bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B19: Role of cell-cell communication in endocrine therapy-resistant breast cancer
Authors: Sengupta Surojeet , Hu Rong , Susswein Zachary , Fagunloye Adeola , Bansal Shweta , Clarke Robert 
Published: June 2020

Abstract
Endocrine therapy is the mainstay for the treatment of estrogen-receptor positive (ER+) breast cancer. However, frequent emergence of endocrine resistance is a major clinical challenge. Cell-cell cooperation in the tumor microenvironment plays a vital role in acquiring resistance, but its role is poorly understood. We studied the interactions among endocrine-resistant (R) and -sensitive (S) breast cancer cells in the presence and absence of ER-targeted endocrine therapy. We measured changes in admixed cell population remodeling by dual fluorescent labeling of LCC1 (S) with eGFP (green fluorescent protein) and their derived resistant variant (selected against the antiestrogen fulvestrant) LCC9 (R) with mCherry (red fluorescent protein), respectively. Thus, unlike most prior studies, these are genetically related cells, rather than ER+ and ER- cell lines obtained from different patients. Our results revealed that “S”cells (LCC1) acquired the phenotype of “R” cells when cultured in a mixed population. A ratio of 5:1 of S:R cells in mixed population was sufficient to confer resistance to fulvestrant to the S cells within a six-day period. Furthermore, we show that acquirement of this resistant phenotype for the S cells was partially blocked by inhibition of either gap junctions or exosome secretion, suggesting a role of cell-cell contact as well as extracellular vesicles. Global proteomic analysis of pure and admixed S and R cell populations showed that R and S can alter key molecular features of each other when present in mixed cell populations. We used a Bayesian approach to fit single culture cell populations to infer density-dependent growth parameters (growth rate, carrying capacity) and a generalized Lotka-Volterra model to understand how S and R coculture populations may be depressing or supporting growth of the other. Our results identify a net mutualistic interaction between the susceptible and resistant cancer strains, demonstrating that there are ecological dynamics to cancer resistance. In some tumors, ecological dynamics may be more mechanistically relevant than simple Darwinian-based clonal selection in driving tumor heterogeneity and determining response to treatment. Our study strongly indicates that different tumor cell types that may exist in tumors are able to influence each other, which leads to alteration of phenotype.
Note: This abstract was not presented at the conference.
Citation Format: Surojeet Sengupta, Rong Hu, Zachary Susswein, Adeola Fagunloye, Shweta Bansal, Robert Clarke. Role of cell-cell communication in endocrine therapy-resistant breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B19.
Abstract B26: A novel dietary advanced glycation end product (AGE) model to assess impact on tumor progression
Authors: Schuster Reid K. , Krisanits Bradley A. , Randise Jamie , Nogueira Lourdes M. , Helke Kristi , LaRue Amanda C. , Turner David P. , Findlay Victoria J. 
Published: June 2020

Abstract
Advanced glycation end products, or AGEs, and their corresponding receptor, the receptor for AGE (RAGE), have roles in several chronic diseases such as diabetes and cardiovascular disease due to their proinflammatory properties. Recently AGE: RAGE signaling has been implicated in a number of cancers, including prostate and breast cancer; however, how AGE: RAGE signaling effects these cancers has not been elucidated. To examine this, we have developed a novel dietary AGE tumor model. Our regular and AGE (TestDiet DIO 58G7) diets consist of equal %k/cal from fat, protein, and carbohydrate; however, the predominant source of carbohydrate in the control diet is starch and in the AGE diet is sugar. To generate the high-AGE diet we autoclave at 120°C for 15 min. In the high-AGE diet, the autoclaving mimics the cooking process in foods and induces the formation of AGEs, allowing us to observe the effects of chronic AGE consumption on both normal developmental processes as well as tumor formation and progression. Specifically, we have been able to show the impact of this diet during time periods where the breast is more susceptible to chronic AGE consumption, namely the “windows of susceptibility.” Additionally, we have applied this novel dietary model to the RAGE null (-/-) mice to explore the role of AGE:RAGE signaling further. Specifically, we have shown that chronic consumption of a high-AGE diet disrupts normal pubertal growth in the mammary gland through the recruitment of aberrant stroma, including fibroblasts and macrophages, and that these aberrant changes persist into adulthood. We further show that dietary AGEs promote aggressive tumor growth through manipulation of the tumor microenvironment and that this is RAGE dependent. We propose that this dietary model can be used as an in vivo method to examine the impact of dietary AGEs on the TME and as a mechanism for potential therapeutic and preventative strategies.
Citation Format: Reid K. Schuster, Bradley A. Krisanits, Jamie Randise, Lourdes M. Nogueira, Kristi Helke, Amanda C. LaRue, David P. Turner, Victoria J. Findlay. A novel dietary advanced glycation end product (AGE) model to assess impact on tumor progression [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B26.
Abstract B40: Minimal mutational determinants of human squamous cell carcinoma
Authors: Planells-Palop Vicente , Koo Angie , Malave Heydi , Lee Katharine , Tward Aaron 
Published: June 2020

