bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB210: MicroRNA function is malleable and can be governed by target gene expression levels
Authors: Svoronos Alexander A. , Campbell Stuart G. , Engelman Donald M. 
Published: July 2021

Abstract
MicroRNAs are short, noncoding RNA molecules that reduce the expression of target genes by inhibiting messenger RNA translation and promoting messenger RNA degradation. They are highly dysregulated in cancer, with many microRNAs appearing to have potent oncogenic or tumor suppressive effects. As a result, there exists substantial interest in targeting microRNAs for cancer therapy. However, the literature is filled with conflicting accounts as to whether specific microRNAs are oncogenic or tumor suppressive, with many microRNAs appearing to exhibit entirely opposite functions when placed in different contexts. One explanation for this duality is that individual microRNAs can target tens to hundreds of different genes, many of which may possess opposing functions. Hence, it is likely that the expression levels of the target genes influence whether an individual microRNA will have a net oncogenic or net tumor suppressive effect. To examine this hypothesis, we developed a computational model of miR-125b's effect on the apoptosis pathway. This is an ideal system for examining the expression level hypothesis, as miR-125b is a microRNA that targets several closely interacting pro- and anti-apoptotic members of the pathway, which can be easily modeled as a system of differential equations. From the model, we elucidate a general trend that miR-125b is more pro-apoptotic when its anti-apoptotic targets are overexpressed and/or its pro-apoptotic targets are underexpressed, while it is more anti-apoptotic when its pro-apoptotic targets are overexpressed and/or its anti-apoptotic targets are underexpressed. To examine this experimentally, we switched miR-125b from being tumor suppressive to being oncogenic in cells by modifying the expression levels of one of miR-125b's anti-apoptotic targets. In addition, we observed that treating cells with anticancer drugs can also reverse miR-125b's status as a tumor suppressor. These results have important implications for the use of microRNAs as therapeutic targets in cancer.
Citation Format: Alexander A. Svoronos, Stuart G. Campbell, Donald M. Engelman. MicroRNA function is malleable and can be governed by target gene expression levels [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 LB210.
Abstract LB214: Actin-Like Protein 6A (ACTL6A) Suppresses p21Cip1 Expression to Maintain an Aggressive Mesothelioma Phenotype
Authors: Shrestha Suruchi , Adhikary Gautam , Xu Wen , Friedburg Joseph , Eckert Richard L. 
Published: July 2021

Abstract
Mesothelioma is a fatal asbestos-caused cancer of the mesothelial cells that arises in the pleural and peritoneal cavities in response to asbestos exposure. ACTL6A is an important protein subunit of the SWI/SNF epigenetic regulatory complex but also has independent pro-cancer actions. It is frequently overexpressed in cancer and drives the malignant phenotype; however, it has not been studied in mesothelioma. In the present report, we show that ACTL6A drives mesothelioma cell proliferation, invasion and migration, and that these activities are markedly reduced in ACTL6A knockdown/knockout cells. Moreover, ACTL6A loss is associated with a significant increase in level of the p21Cip1 cyclin-dependent kinase inhibitor. ACTL6A binding to the proximal Sp1 and distal p53 sites on the p21Cip1 gene promoter is associated with reduced p21Cip1 promoter activity, and mRNA and protein level. Similar regulation was observed in cells derived from plural and peritoneal mesothelioma. Moreover, inhibiting the p21Cip1 increase in ACTL6A knockout cells reverses the reduction in cancer phenotype, suggesting the p21Cip1 is an authentic downstream mediator of ACTL6A action. These studies suggest that ACTL6A suppression of p21Cip1 expression contributes to the mesothelioma cell aggressive cancer phenotype and that inhibition of ACTL6A function may be a suitable mesothelioma cancer treatment strategy.
Citation Format: Suruchi Shrestha, Gautam Adhikary, Wen Xu, Joseph Friedburg, Richard L. Eckert. Actin-Like Protein 6A (ACTL6A) Suppresses p21Cip1 Expression to Maintain an Aggressive Mesothelioma Phenotype [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 LB214.
Abstract LB216: Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity
Authors: Sheppard Hadley E. , Dall'Agnese Alessandra , Park Woojun D. , Shamim Hamza , Dubrulle Julien , Johnson Hannah L. , Stossi Fabio , Cogswell Patricia , Sommer Josh , Levy Joan , Sharifnia Tanaz , Wawer Mathias J. , Clemons Paul A. , Nabet Behnam , Gray Nathanael S. , Schreiber Stuart L. , Workman Paul , Young Richard A. , Lin Charles Y. 
Published: July 2021

