bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2862: BMP4 mediated suppression of cholesterol synthesis and breast cancer metastasis
Authors: Anderson Robin L. , Chi Lap Hing , Burrows Allan D. , Roslan Suraya , Redfern Andrew 
Published: July 2021

Abstract
Breast cancer affects one in seven women and kills more than 600,000 women each year. Compared to the 98.9% survival rate of patients with localized breast cancer, the five-year survival rate of patients with distant metastasis is only 28.1%. Using cDNA arrays and patient datasets, we found that a protein called bone morphogenetic protein 4 (BMP4) is downregulated in highly metastatic breast cancer cells and in high-grade breast tumors. BMP4 is a ligand in the TFGβ/BMP cytokine family and has the capacity to suppress TGFβ signaling through induction of SMAD6 and SMAD7. In several different preclinical metastasis models, we have shown that restored BMP4 expression in breast cancer cells with metastatic capacity does not alter primary tumor growth but results in significantly reduced metastasis to lung, liver and spine (p&lt; 0.01), following primary tumor resection. MDA-MB-231HM cells with or without enforced BMP4 expression were recovered from primary mammary tumors and subjected to transcriptomic profiling by RNAseq. This analysis revealed that BMP4 suppressed multiple genes involved in the cholesterol biosynthesis pathway (p=2.56×10-7) and down-regulated cholesterol levels in the tumors (p=0.042). In a patient cohort of over 2000 predominantly luminal breast cancers, we found that stage, as measured by size and lymph node status, was not altered by statin use, however statin users had less high grade tumors and more luminal A tumors. In terms of recurrence, we found a marked risk reduction in patients with luminal B tumors (p=0.014) and particularly in Her2+ luminal B tumors (p=0.045). Lung, liver and brain metastases were most reduced in statin users. Current experiments involve testing a statin therapy, with the knowledge that statins are not effective in mice, but should inhibit cholesterol synthesis in human tumors in xenograft models. In addition, we are testing an inhibitor of the nuclear receptor RORγ that has been reported to activate cholesterol synthesis through SREBP2, a master regulator of cholesterol synthesis.
Citation Format: Robin L. Anderson, Lap Hing Chi, Allan D. Burrows, Suraya Roslan, Andrew Redfern. BMP4 mediated suppression of cholesterol synthesis and breast cancer metastasis [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 2862.
Abstract 2915: Synergistic, cytokine mediated stimulation (IL-1α/β + IL-6) of colon cancer cells reveals a novel mechanism of DNA damage facilitated by up-regulation of NOX1 and DUOX2
Authors: Meitzler Jennifer L. , Wu Yongzhong , Juhasz Agnes , Rapisarda Annamaria , Campbell Petreena , Diebold Becky A. , Antony Smitha , Jiang Guojian , Lu Jiamo , Mallick David J. , Konaté Mariam M. , Roy Krishnendu , Doroshow James H. 
Published: July 2021

