , Zhou Lanlan , El-Deiry Wafik S. 
Published: April 2023

Abstract
Cancer associated fibroblasts (CAF) are major stromal cells in the tumor microenvironment (TME) and support cancer cell growth. Chemotherapy can induce CAF senescence in which p21 (the cyclin-dependent kinase inhibitor) permanently arrests the cell cycle. Cellular senescence and its associated secretory phenotype (SASP) can promote cancer progression and lead to drug resistance. We explored molecular mechanisms of p21 in the cellular communication between cancer and senescent fibroblasts. We induced fibroblast cell senescence by treatment with etoposide. Cellular senescence was confirmed by cytokine profiling, beta-gal staining and high p21 expression. To evaluate the role of p21 in the SASP of senescent fibroblasts, we transiently knocked down p21 expression in senescent fibroblast cells using siRNA. SA-beta-gal staining showed a strong beta-gal expression around nuclei in the senescent fibroblast cells with the knockdown of p21, which is the same as it was in the cells with siRNA control. Further cytokine profiling showed two panels of SASP upon p21 knockdown in senescent cells: 1) decrease of cytokines such as CCL2 and IL8 and 2) increase of cytokines such TNF-alpha correlated to the knockdown of p21 in the senescent cells. These results suggest that p21 drives a SASP in senescent fibroblast cells, in addition to its function in cell cycle arrest. We examined the effect of the p21-driven SASP in senescent fibroblasts on bystander cancer cell growth in the TME. Our co-culture system showed knockdown of p21 in senescent fibroblasts suppressed bystander cancer cell growth. We found that knockdown of TNF partially blocked the antiproliferation effect of p21-knockdown on bystander cancer cells. Our results suggest that senescent fibroblasts support bystander cancer cell growth via a p21-driven SASP in the TME and provides a new strategy for targeting p21-driven SASP in the TME for cancer therapy.
Citation Format: Shengliang Zhang, Kelsey E. Huntington, Lanlan Zhou, Wafik S. El-Deiry. p21 (WAF1/CIP1) drives a secretory phenotype in senescent fibroblasts and promotes bystander cancer cell growth in the 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 1345.
Abstract 1425: TTFields reduce sensitivity in glioblastoma is associated with the functional expression of the chloride intracellular channel 1 and with voltage dependent sodium channel
Authors: Castiglione Stefania , Cannavale Gaetano , Cianci Francesca , Verduci Ivan , Biella Chiara , Mercurio Chiara , Pastorelli Emanuela , Lupi Monica , Paracchini Laura , Mannarino Laura , Krex Dietmar , Brandalise Federico , Mazzanti Michele 
Published: April 2023

Abstract
Glioblastoma (GBM) is the most aggressive type of brain tumor, and existing treatments are inadequate at preventing recurrence. Tumor Treating Fields (TTFields) is a novel treatment that has been proven to extend patients' lives during the previous two decades. The antitumoral impact of TTFields involve different mechanism and is an optional add-on to standard temozolomide maintenance. Although TTFields therapy slows tumor progression initially, it does not prevent tumor relapse in most patients. We subjected patient-derived GBM primary cultures to continuous TTFields stimulation to mimic the GBM standard of care and examine the molecular pathways behind GBM sensitivity to TTFields treatment. TTFields initially limit cellular growth well. However, even under constant TTFields administration, the remaining cells regain their ability to proliferate at their own rate in long-term trials. Prolonged treatment with TTFields increases the expression of many stemness markers as well as the overexpression of different genes involved in cell cycle progression. There is also a rise in membrane ionic conductance activity. After sustained exposure to TTFields, sodium, potassium, and chloride channels are functionally increased. This influences the properties of tumor cells. Increased sodium channel functional activity, for example, promotes membrane potential depolarization. Furthermore, earlier research has shown that the membrane form of the chloride intracellular channel 1 (tmCLIC1) is important in the development of GBM. In patient-derived GBM cells exposed to TTFields, tmCLIC1 is significantly concentrated, and membrane depolarization improves its function. The evaluation of GBM tissues obtained from many patients who were treated with TTFields validates the in vitro tumor relapse model.Our findings imply that the process by which GBM cells develop a decrease in sensitivity to TTFields correlates with an increase in stemness markers and an increase in ionic channel functional expression.
Citation Format: Stefania Castiglione, Gaetano Cannavale, Francesca Cianci, Ivan Verduci, Chiara Biella, Chiara Mercurio, Emanuela Pastorelli, Monica Lupi, Laura Paracchini, Laura Mannarino, Dietmar Krex, Federico Brandalise, Michele Mazzanti. TTFields reduce sensitivity in glioblastoma is associated with the functional expression of the chloride intracellular channel 1 and with voltage dependent sodium channel [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 1425.
Abstract 1464: Exosomal delivery of tumor suppressive microRNA-7 as a novel approach to regulating cervical cancer cell growth
Authors: McWilliams Gabriella , Roy Molly , Cortes Daniel Bilbao , Yang Yu-Ping , Daunert Sylvia , Deo Sapna 
Published: April 2023