Abstract
Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape, autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Both transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition which globally downregulates transcription leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop.
Citation Format: Hadley E. Sheppard, Alessandra Dall'Agnese, Woojun D. Park, Hamza Shamim, Julien Dubrulle, Hannah L. Johnson, Fabio Stossi, Patricia Cogswell, Josh Sommer, Joan Levy, Tanaz Sharifnia, Mathias J. Wawer, Paul A. Clemons, Behnam Nabet, Nathanael S. Gray, Stuart L. Schreiber, Paul Workman, Richard A. Young, Charles Y. Lin. Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [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 LB216.
Abstract LB219: Methods to improve representation of racial and ethnic minorities in lung cancer screening programs: A systematic review
Authors: Gilliard Tiffany J. , Perez-Morales Jaileene , Schabath Matthew , Haver Mary Katherine 
Published: July 2021

Abstract
Background: Most lung cancer screening trials to date and current screening guidelines overlook vulnerable populations with disproportionate lung cancer burden such as racial and ethnic minorities. Given the barriers, perceptions, and socioeconomic burden of these underserved populations, uptake of lung cancer screening has minimal. To develop and implement better methods of recruitment underserved populations, concerted efforts to understand the barriers and perceptions of these population are needed. Objective: Conduct a systematic review of methods for recruitment of racial and ethnic minorities into lung cancer screening trials or programs. Methods: We searched for studies that reported methods of recruitment and racial and ethnic minorities into lung cancer screening from 2010 to June 2020, using Ovid MEDLINE and Embase databases. Full-text screening and data extraction were completed independently by two reviewers and adjudication was performed by a third, independent reviewer. We compared referral rates of the recruitment modalities by racial/ethnic subgroups and by sex. Results: We identified 525 studies of which 25 were included in the systematic review corresponding to 291,329 patients. The most frequent methods of recruitment were referral, physical mail, community-based strategies, targeted strategies, phone, advertisement, and social media. Referral (n=7; 2,510 patients) was the most effective method of recruitment with response rates ranging from 31% to 97%. Direct mail (n=8 studies; 189,799 patients) was the second most extensively used recruitment method with response rates of 28% to 79%. Direct mail to Hispanic patients (2,995 total) for lung cancer screening programs was more effective than other methods of recruitment. Direct mail was more effective in recruiting African American patients (8,331 total) compared to referral (1,083 total). Conclusion: This review identified recruitment modalities that were more successful and less unsuccessful in recruiting racial and ethnic minorities into lung cancer screening trials and programs. This work highlights priorities and next steps required to improve recruitment of racial and ethnic minorities in lung cancer screening. There is a need to develop culturally relevant lung cancer screening interventions for Hispanics/Latino patients and to create targeted intervention for African American patients.
Citation Format: Tiffany J. Gilliard, Jaileene Perez-Morales, Matthew Schabath, Mary Katherine Haver. Methods to improve representation of racial and ethnic minorities in lung cancer screening programs: A systematic review [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 LB219.
Abstract LB228: PD-L1/PD-1 and arsenic lung tumorigenesis
Authors: Xu Wenhua , Chen Gang 
Published: July 2021

Abstract
Chronic exposure of environmental arsenic promotes lung cancer. Emerging evidence indicates that compromised host immunity, particularly T cell anti-tumor immunity, may play a critical role in cancer development. However, there is a knowledge gap in terms of the effects of arsenic exposure on T cell anti-tumor immunity and how that may contribute to arsenic lung carcinogenicity. Immunosuppression has been known as a risk factor for many types of cancer, including lung cancer. The development of cancer indicates a success of immunosuppression and escape of cancer cells from host anti-tumor immunity in which T cells are the major component. The anti-tumor immunity is mainly executed by CD8 cytotoxic T cells through their anti-tumor effector function. A/J mice are naturally sensitive to pulmonary carcinogens and prone to develop spontaneous lung tumors later in life and have been frequently used as an animal model for lung tumorigenesis research. Chronic arsenic administration through drinking water has been shown to enhance tumor formation in the lungs of A/J mice. In the current study, using this mouse model we determined that prolonged arsenic exposure up-regulated PD-1/PD-L1, inhibited T cell antitumor function and enhanced lung tumor formation, while inhibition of PD-1/PD-L1 restored T cell anti-tumor effector function and mitigated arsenic-enhanced lung tumorigenesis. In addition, inhibition of PD-1/PD-L1 could be a preventive approach to mitigate tumorigenic action of chronic arsenic exposure.
Citation Format: Wenhua Xu, Gang Chen. PD-L1/PD-1 and arsenic 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 LB228.
Abstract LB232: Imbalance of TGF-β1/BMP-7 pathway induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness
Authors: Ning Junya , Ye Yingnan , Yu Jinpu 
Published: July 2021