Abstract
Dozens of driver mutations and copy number changes have been implicated in human squamous cell carcinomas (SCCs), and each tumor harbors multiple putative driver mutations. However, the minimal set of mutations sufficient to transform a normal keratinocyte into squamous cell carcinoma is unknown. By analyzing TCGA data and previously published datasets, we have identified common combinations of driver mutations in SCCs. Among the most common driver events are mutations in TP53, CDKN2A, and NOTCH1. Using CRISPR editing at endogenous loci in primary human keratinocytes, we demonstrate that no single driver mutation is sufficient to transform keratinocytes, and in fact many single gene mutations appear toxic to keratinocytes. The combination of loss-of-function mutations in TP53 and CDKN2A is sufficient to immortalize both skin and oral primary human keratinocytes in 2D culture and confer a selective advantage in competition assays. Simultaneous mutation of TP53, CDKN2A, and NOTCH1 demonstrates a very similar phenotype in 2D culture as mutation of TP53 and CDKN2A alone. However, using 3D organotypic squamous epithelial cultures consisting of genome-edited keratinocytes grown on decellularized dermis impregnated with fibroblasts and grown at an air-liquid interface demonstrates that keratinocytes with TP53 and CDKN2A mutation alone are sufficient to induce dysplasia, whereas keratinocytes harboring TP53, CDKN2A, and NOTCH1 mutation exhibit an SCC-like phenotype, including invasion through the basement membrane. RNAseq analysis demonstrates that the transition to SCC by NOTCH1 loss involves a partial EMT-like program. Targeted hybrid capture sequencing of edited keratinocytes revealed no other driver mutations or copy number changes other than the experimentally induced ones, consistent with the notion that TP53, CDKN2A, and NOTCH1 mutations alone are sufficient to reprogram a normal keratinocyte into SCC. Thus, despite a high mutation burden and frequent chromosomal instability, as few as three mutational events appear to be sufficient to induce SCC.
Citation Format: Vicente Planells-Palop, Angie Koo, Heydi Malave, Katharine Lee, Aaron Tward. Minimal mutational determinants of human squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B40.
Abstract B47: Mutation of K104 abrogates the oncogenic properties of K-RasG12D
Authors: Yang Moon Hee , Hunt Bethany , Johnson Christian , Simanshu Dhirendra , Haigis Kevin 
Published: June 2020

Abstract
Ras proteins function as small GTPases to regulate a wide range of cellular processes. The activity of Ras is dependent on its nucleotide-binding status, which is modulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Previously, we demonstrated that mutation of K104 to glutamine (K104Q) attenuates the transforming capacity of ectopic oncogenic K-Ras by interrupting GEF-induced nucleotide exchange. In order to assess the biologic relevance of this mutation in vivo, we used CRISPR/Cas9 to generate mouse models carrying the K104Q point mutation in wild-type and conditional K-RasLSL-G12D alleles. Animals homozygous for K104Q were viable, fertile, and arose at Mendelian frequency, indicating that K104Q is not a complete loss-of-function mutation. Consistent with our previous findings from in vitro studies, however, the oncogenic activity of K-RasG12D was significantly attenuated by mutation at K104. These data demonstrate that lysine at position 104 is critical for the full oncogenic activity of mutant K-Ras and suggest that modification at K104, for example acetylation, may also regulate its activity. Using biochemical and structural analysis, we found that the G12D and K104Q mutations cooperate to suppress GEF-mediated nucleotide exchange, explaining the preferential effect of K104Q on oncogenic K-Ras. Finally, we discovered an allosteric regulatory network consisting of K104 and residues on switch II that is key for regulating the stability of the switch II alpha helix. Given the high frequency of KRAS mutations in human cancers, modulation of this network may provide a unique therapeutic approach.
Citation Format: Moon Hee Yang, Bethany Hunt, Christian Johnson, Dhirendra Simanshu, Kevin Haigis. Mutation of K104 abrogates the oncogenic properties of K-RasG12D [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B47.
Abstract IA17: Defining cancer dependency maps
Authors: Hahn William C. 
Published: June 2020