Abstract
There is an unmet need for more safe, effective, targeted therapy in cervical cancer which this study seeks to meet through the use of exosomes and miRNA. Although cervical cancer is the fourth most prevalent female cancer worldwide, it currently has sparce options for treatment. Early-stage tumors are often surgically removed, while later stage cancers are treated with traditional radiation and chemotherapy methods, which have limited efficacy. Thus, to bridge this gap, we propose the use of exosomes, which are naturally occurring cell-derived vesicles, in combination with microRNA-7 (miR-7), a known tumor-suppressive microRNA, as a potential treatment for cervical cancer. We first transfected adipocyte-derived stem cells (ADSC) with miR-7. ADSC produce exosomes that are immune-compatible, have a long half-life, and have an especially low toxicity, making them a versatile nanocarrier. We collected the conditioned media produced by the ADSC, from which we isolated the miR-7-containing exosomes. The collected exosomes were confirmed to contain the appropriate miRNA by qPCR and applied to HeLa cells, and cellular response and gene expression changes were analyzed via qPCR. Functional assays including proliferation and migration were also performed to analyze the effect of exosome treatment on cell function. Controls for this study included a parallel ADSC transfection with a non-coding, scramble miRNA, as well as HeLa cells treated with exosomes from non-transfected ADSC. Our studies demonstrate that transfection of ADSC with miR-7 produces exosomes with significantly increased levels of this regulatory miRNA, and that these exosomes can specifically deliver their cargo and effectively downregulate the target gene Epidermal Growth Factor Receptor (EGFR), which is involved in tumor progression in cervical cancer. Additionally, we show that these miR-7-containing exosomes decrease proliferation and migration of HeLa cells in our in vitro functional analysis. Ultimately, this technology provides an alternative treatment option that will improve clinical outcomes of women who are affected by cervical cancer.
Citation Format: Gabriella McWilliams, Molly Roy, Daniel Bilbao Cortes, Yu-Ping Yang, Sylvia Daunert, Sapna Deo. Exosomal delivery of tumor suppressive microRNA-7 as a novel approach to regulating cervical cancer cell growth [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 1464.
Abstract 16: The role of innate and adaptive immunity in the sex bias of LKB1-mutant lung adenocarcinoma
Authors: Fan Yijian , Monterroza Lenore , Jin Rui , Liu Xiuju , Selvaraj Periasamy , Tirouvanziam Rabindra , Zhou Wei 
Published: April 2023

Abstract
The tumor suppressor gene, LKB1/STK11, is one of the most frequently mutated genes in lung adenocarcinoma (LUAD). A multidimensional analysis of TCGA-LUAD patient data indicates that LKB1 mutation is one of the top sex-biased mutations, being more frequent in males than in females. A similar pattern was observed in other large LUAD cohorts. However, the underlying mechanism was unknown, partially due to a lack of an appropriate mouse model to represent this clinical phenomenon. We previously demonstrated a similar sex bias in a Lenti-Cre-induced KRAS/LKB1-mutant genetically engineered mouse model (GEMM) and a syngeneic tail-vein injection model. Here, we demonstrated that intravenous injection of the same cell line in male and female NOD scid gamma (NSG) mice does not exhibit a sex-bias pattern of lung metastasis formation (P=0.9746). However, sex bias was observed when we used CB17-SCID mice. This data suggest that innate immunity is partly responsible for the sex bias of LKB1-mutant lung cancer formation. We also characterized immune cells from the lung with LKB1-mutant tumors. Monocytes/macrophages decreased from 23% to 19%, and neutrophils increased from 15% to 19%. Lymphoid cells remained the same at 58%, and T-cells account for 34% of all CD45+ cells. Interestingly, T-cells doubled to account for 81% of all CD45+ cells from the lung in female mice resistant to the formation of lung metastasis. Our data indicated that both the innate and the adaptive immunity are responsible for eliminating LKB1-mutant lung adenocarcinoma in female mice.
Citation Format: Yijian Fan, Lenore Monterroza, Rui Jin, Xiuju Liu, Periasamy Selvaraj, Rabindra Tirouvanziam, Wei Zhou. The role of innate and adaptive immunity in the sex bias of LKB1-mutant lung adenocarcinoma [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 16.
Abstract 1653: Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation non-small cell lung cancer
Authors: Castro Maria del Carmen Chacon , Berisha Eranda , Salamat Narges , Zhang Li 
Published: April 2023

