bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3035: Identifying potential druggable targets for synovial sarcoma using comparative RNA-seq analysis
Authors: Vasquez Yvonne A. , Pfeil Jacob , Mueller Letitia , Beale Holly , Lyle Alfred G. , Sanders Lauren , Learned Katrina , Kephart Ellen , van den Bout Anouk , Cheney Allison , Hosseinzadeh Sahar , Bjork Isabel , Salama Sofie R. , Vaske Olena 
Published: July 2021

Abstract
Synovial sarcoma (SS) is an aggressive soft-tissue malignancy, accounting for 10% of all soft-tissue sarcomas. These tumors can occur at any age but most often affect young adults and adolescents, developing deep in the distal extremities. The prognosis of SS tumors is poor, with a 5-year survival rate of 36-76%, a high rate of metastasis and few treatments. The purpose of this study was to identify novel overexpressed oncogenes that could serve as druggable targets for treating synovial sarcoma patients. We compared the RNA-Seq expression profiles of a cohort of 36 synovial sarcomas to our compendium of RNA-Seq expression data from 12,236 tumor samples (treehousegenomics.ucsc.edu) from pediatric and adult cancer patients. In comparing gene expression in the synovial sarcoma cohort samples against the compendium samples, gene expression outliers were defined as having expression above the gene-specific outlier threshold as defined by the Tukey's outlier method. Among the overexpression outliers, pathway enrichment analysis was used to identify common and druggable pathways, with implications for potential therapeutics for patients with SS. Our analysis identified the overexpression of members of the Sonic Hedgehog pathway in the majority of synovial sarcoma samples. For example, GLI1 expression exceeded the outlier threshold in 35 out of 36 samples. This pathway can be targeted by available small molecule inhibitors. Ongoing work focuses on evaluating the role of Sonic Hedgehog signaling in the pathogenesis of SS using pharmacological inhibition, CRISPRi studies in cell line models of the disease and nanopore sequencing. We currently have 4 patient-derived synovial sarcoma cell lines (HSSY-II, SYO-1, YAMATO, and ASKA) that we can grow in both adherent conditions and in 3D cell culture as sarcospheres. We detected the expression of the SYT-SSX fusion transcript in each of the cell lines by RT-PCR to confirm the cell lines maintained expression of the pathogenic fusion. This work has implications for using comparative tumor RNA-seq derived gene expression data for nominating novel druggable targets specific to synovial sarcoma tumors.
Citation Format: Yvonne A. Vasquez, Jacob Pfeil, Letitia Mueller, Holly Beale, Alfred G. Lyle, Lauren Sanders, Katrina Learned, Ellen Kephart, Anouk van den Bout, Allison Cheney, Sahar Hosseinzadeh, Isabel Bjork, Sofie R. Salama, Olena Vaske. Identifying potential druggable targets for synovial sarcoma using comparative RNA-seq analysis [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 3035.
Abstract 3041: ASPSCR1-TFE3 gene fusion in transgenic mouse as a new pediatric kidney cancer model
Authors: Alasonyalilar-Demirer Aylin , Miller James L. , Miller Erin E. , Gleba Justyna J. , Tun Han W. , Copland John A. 
Published: July 2021