Abstract
Inflammatory bowel diseases are states of long-term inflammation of the colon resulting from an interplay of environmental factors and dysregulated immune responses. As inflammatory exposure increases over the time frame of active disease, patients with these chronic conditions are at risk of developing colorectal cancers. Chronic inflammation is thought to contribute to cancer initiation through persistent release of reactive oxygen species (ROS), leading to genome damage. Accumulating evidence suggests inflammatory cells contribute to this process, as the secretion of cytokines and growth factors in response to gut inflammation also supports cancer cell progression. Specifically, IL-1 family members play a pivotal role in the pathogenesis of acute and chronic intestinal inflammation, regulating both innate and adaptive immune responses. To elucidate a direct link between IL-1 family cytokines, ROS generation and colorectal cancer, we observed that treatment of HT29 or T84 cells with IL-1α or IL-1β, in cooperation with IL-6, resulted in oxidant production through up-regulation of both NOX1 and DUOX2 enzymes. Up-regulation of the hydrogen peroxide generating DUOX2/DUOXA2 enzyme complex was directly associated with enhanced histone H2AX phosphorylation (γH2AX), a marker of DNA double strand breaks. Interestingly, this concentration and time-dependent induction of expression and oxidative response was absent in Caco2 cells and was not mediated by other IL-1 family members (IL-18, IL-33 or IL-37). Prior studies from our group have demonstrated significant up-regulation of DUOX2 and DUOXA2 in surgically resected colon cancer specimens compared with adjacent normal colonic epithelium. Future studies will focus on cytokine stimulation of colon organoids derived from patient tumor and adjacent non-malignant tissues to evaluate enzymatic expression and oxidant level changes in a novel patient-derived colon model system.
Citation Format: Jennifer L. Meitzler, Yongzhong Wu, Agnes Juhasz, Annamaria Rapisarda, Petreena Campbell, Becky A. Diebold, Smitha Antony, Guojian Jiang, Jiamo Lu, David J. Mallick, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow. Synergistic, cytokine mediated stimulation (IL-1α/β + IL-6) of colon cancer cells reveals a novel mechanism of DNA damage facilitated by up-regulation of NOX1 and DUOX2 [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 2915.
Abstract 2931: Pharmacological inhibition of 17β-hydroxysteroid dehydrogenase impairs endometrial cancer growth in an orthotopic xenograft mouse model
Authors: Xanthoulea Sofia , Konings Gonda , Saarinen Niina , Delvoux Bert , Kooreman Loes , Koskimies Pasi , Häkkinen Merja , Auriola Seppo , d'Avanzo Elisabetta , Walid Youssef , Verhaegen Frank , Lieuwes Natasja , Caiment Florian , Kruitwagen Roy , Romano Andrea 
Published: July 2021

Abstract
Endometrial cancer (EC) is the most common gynaecological tumor in developed countries and its incidence is increasing. Approximately 80% of newly diagnosed EC cases are estrogen-dependent. Type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1) is the enzyme that catalyzes the final step in estrogen biosynthesis by reducing the weak estrogen estrone (E1) to the potent estrogen 17β-estradiol (E2), and previous studies showed that this enzyme is implicated in the local E2 generation in EC. In the present study we employed a recently developed orthotopic and estrogen-dependent xenograft mouse model of EC to show that pharmacological inhibition of the 17β-HSD-1 enzyme inhibits disease development. Tumors were induced in one uterine horn of athymic nude mice by intra-uterine injection of the well-differentiated human endometrial adenocarcinoma Ishikawa cell line that was modified to express 17β-HSD-1 in levels comparable to humans and, in addition, the luciferase and green fluorescent protein reporter genes. After tumor engraftment, controlled estrogen exposure was achieved using subcutaneous MedRod implants that released either E1 or placebo. A subgroup of the E1 supplemented mice received daily gavage of FP4643, a well characterized 17β-HSD-1 inhibitor. Bioluminescence imaging (BLI) was used to measure tumor growth non-invasively. At sacrifice, mice receiving E1 and treated with the FP4643 inhibitor showed a significant reduction in tumor growth by approximately 65% compared to mice receiving E1 alone. Tumors exhibited metastatic spread to the peritoneum, to the lymphovascular space (LVI) and to the thoracic cavity. Metastatic spread and LVI were both reduced in the inhibitor treated group. Transcriptional profiling of tumors indicated that FP4643 treatment reduced the oncogenic potential at the mRNA level. In conclusion, we show that the FP4643 inhibition represents a potential promising novel endocrine treatment for EC
Citation Format: Sofia Xanthoulea, Gonda Konings, Niina Saarinen, Bert Delvoux, Loes Kooreman, Pasi Koskimies, Merja Häkkinen, Seppo Auriola, Elisabetta d'Avanzo, Youssef Walid, Frank Verhaegen, Natasja Lieuwes, Florian Caiment, Roy Kruitwagen, Andrea Romano. Pharmacological inhibition of 17β-hydroxysteroid dehydrogenase impairs endometrial cancer growth in an orthotopic xenograft mouse 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 2931.
Abstract 2936: Ago2 induces Kras signaling and promotes tumor progression in mouse models of lung adenocarcinoma
Authors: Tien Jean C. , Chugh Seema , Goodrum Andrew E. , Cheng Yunhui , Wang Lisha , Mannan Rahul , Wang Xiaoming , Dommeti Vijaya L. , Zhang Yuping , Xu Alice , Su Fengyu , Cao Xuhong , Shankar Sunita , Chinnaiyan Arul M. 
Published: July 2021