Abstract
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. KRAS mutations and LKB1 inactivation commonly occur in NSCLC and are associated with poor prognosis. Several studies enunciate the role of the immune system in lung cancer progression through cancer cells' ability to escape immune surveillance. Therefore, understanding NSCLC progression requires the examination of the molecular mechanisms behind this process. The importance of oxidative phosphorylation (OXPHOS) and mitochondrial metabolism in lung cancer has been continuously emphasized; OXPHOS and mitochondrial biogenesis markers predict low survival in NSCLC patients. Additionally, heme is an essential molecule in the OXPHOS pathway, and previous studies have shown that heme sequestration using heme sequestering protein 2 (HeSP2) arrests tumor progression. HeSP2 can potentially normalize the tumor immune microenvironment (TIME) via multiple mechanisms including the normalization of vessels which may promote immune cell infiltration, the reduction of hypoxia which may promote antitumor immune function, and the reduction of heme levels which potentially decreases the production of immunosuppressive enzymes requiring heme as a cofactor. In this study, control and HeSP2-treated tumors generated from a genetically engineered mouse model LSL-KrasG12D LKB1-/- (LSL-KRASG12D; LKBloxP/loxP; LSL-Luciferase (KLLuc) infected with AdenoCre virus and sacrificed at 10 months were used for immunohistochemical analysis. We examined immune markers under HeSP2 treatment to determine the immune system response to heme targeting and its effects on tumor progression. Results demonstrated that HeSP2 can modulate the tumor immune microenvironment increasing the levels of immune markers, which suggests that heme targeting can potentiate immunotherapy efficacy in lung cancer treatment.
Citation Format: Maria del Carmen Chacon Castro, Eranda Berisha, Narges Salamat, Li Zhang. Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation 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 1653.
Abstract 1676: PRMT5 regulates the chemoresistnace of ovarian cancer cells
Authors: Do Yen Thi , Kim Jin Young , Lee Seungmee , Vo Tam Thuy Lu , Pham Thi Tuyet Mai , Ha Eunyoung , Cho Chi-Heum , Shin So-Jin , Seo Ji Hae 
Published: April 2023

Abstract
Ovarian cancer resistance to chemotherapy accounts for the most therapeutic challenge, leading to the high mortality rate of gynecological cancer worldwide. Meanwhile, cancer stem cells (CSCs) are identified as key features in regulating ovarian chemoresistant cancer. In this study, we first found that PRMT5 was upregulated in paclitaxel (PTX)-resistant ovarian cancer cells compared with non-resistant cancer cells. Then, we determined the oncogenic role of PRMT5 in chemoresistant ovarian cancer by using its potent and selective inhibitor, GSK3326595. Disruption of PRMT5 activity by GSK3326595 or depletion of PRMT5 in PTX-resistant ovarian cancer cells restored the sensitivity to chemotherapeutic drug via triggering cell apoptosis. Then, we also validated that inhibition of PRMT5 decreased cell migration ability through the transition of motile mesenchymal phenotypes into epithelial characteristics. Moreover, PRMT5 inhibitor significantly decreased the number of sphere formation and attenuated the stem cell-like properties in PTX-resistant ovarian cancer cells. Therefore, our study suggests that PRMT5 is a powerful target to overcome resistance to conventional chemotherapy for the treatment strategy in ovarian cancer.
Citation Format: Yen Thi Do, Jin Young Kim, Seungmee Lee, Tam Thuy Lu Vo, Thi Tuyet Mai Pham, Eunyoung Ha, Chi-Heum Cho, So-Jin Shin, Ji Hae Seo. PRMT5 regulates the chemoresistnace of ovarian cancer 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 1676.
Abstract 1682: Bridging gaps in treatment resistance 2D models with the incorporation of 3D models
Authors: Gadde Manasa , Schwabe Elizabeth , Mulam Kshithija , Hill Lindsay , Bulow Christopher 
Published: April 2023