Abstract
A novel genetically engineered mouse (GEM) model for pediatric kidney cancer expressing proximal tubule specific ASPSCR1 :TFE3 fusion gene has been developed. The Rosa26 knock-in ASPSCR1 :TFE3 mouse was crossed with SGLT2-Cre mouse that expresses Cre recombinase in the proximal tubules of the kidney. The ASPSCR1 :TFE3 fusion gene retains the DNA binding and activation domain of TFE3, whereas the N-terminal region of TFE3 is replaced with ASPSCR1 sequences. ASPSCR1 :TFE3 is known to up-regulate the Met receptor tyrosine kinase gene and induce oncogenic phenotypes such as uncontrolled cell proliferation, invasion, and metastasis. However, the molecular roles of ASPSCR1 :TFE3 are poorly understood and no standard of care (SOC) exists for pediatric TFE3 fusion renal cell carcinoma (RCC). Ultrasound (US) and histological analyses of the kidneys of 5, 6 and 7 month old mice revealed bilateral cysts and tumors, while 6-week-old mouse kidney appears normal. At gross inspection, 5-month-old mouse had cysts with a diameter of 1-2 mm while 7-month-old mouse had a polycystic kidney and in the end stage disease. Histopathology revealed neoplastic changes in initial stages in the 5-month-old mouse whereas the neoplasia was predominantly a papillary cystic renal carcinoma; solid tumor formations were observed in the 7-month-old mouse. Neoplastic cells seen in within the blood vessel walls of the 7-month-old mouse indicated future metastasis. This new TFE3 fusion GEM will provide an avenue to understand molecular events of tumorigenesis and progression as well as a model for testing novel therapeutics with survival benefit for a cancer with no current SOC.
Citation Format: Aylin Alasonyalilar-Demirer, James L. Miller, Erin E. Miller, Justyna J. Gleba, Han W. Tun, John A. Copland. ASPSCR1-TFE3 gene fusion in transgenic mouse as a new pediatric kidney cancer model [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 3041.
Abstract 3051: On the origin of pediatric leukemia: studying somatic mutations in human blood
Authors: Brandsma Arianne 
Published: July 2021

Abstract
The acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis and aging is the biggest risk factor for cancer. However, children can also develop cancers even though their cells are less damaged by age. Here, we studied the cellular origin and time of onset during development of pediatric acute myeloid leukemia (pAML) to increase our understanding of why children can get cancer. We compared by whole genome sequencing individual hematopoietic stem and progenitor cells (HSPCs) and pAML blasts of the same leukemic bone marrow as well as nonmatching healthy HSPCs. We found that the number of clonal mutations in the majority of pAML cases was increased and mutational process contribution altered as compared to normal HSPCs, showing activity of specific processes that are either unique to fetal development or normally not observed in healthy HSPCs. These observations could be explained by altered selection dynamics early in life. Surprisingly, pAML cases with an overall mutation burden comparable to age matched healthy HSPCs showed worse overall and event-free survival. Identifying shared somatic mutations between individual HSPC clones and pAML using single-cell genotyping allowed us to pinpoint the developmental lineage that gave rise to the pAML. Our study provides new insights into the etiology of pAML and underscores the clinical potential of whole genome sequencing in pediatric leukemia.
Citation Format: Arianne Brandsma. On the origin of pediatric leukemia: studying somatic mutations in human blood [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 3051.
Abstract 3089: Study of HOX genes in the stem cell origin of CRC
Authors: Osmond Brian , Facey Caroline O. , Opdenaker Lynn M. , Boman Bruce M. 
Published: July 2021

Abstract
Our goal is to ascertain how HOX-regulatory mechanisms play a role in the SC origin of colorectal cancer (CRC). While HOX genes encode master regulatory transcription factors that regulate stem cells (SCs), their role in cancer etiology is under-studied. We and others find that HOX genes are aberrantly expressed in CRC. We previously reported that HOXA4 and HOXD10 along with aldehyde dehydrogenase (ALDH) and the other components of the retinoic acid (RA) signaling pathway are selectively expressed in human colon SCs. That RA signaling regulates HOX expression indicates that RA regulation of HOX gene expression mainly occurs through ALDH+ SCs in the colon. We hypothesize that specific HOX genes regulate growth and differentiation of SCs in human colon and HOX gene dysregulation leads to decreased differentiation and SC overpopulation. Indeed, our bioinformatics analysis shows that many HOX genes are overexpressed in CRCs, which parallels the overpopulation of ALDH+ SC that occurs during CRC tumorigenesis. We are using immunohistochemical mapping to measure proportions of SCs and HOX-positive cells in normal and malignant human colon tissues. We find that specific HOX proteins have increased expression levels in malignant colon tissues. In addition, immunofluorescence co-staining of human colon tissues is used to validate HOX gene expression in ALDH+ SCs. We are also evaluating the effects of all-trans-RA (ATRA) on HOX gene expression and on cellular proliferation and differentiation using CRC cell lines. Our results show that ATRA treatment of HT29 CRC cells leads to reduced proliferation and decreased expression of select HOX genes. These results indicate that HOX genes like HOXA4, HOXA9, and HOXD10, are expressed colonic SCs, and are regulated by RA signaling. Overall, the overexpression of HOX genes in cancer SCs appears to contribute to the SC origin of CRC.
Citation Format: Brian Osmond, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Study of HOX genes in the stem cell origin of CRC [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 3089.
Abstract 3090: Targeting WNT and retinoid signaling pathways to promote differentiation of cancer stem cells along the neuroendocrine lineage in CRC
Authors: Facey Caroline O. , Hunsu Victoria O. , Osmond Brian T. , Opdenaker Lynn M. , Boman Bruce M. 
Published: July 2021