Abstract
The transforming growth factor-beta (TGF-β) signaling represented the predominant cytokine signaling involved in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of TGF-β superfamily, was frequently found to have cross-talk with TGF-β pathway. However, the complex interaction between TGF-β and BMP pathways has not been fully elucidated in HCC. In this study, we found that the imbalance of TGF-β1/BMP-7 pathway was associated with aggressive pathological features and poor clinical outcome in HCC, and it could significantly promote HCC cells invasion and stemness by increasing inhibitor of differentiation 1 (ID1). Next, we indicated that the miR-17-92 cluster could disrupted the balance of TGF-β1/BMP-7 pathway in HCC cells by inducing TGFBR2 post-transcriptional silence and inhibiting ACVR1 post-translational ubiquitylation via targeting Smurf1. Furthermore, we demonstrated that miR-17-92 cluster was originated from the extracellular vesicles (EVs) of M2-polarized tumor associated macrophages (M2-TAMs) infiltrated in HCC microenvironment and induced the imbalance of TGF-β1/BMP-7 pathway. Finally, we found that sh-MIR17HG lentivirus, TGFBR2 lentivirus and ACVR1 inhibitor could profoundly inhibit M2-TAMs-stimulated the growth and metastasis of HCC xenografts in vivo. We propose that imbalance of TGF-β1/BMP-7 pathway may serve as a prognostic biomarker, M2-TAMs and miR-17-92 cluster could be a therapeutic target for this subtype of HCC.
Citation Format: Junya Ning, Yingnan Ye, Jinpu Yu. Imbalance of TGF-β1/BMP-7 pathway induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness [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 LB232.
Abstract LB246: E-cadherin loss drives Id2-dependent dampening of cell cycle progression and predicts increased susceptibility to CDK4/6 inhibition in lobular breast cancer
Authors: Rätze Max Antonius Klaus , Koorman Thijs , Sijnesael Thijmen , Bassey-Archibong Blessing , van de Ven Robert , Enserink Lotte , Visser Daan , Jaksani Sridevi , Bakker Elvira , Richard François , Tutt Andrew , Steele Rebecca , Pettitt Stephen , Lord Christopher J. , Fitzpatrick Amanda , Isacke Clare , van Diest Paul J. , Desmedt Christine , Daniel Juliet M. , Derksen Patrick W.B. 
Published: July 2021

Abstract
Invasive lobular breast carcinoma (ILC) is a low grade and mostly chemo-refractory luminal-type breast cancer that has been linked to sustained proliferative quiescence and long-term latency relapses (15-20 years). Loss of E-cadherin causes metastatic lobular breast cancer, partly through acquisition of anchorage independence. It is however still unknown how ILC cells control the balance between proliferative indolence and cell cycle re-entry at the metastatic site. We show here that E-cadherin loss leads to upregulation of Id2 through p120-catenin/Kaiso-dependent transcriptional derepression. Anchorage independent conditions further exacerbate p120-driven Id2 expression, leading to a sustained G0/G1 cell cycle arrest through binding of cytosolic Id2 to hypo-phosphorylated Rb. Intriguingly, we find that E-cadherin inactivation causes increased sensitivity to CDK4/6 inhibition in mouse and human breast cancer cell lines and primary tumor organoids. Finally, we find that Id2 expression is elevated in human ILC when compared to ductal breast cancers. Based on these data, we propose that combined E-cadherin loss and cytosolic Id2 expression can be used for the differential diagnosis of ILC and represent a candidate predictive biomarker pair for cell cycle targeting drug efficacy.
Citation Format: Max Antonius Klaus Rätze, Thijs Koorman, Thijmen Sijnesael, Blessing Bassey-Archibong, Robert van de Ven, Lotte Enserink, Daan Visser, Sridevi Jaksani, Elvira Bakker, François Richard, Andrew Tutt, Rebecca Steele, Stephen Pettitt, Christopher J. Lord, Amanda Fitzpatrick, Clare Isacke, Paul J. van Diest, Christine Desmedt, Juliet M. Daniel, Patrick W.B. Derksen. E-cadherin loss drives Id2-dependent dampening of cell cycle progression and predicts increased susceptibility to CDK4/6 inhibition in lobular breast 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 LB246.
Abstract LB261: BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma
Authors: Liu Tianyi , Zhou Linli , Zhang Yuhang 
Published: July 2021