Abstract
Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases, and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g. KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA induced silencing complex (RISC)—physically interacts with KRAS and stabilizes it at the protein level. In multiple cell lines, AGO2 knockdown reduces KRAS protein level and attenuates cell proliferation. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation in tumor nodules, indicating impaired KRAS signaling. Furthermore, RNA-seq analysis of KPC nodules demonstrated broadly reduced expression of Kras-related genes. Taken together, our data demonstrate a novel pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work has future translational relevance.
Citation Format: Jean C. Tien, Seema Chugh, Andrew E. Goodrum, Yunhui Cheng, Lisha Wang, Rahul Mannan, Xiaoming Wang, Vijaya L. Dommeti, Yuping Zhang, Alice Xu, Fengyu Su, Xuhong Cao, Sunita Shankar, Arul M. Chinnaiyan. Ago2 induces Kras signaling and promotes tumor progression in mouse models of 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 2936.
Abstract 2944: Altering RAS oncogenic activity defines unique oncogenic fates
Authors: Erdogan Ozgun , Pershing Nicole L. , Counter Christopher M. 
Published: July 2021

Abstract
RAS family oncogenes demonstrate a tropism of specific driver mutations towards different cancers and understanding the impact of individual RAS mutations on oncogenic activity, signaling, and tissue-specific cellular responses could inform on the origin of cancer as well as development of potential therapies. To genetically interrogate how each mutation could differentially alter RAS signaling output in vivo, we created a panel of mice whereby two very different oncogenic mutations, G12D and Q61R, were expressed from a Cre-inducible LSL-Kras allele encoded with native (nat) or common (com) codons to generate low or high levels of oncoprotein. We show that this panel leads to a stepwise increase in RAS activity (GTP loading) with comQ61R &gt; comG12D &gt; natQ61R &gt; natG12D. Global activation of these alleles induced a restricted number of tumors, with increasing active Kras generally leading to a more severe disease and decreased survival. Histopathological analysis revealed that high oncogenic activity induces highly aggressive myeloproliferative disease while there is a shift to more solid tumors as the signaling is dampened. RNASeq revealed that low levels of active Kras induce transcriptional features of a plastic state while high levels have all the hallmarks of potent oncogenic activity and resultant oncogenic stress. Such findings are suggestive of potential unique vulnerabilities during tumor initiation driven by different RAS mutants that may find clinical utility in the treatment of early stage cancer to prevent recurrence.
Citation Format: Ozgun Erdogan, Nicole L. Pershing, Christopher M. Counter. Altering RAS oncogenic activity defines unique oncogenic fates [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 2944.
Abstract 2960: A novel mouse model of pancreatic cancer reveals new insights into cell cycle deregulation
Authors: Adams Christina , Wang Lynn , Wang Tim S. , Miller Nichol , McMillan Elizabeth , Ramstetter Monica , Chionis John , Eisele Koleen , Almaden Jonathan , Affolter Timothy , Pillai Smitha , VanArsdale Todd , Dillon Chris , Dann Stephen G. 
Published: July 2021