Abstract
Since APC mutations lead to overpopulation of ALDH+ stem cells (SCs) in colorectal cancers (CRCs) and that ALDH is a key component of the retinoic acid (RA) signaling pathway, the hypothesis was developed that human CRC evolves due to an imbalance between WNT and RA signaling. Indeed, we previously discovered that progressive overpopulation of ALDH+ SCs occurs in normal, mutant, adenomatous, and malignant colon crypt tissues, which coincided with the change in the APC mutation zygosity state in familial adenomatous polyposis (FAP) patients. Therefore, the SC overpopulation that drives development of CRC appears to result from dysregulated WNT signaling, of which APC is a negative regulator. Normal colonic SC differentiation is feedback regulated by neuroendocrine cells (NECs) that reside adjacent to SCs in the bottom of the colon crypt. Our goal was to determine if APC mutation and subsequent dysregulated WNT signaling contributes to the inability of SCs to differentiate into NECs, leading to overpopulation of cancer SCs (CSCs) during tumor development. Although RA signaling is altered in CRC, we still found that all- trans-retinoic acid (ATRA) could reduce the number of ALDH+ CSCs in several CRC cell lines. We also found that administering ATRA promotes differentiation of CSCs along the neuroendocrine lineage. Moreover, induction of wild-type (wt)-APC expression in HT29 CRC cells led to increased expression of several NEC markers including CGA, GLP2R, NSE, SSTR1; and decreased WNT/β-catenin signaling when tested via TCF reporter assay. Inducing wt-APC also led to reduced β-catenin and change in protein expression of several proteins known to be targeted by WNT signaling including c-MYC, c-JUN, MET, and CD44. Our preliminary results also show that inducing wt-APC expression increases the number of GLPR2+ NECs. Thus, a link between WNT and RA signaling provides a possible mechanism that might explain how mutant APC leads to decreased maturation of ALDH+ SCs along the NEC lineage and an increased the number of ALDH+ SCs. Therefore, discovering ways to increase differentiation of SCs along the NEC lineage in vivo might lead to new more effective treatment strategies for CRC patients.
Citation Format: Caroline O. Facey, Victoria O. Hunsu, Brian T. Osmond, Lynn M. Opdenaker, Bruce M. Boman. Targeting WNT and retinoid signaling pathways to promote differentiation of cancer stem cells along the neuroendocrine lineage in CRC [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 3090.
Abstract 3092: Effect of cancer stem cell-specific progerin expression on metastatic potential
Authors: Morgenroth Philipp , Söhnchen Christoph , Spitschak Alf , Puetzer Brigitte M. , Logotheti Stella 
Published: July 2021