Abstract
Introduction: 3D cellular models have become of increasing interest in anti-cancer drug discovery as a bridge between clinical models and traditional in vitro methods. An important component of this research is the comparison of drug-to-cell interactions and morphological characteristics between cells in mono-layer culture and the cells in 3D spheroids.
Materials and Methods:The ResCu system is a novel long term, physiologically relevant culture system that avoids the need for passaging. It propagates tumoroids in a microenvironment that resembleshuman tissue. Cells with KRAS G12C mutation were cultured in the ResCu system for three months, during which they were constantly exposed to G12C inhibitors (G12Ci) for the evolution of resistant cell populations. Cells were also cultured in traditional 2D cultures and exposed to G12Ci. Transcriptomics was performed to determine resistant networks and identify different resistant subclones in each group.
Results: We applied the ResCu system to model clinical resistance. We captured 95% of clinically identified on-target and pathway bypass resistance changes, and in the 2D system, only a fraction of mechanisms were discovered. Additionally, we noticed certain cell populations could tolerate higher doses of the G12Ci after resistance evolution in ResCu compared to 2D. A few had similar responses suggesting that the origin of the cell line plays a role in the microenvironment's impact on cellular response.
Conclusion: By comparatively analyzing resistance evolution data for KRAS G12Ci in traditional 2D and ResCu, we were able to collect physiologically relevant data that can more confidently be applied to clinical studies than mono-layer cell culture data alone.
Citation Format: Manasa Gadde, Elizabeth Schwabe, Kshithija Mulam, Lindsay Hill, Christopher Bulow. Bridging gaps in treatment resistance 2D models with the incorporation of 3D 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 1682.
Abstract 1736: Role of brain fatty acid binding protein in glioblastoma microtube formation
Authors: Choi Won-Shik , Mak Caitlin , Githaka John M. , Glubrecht Darryl , Jeon Pureunsol , Godbout Roseline 
Published: April 2023

Abstract
Glioblastoma (GBM) is a highly infiltrative brain cancer with a dismal prognosis. Conventional treatment using surgery, radiation therapy, and chemotherapy (usually temozolomide) invariably fails. GBM microtubes, which are ultra-long membrane-enclosed protrusions, are associated with therapy resistance and are believed to function by forming multicellular communication networks. Growth-associated protein GAP43 is an important protein for GBM microtube formation.
Although lipids are important for GBM progression, the roles of lipid chaperones such as the fatty acid-binding proteins (FABPs) are not well understood. FABPs are involved in fatty acid uptake from the microenvironment and intracellular transport of fatty acids. Brain fatty acid binding protein (FABP7) is highly expressed and is associated with a poor prognosis in GBM. FABP7 levels increase in therapy-resistant GBM cells, suggesting that FABP7 provides a cancer cell survival advantage when GBMs are treated with conventional therapy. FABP7 has a high affinity for polyunsaturated fatty acids (PUFAs), such as omega-3 docosahexaenoic acid (DHA) and omega-6 arachidonic acid (AA), both of which are abundant in brain. Previous studies have shown a correlation between FABP7 expression, increased neural stem cell properties, and increased cell migration in glioblastoma cells, especially when FABP7 is bound to AA. We have recently found that FABP7 is expressed in microtubes, leading to the hypothesis that FABP7 along with its fatty acid ligands can be transported to sites distant from the main tumor mass through these connecting tubes. We are studying the mechanism of action of FABP7 in microtubes by: (i) examining the effect of DHA and AA, as well as FABP7 inhibition on microtube formation and cell migration, and (ii) using both neurosphere cultures and animal models of glioblastoma to investigate the pathways that are activated by FABP7. Our results to date support the use of FABP7 inhibitors to sensitize therapy-resistant cells as part of the standard-of-care for the treatment of GBM patients.
Citation Format: Won-Shik Choi, Caitlin Mak, John M. Githaka, Darryl Glubrecht, Pureunsol Jeon, Roseline Godbout. Role of brain fatty acid binding protein in glioblastoma microtube formation [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 1736.