Abstract
Overcoming checkpoints to cell cycle control is the basis for tumorigenesis and malignant growth. Therefore, models that recapitulate clinically relevant cell cycle deregulation enhance our understanding of defined tumors subsets. Specifically, pancreatic ductal adenocarcinomas (PDAs) frequently delete the 9p21 locus which contains the cyclin dependent kinase (CDK) inhibitors CDKN2A (p16, p14) and CDKN2B (p15), as well as methylthioadenosine phosphorylase (MTAP), a metabolic gene required for methionine salvage from methylthioadenosine. No model currently exists that accurately represents loss of the entire locus in a relevant disease context. Moreover, the contribution of MTAP to tumor progression remains largely unknown. Therefore, we have developed a novel genetically engineered mouse model (GEMM) of PDA which combines loss of the orthologous murine 9p21 region (4qC4) with activated KRAS [Pdx-Cre; LSL-KrasG12D; 9p21L/L (K9C)], which results in rapid adenocarcinoma formation and subsequent mortality in mice homozygous for 9p21 deletion. Single-cell RNA sequencing revealed a remarkable level of inter- and intra-tumoral heterogeneity, including a significant immune and stromal component that contribute to tumor growth and progression. Additionally, K9C derived cell lines are responsive to Pfizer's first-in class CDK2/4/6 selective inhibitor while displaying de novo resistance to CDK4/6 inhibitor Palbociclib. Allograft and single-cell RNA sequencing experiments corroborated these findings and implicate Myc in contributing to CDK2/4/6i sensitivity. Furthermore, phenotypic-based screens revealed synthetic-lethal hits with 9p21 loss, indicating ample opportunities for combination strategies in this select patient population. Thus, we show that the K9C model recapitulates salient aspects of PDA and is amenable to novel therapeutic intervention strategies that may aid in improving the outcomes of patients with this precise genetic background.
*All procedures performed on animals were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and use committee
Citation Format: Christina Adams, Lynn Wang, Tim S. Wang, Nichol Miller, Elizabeth McMillan, Monica Ramstetter, John Chionis, Koleen Eisele, Jonathan Almaden, Timothy Affolter, Smitha Pillai, Todd VanArsdale, Chris Dillon, Stephen G. Dann. A novel mouse model of pancreatic cancer reveals new insights into cell cycle deregulation [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 2960.
Abstract 2968: Organoid based functional genomics approach to identify treatment options for patients with rare cancers
Authors: Hopkins Benjamin David , Cavallo-Fleming Julie-Ann , Claridge Sally , De Boni Lamberto , Pauli Chantal 
Published: July 2021

Abstract
Rare cancers present a distinct challenge for the identification of effective therapeutic strategies. While these tumors make up 20% of total cancer cases in the United States, they are categorically defined as occurring in less than 6 of every 100,000 people, limiting the utility of traditional methods to study, and identify treatments for these cancers. Though there have been tremendous advances in cancer therapeutics, identification of treatments for rare tumors have lagged, leaving patients with rare tumors with worse 5 year survival rates than individuals diagnosed with common cancer types. The goal of precision oncology is to identify effective therapeutic strategies for each individual patient. With high throughput sequencing it is now possible to identify the genetic events that give rise to and sustain each individual tumor in clinically relevant time frames, however our capacity to leverage this information to identify effective therapeutic options remains limited. This gap in our capacity stems from a lack of clinically relevant approaches that would allow physicians to accurately gauge the impact of multiple therapeutic strategies and relate them to clinical responses. Through the establishment of an iterative Functional Genomics Pipeline which integrates the development and analysis of high-fidelity patient derived organoid models of rare cancers with personalized drug sensitivity testing, and comprehensive genomics our work suggests that personalized modeling could have clinical utility for the identification of treatment options for individual patients with rare cancers.
Citation Format: Benjamin David Hopkins, Julie-Ann Cavallo-Fleming, Sally Claridge, Lamberto De Boni, Chantal Pauli. Organoid based functional genomics approach to identify treatment options for patients with rare cancers [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 2968.
Abstract 2974: Loss of TSC1 or TSC2 drives lineage infidelity and hamartoma formation in a renal organoid model of angiomyolipoma
Authors: Pietrobon Adam , Delaney Sean P. , Doré Carole , Yockell-Lelievre Julien , Julian Lisa , Stanford William L. 
Published: July 2021