Abstract
Metastasis signals the final and treatment-refractory stage of cancer disease. Formation of metastases is fueled by a small cell subpopulation within the tumor, the so-called cancer stem cells (CSCs), which have the ability to rejuvenate the heterogeneous tumor population and support self-renewal, survival and tumor cell heterogeneity. Stemness is a cell property rather than a distinct subpopulation of the tumor structure. In this respect, even if CSCs are specifically targeted to be killed, their surrounding cells dedifferentiate to replace assaulted CSCs. Herein, we sought to target CSCs with progerin, a truncated form of lamin A, which causes the Hutchinson-Gilford childhood progeria syndrome, a rare genetic disease of accelerated aging. We combined a promoter responsive to two stemness factors (Yamanaka factors) with the progerin gene and produced a lentiviral construct, where progerin is set under the transcriptional control of stemness cascades. Stable transduction of cancer cells with this construct establishes a dynamic gene modification of the tumor cell population, where all tumor cells carry the progerin gene, but only the ones where the levels of stemness factors are initially high or secondarily upregulated are able to express it. This way, stemness programs are transcriptionally linked with a gene that, when expressed in normal stem cells, causes premature exhaustion of adult stem cells, inhibits the regenerative capacity of tissues and accelerates senescence. We monitor the effects of CSC-specific progerin expression on the CSC reservoir and the tumor cell population dynamics over time, in comparison with CSC-specific expression of its wild-type laminA counterpart, as well as non CSC-specific progerin expression. We further examine how targeting the CSC turnover within the tumor population projects into metastasis-initiating processes, such as cell invasion, migration, epithelial-mesenchymal transition, and tumor metabolism. Our approach provides a model for addressing the potential crosstalk between stemness and senescence in the context of CSCs and holds promise to translate the findings into anti-metastatic therapeutic solutions.
Funding: This project is funded by FORUN (889040) and P.M. has a scholarship from the German Cancer Aid (70114135).
Citation Format: Philipp Morgenroth, Christoph Söhnchen, Alf Spitschak, Brigitte M. Puetzer, Stella Logotheti. Effect of cancer stem cell-specific progerin expression on metastatic potential [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 3092.
Abstract 3095: Targeting ALDH1A1 and regulatory networks that support stemness in ovarian cancer cells
Authors: Muralikrishnan Vaishnavi , Nephew Kenneth P. , Hurley Thomas D. 
Published: July 2021

Abstract
Epithelial ovarian cancer (OC) is the deadliest amongst gynecologic cancers with the majority of deaths caused by cancer recurrence. A new paradigm explaining tumor relapse involves the persistence of cancer stem cells after chemotherapy. OC stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors, and we have previously shown that OCSCs contribute to recurrent, drug resistant high-grade serous OC (HGSOC) using ALDH (aldehyde dehydrogenase) activity as a robust functional marker to identify OCSCs. Of the ALDH isoforms, ALDH1A1 is an intracellular enzyme that oxidizes toxic aldehydes to carboxylic acids and plays a role in controlling cell differentiation pathways. High levels of ALDH1A1 expression have been associated with poor outcome in OC patients. Our group and others have demonstrated that OCSCs with high expression of ALDH1A1 have a greater ability to initiate ovarian tumors in vivo. However, the mechanism by which ALDH1A1 maintains stemness phenotype remains poorly understood. In the current study, we hypothesized that ALDH1A1 upregulation in OCSCs was associated with genetic changes that mediate the cellular signals needed for survival. To test this hypothesis, we used a novel ALDH1A1-specific small molecule inhibitor named compound 974. Treatment of HGSOC cell lines with compound 974 reduced ALDH enzyme activity (p&lt;0.01) and inhibited stem-like properties including spheroid formation (p&lt;0.01) and clonogenic survival (p&lt;0.05). To further examine the effect of compound 974 to inhibit ALDH1A1 and consequently tumor initiation, mice were injected with 106, 105 and 104 OVCAR3 cells treated in vitro with compound 974 (5µM for 48h). Tumor initiation was delayed by 974 treatment compared to vehicle-treated group. Extreme limiting dilution analysis revealed that compound 974 reduced CSC frequency compared to control. Transcriptomic sequencing of ovarian cancer cells treated with compound 974 revealed significant inhibition of genes and pathways associated with stemness (NF-κB, KLF4, FZD7), chemoresistance (ABCB1) and senescence pathway genes (p15, p21). Furthermore, key genes associated with senescence associated secretory phenotype (SASP) such as IL6, IL8 and IL1α were significantly inhibited. Taken together, these data warrant further investigation into the mechanism of ALDH1A1 inhibition and loss of stemness in HGSOC.
Citation Format: Vaishnavi Muralikrishnan, Kenneth P. Nephew, Thomas D. Hurley. Targeting ALDH1A1 and regulatory networks that support stemness in ovarian cancer cells [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 3095.
Abstract 3104: EMT and CSC Enrichment Induced by ERK Inhibition in NSCLC
Authors: Cai Shurui , Bai Xuetao , Li Na , Banerjee Ananya , Lavudi Kousalya , Pal Tejinder 
Published: July 2021