Abstract
The tumor stroma and its cellular components are known to play important roles in tumor resilience towards treatment but remain to be urgently characterized in melanoma targeted therapy. By performing a paired-analysis of melanoma tissue samples collected from the patients before and after combined BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) treatment, we discovered that the number of intratumoral cancer-associated fibroblasts (CAFs) increased significantly in BRAFi/MEKi-treated melanoma stroma comparing with the samples before the therapy. Those intratumoral CAFs exhibit increased amounts of nuclear β-catenin under BRAFi/MEKi therapy. Further studies show that BRAFi not only leads to increased β-catenin nuclear accumulation in CAFs and enhances their biological properties, suggesting BRAFi induces a new resistant phenotype in CAFs. In both in vitro and in vivo models, depleting β-catenin in CAFs abolishes their ability to elicit melanoma cell growth and drug resistance. BRAFi induces BRAF and CRAF dimerization and subsequently the activation of MEK/ERK signaling in CAFs, leading to the inactivation of the β-catenin destruction complex. RNA-Seq data reveals that nuclear β-catenin is a major regulator of CAF phenotype. We identify matricellular protein periostin (POSTN) as a downstream effector of β-catenin. In melanoma, POSTN is uniquely expressed in CAFs, and BRAFi can specifically upregulate POSTN production in CAFs but not in melanoma cells. Recombinant POSTN contributes to melanoma cell BRAFi/MEKi resistance and can compensate for the loss of β-catenin in CAFs. By reactivating ERK pathway in melanoma cells through PI3K/AKT signaling, POSTN compensates for the loss of β-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. In summary, our data reveal a novel resistance mechanism in melanoma that is elicited by BRAFi-induced non-canonical nuclear β-catenin signaling in CAFs and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma.
Citation Format: Tianyi Liu, Linli Zhou, Yuhang Zhang. BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma [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 LB261.
Abstract NG06: Addressing scaffolding roles of oncogenic kinases with targeted protein degradation
Authors: Burslem George 
Published: July 2021

Abstract
Proteolysis Targeting Chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of proteins. PROTACs are heterobifunctional small molecules which co-opt the ubiquitin proteasome system to destroy oncogenic proteins. The development of PROTACs for receptor tyrosine kinases (EGFR, Her2 and c-MET), a protein family previously thought to be intractable for induced protein degradation, will be described. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone including more potent inhibition of cell proliferation, a more durable and sustained downstream signaling response. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach. Application of the PROTAC technology to targets, including RTKs, in hematological malignancies has also provided potential therapeutic approaches and enhanced understanding of scaffolding roles of oncogenic kinases. The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, traditional small molecule inhibitors suffer from limited efficacy in the clinic. A FLT-3 targeting PROTAC with sub-nanomolar antiproliferative activity and the ability to induce tumor regression in vivo will be described. Additionally, the discovery of apoptosis suppression as a kinase independent activity of FLT-3 ITD will be described. While the use of kinase inhibitors of oncoprotein BCR-Abl have enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. An allosteric BCR-Abl PROTAC demonstrates significant advantages compared to inhibition and identified scaffolding roles for BCR-Abl which are not addressed by inhibitors but can be abrogated by protein degradation. Concurrent treated with the allosteric PROTAC and orthosteric inhibitors proved synergistic, particularly against some clinically relevant BCR-Abl kinase domain mutants. Furthermore, investigation into the kinase independent roles of BCR-Abl in patient stem cells suggest that these persistent leukemic stem cells are BCR-Abl agnostic.
Citation Format: George Burslem. Addressing scaffolding roles of oncogenic kinases with targeted protein degradation [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 NG06.
Abstract PL02-02: Harnessing the value of mutational signatures in whole cancer genomes
Authors: Nik-Zainal Serena 
Published: July 2021

Abstract
Mutational signatures are the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis. They are biologically informative, reporting on the processes that have contributed to the developmental history of each patient's cancer. In this lecture, on behalf of my team and my collaborators, I shall provide an update on the field, focusing on validation of these abstract mathematical concepts, untangling the mechanisms underpinning mutation patterns in human somatic cells, and describing the new insights that we have gained through combinations of computational analysis and experiments in cell-based systems. We showcase how mutational-signature-based clinical algorithms have been developed, describe the path taken in translating these towards medical utility and for balance, highlight some of the hurdles that need to be navigated in this type of translational research.
Citation Format: Serena Nik-Zainal. Harnessing the value of mutational signatures in whole cancer genomes [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 PL02-02.