Abstract
Renal angiomyolipomas (R-AMLs) are hamartomatous kidney tumors which stain positively for markers of adipocytic, vascular, smooth muscle, and melanocytic lineages. These lesions possess loss of function mutations in either TSC1 or TSC2, which are canonical negative regulators of mTORC1 signaling. To date, there exists no in vitro or in vivo model which faithfully recapitulates the architectural and molecular complexity of R-AMLs. Considering these lesions can be detected very early in life- even congenitally- we hypothesized they arise as a consequence of aberrant tissue development. To test this hypothesis, we generated TSC1-/- and TSC2-/- mutants in four human pluripotent stem cell (hPSC) backgrounds using CRISPR/Cas9 genome engineering. Wild type hPSCs differentiated into renal organoids express markers of the glomerulus, proximal and distal tubules, in a topology that resembles human nephron patterning. Remarkably, wild type renal organoids downregulate mTORC1 signaling compared to adjacent undifferentiated cells. In contrast, both TSC1-/- and TSC2-/- hPSCs exhibit substantial lineage infidelity upon differentiation, staining positively for adipocytic and melanocytic markers which are absent in matched wild type controls. Additionally, knockout lines formed nodular growths with disorganized architecture, resembling the hamartomatous organization of R-AML lesions. These lesions exhibit hyperactive mTORC1 signaling, consistent with human pathology. Together, these data suggest three primary findings: loss of TSC1/2 drives lineage infidelity; TSC1/2 may be required for architectural organization of the kidney parenchyma; and a developmental approach to R-AML modelling may best recapitulate the human disease.
Citation Format: Adam Pietrobon, Sean P. Delaney, Carole Doré, Julien Yockell-Lelievre, Lisa Julian, William L. Stanford. Loss of TSC1 or TSC2 drives lineage infidelity and hamartoma formation in a renal organoid model of angiomyolipoma [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 2974.
Abstract 3004: Establishment of KRAS G12C mutant patient-derived xenograft (PDX) models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy
Authors: Shi Wenting , Tang Xuzhen , Zhang Jingying , Kuang Xinhong , Zhang Yan , Wang Jingjing , Gu Qingyang , Ji Qunsheng 
Published: July 2021

Abstract
KRAS is one of the most prevalent oncogenes in human cancers. The G12C mutation results in an amino acid substitution at position 12 in KRAS, from a glycine (G) to a cysteine (C), lead to accretion of GTP-bound activated state KRAS and activation of downstream signaling pathways. In non-small cell lung cancer (NSCLC), KRAS p.G12C is the most common mutation, comprising nearly half of all KRAS mutations. Recent breakthrough work led to the development of selective inhibitors targeting the KRAS G12C mutation, which have shown promise in early clinical trials. However, the therapeutic benefit of targeted therapies can be impaired by intrinsic or acquired resistance mechanisms, suggesting an urgent need of combinatorial strategies to overcome the resistance to drugs targeting KRAS G12C.Here we report on the establishment of a panel of KRAS G12C mutant PDX models, encompass non-small cell lung cancer, colorectal cancer and gastric cancer. The activity of AMG510, a selective KRAS G12C inhibitors in clinical trial, was characterized in these PDX models. Data showed that the validated KRAS G12C mutant models display a range of sensitivity to single treatment of AMG510. Given that in clinic only 50% of NSCLC patients with KRAS G12C mutation would benefit from KRAS G12C targeted inhibitors, in order to provide an insights for clinical therapeutic strategy, we investigated the combinatorial strategies in NSCLC PDX models: (1) AMG510 combined with Opdivo in KRAS G12C/CD274 amplification models in hPBMC humanized mice; (2) AMG510 combined with EGFR inhibitor in KRAS G12C/EGFR overexpression models. The possible mechanisms of combination effect were discussed. Altogether, the panel of KRAS G12C mutant PDX models are valuable for the pre-clinical evaluation of KRAS G12C targeted anti-cancer therapies.
Citation Format: Wenting Shi, Xuzhen Tang, Jingying Zhang, Xinhong Kuang, Yan Zhang, Jingjing Wang, Qingyang Gu, Qunsheng Ji. Establishment of KRAS G12C mutant patient-derived xenograft (PDX) models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy [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 3004.