Abstract
The activation of Mitogen-activated protein kinase pathway (MAPK/ERK pathway) has been found to play an important role in many cancers including lung cancer, and multiple inhibitors targeting this pathway have been developed. Several ERK inhibitors (ERKi, e.g., Ulixertinib, SCH772984) have been shown to be active against different cancers harboring RAS, BRAF, or MEK mutations, as well as cancers with developed BRAF/MEK inhibitor resistance. Nevertheless, sustained inhibition of ERK can lead to resistance and is likely to cause tumor relapse as well. Studies over the years have shown that a small portion of cells within tumors, which can reproduce themselves and sustain cancer, being called “cancer stem cells (CSCs)”, is the cause of tumor initiation and progression. Many reports have implicated the association of Epithelial-to-Mesenchymal Transition (EMT) program with CSCs and identified EMT-transcription factors (TFs) as CSC regulators. Here, we demonstrated that ERKi treatment induces EMT in non-small cell lung cancer cells (NSCLC), probably by inducing Slug expression. We also found that ERKi treatment can enrich the cancer stem cell (CSC) like population in NSCLC cells, evidenced by increased ALDH+ cells, enhanced in vitro sphere formation capability, and enhanced tumorigenicity in immunodeficient mice. Moreover, in NSCLC cells, we proved ERK knockdown or ERKi treatment can reduce C/EBPα expression, which is believed to be a master epithelial “gatekeeper” whose expression is required to prevent unwarranted mesenchymal transition. Our findings reveal a novel mechanism underlying the tumor relapse after ERKi treatment in NSCLC, and ultimately will help us improve current NSCLC therapeutic methods.
Citation Format: Shurui Cai, Xuetao Bai, Na Li, Ananya Banerjee, Kousalya Lavudi, Tejinder Pal. EMT and CSC Enrichment Induced by ERK Inhibition in NSCLC [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 3104.
Abstract 3108: Human telomerase reverse transcriptase regulates stemness of pancreatic cancer
Authors: Ye Juanjuan , Yamakawa Keiko , Narusawa Yuko , Matsuda Yoko 
Published: July 2021

Abstract
Backgrounds: Human telomerase reverse transcriptase (hTERT) plays a key role on immortalization of cancer cells. In the present study, we clarified the effect of small interfering RNA (siRNA) targeting hTERT in pancreatic cancer cell lines.
Methods: Two sequences of siRNA targeting hTERT and negative control siRNA were transfected into PANC-1 and MIA PaCa-2 human pancreatic cancer cell lines. Cell proliferation (WST-8 cell counting assay), stemness (sphere formation) and migration (scratch assay) were analyzed using hTERT-siRNA transfected cells and control-siRNA transfected cells. The expression levels of CDK1, SOX9 and nestin were analyzed by real time PCR.
Results: As compared to control-siRNA, hTERT-siRNA suppressed cell proliferation and stemness of pancreatic cancer cell lines. Cell migration did not show any difference between hTERT-siRNA and control-siRNA transfected cells. The expression levels of CDK1, SOX9 and nestin in hTERT-siRNA transfected cells were lower than those in control-siRNA transfected cells.
Conclusion: The present study indicates that inhibition of hTERT in pancreatic cancer cells suppressed stemness via alteration of the expression levels of CDK1, SOX9 and nestin.
Citation Format: Juanjuan Ye, Keiko Yamakawa, Yuko Narusawa, Yoko Matsuda. Human telomerase reverse transcriptase regulates stemness of pancreatic 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 3108.