Abstract
Although molecular profiling of human tumors is becoming increasingly routine, the use of this data to guide remains limited to a subset of patients. To complement genome characterization studies, we have used genome-scale gain- and loss-of-function approaches to identify genes required for cell survival and transformation. Specifically, we have used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome-scale RNAi and CRISPR-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. Integrating these studies with genome characterization of human tumors and protein-protein interaction databases facilitates the identification of genes and pathways required for the survival of specific cancer subtypes. In recent studies, we have expanded these efforts to patient-derived organoids and cell lines, which will expand the number and types of cancers represented and allow for the interrogation of other cancer phenotypes. These studies allow us to define a global cancer dependencies map, which will help further operationalize precision cancer medicine.
Citation Format: William C. Hahn. Defining cancer dependency maps [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA17.
Abstract PHA04: A new somatic engineering-based model of small-cell lung cancer development
Authors: Kim Kee-Beom , Kim Dong-Wook , Park Kwon-Sik 
Published: June 2020

Abstract
Defining the cancer genome is essential for understanding the pathogenesis, but it remains challenging due to the paucity of robust models for characterizing recurrent mutations found in cancer. To understand the molecular mechanisms underlying the development of small-cell lung cancer (SCLC), an aggressive type of lung cancer initiated by inactivation of both RB and P53, it is important to determine the functional impact of recurrent mutations found in the patient tumors. To this end, we developed a somatic engineering approach, using a CRISPR/Cre hybrid tool that expresses guide RNA, Cas9 endonuclease, and Cre recombinase from a single adenoviral vector (Ad-target of gRNA-CRISPR/Cre). Intratracheal instillation of this recombinant virus causes mutation in a candidate tumor suppressor gene while recombining floxed alleles of Rb1, Trp53, and Rbl2 in the same epithelial cell. To determine functions of Ep300, Slit2, and Fhit, whose orthologous genes are frequently mutated in SCLC patient tumors, we infect the Rb1/Trp53/Rbl2 conditional mice with the viral vectors carrying gRNAs against these genes. The mice infected with Ad-Ep300-CRISPR/Cre or Ad-Fhit-CRISPR/Cre have higher tumor burden in the lungs than those infected with Ad-lacZ-CRISPR/Cre used as control. Although Slit2 is significantly mutated in SCLC, the mice infected with Ad-Slit2-CRISPR/Cre do not increase tumor burden relative to those with Ad-lacZ-CRISPR/Cre. These results for the first time validate the oncogenic impact of Ep300 and Fhit mutations. This study demonstrates the feasibility and robustness of a new somatic engineering-based model for characterizing candidate mutations, which will facilitate the discovery of key oncogenic drivers and pathways from the large number of novel somatic alterations in SCLC. Ongoing efforts with this new approach are focused on validation of functionally unknown mutations alone or in combinations.
This abstract is also being presented as Poster A39.
Citation Format: Kee-Beom Kim, Dong-Wook Kim, Kwon-Sik Park. A new somatic engineering-based model of small-cell lung cancer development [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA04.
Abstract PR01: Developmental reprogramming via Hedgehog pathway activation in nonmyogenic endothelial progenitors drives fusion-negative rhabdomyosarcoma
Authors: Drummond Catherine J. , Gadek Kathrine E. , Bush Madeline , Garcia Matthew R. , Hatley Mark E. 
Published: June 2020

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite aggressive chemotherapy, radiotherapy, and surgery, clinical outcomes for RMS have not improved for three decades, emphasizing the need to uncover the molecular underpinnings of the disease. RMS has been presumed to originate from derailed muscle progenitors based on the histologic appearance and gene expression pattern of the tumors, resembling embryonic developing skeletal muscle. However, an origin restricted to skeletal muscle does not explain RMS occurring in tissues devoid of skeletal muscle such as the prostate, bladder, salivary gland, biliary tree, and omentum. Previously, we described that activation of Sonic Hedgehog signaling through expression of a conditional, constitutively active Smoothened allele, SmoM2, under control of a presumed adipocyte-restricted adipose protein 2 (aP2)-Cre recombinase transgene in mice, gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human embryonal RMS (ERMS). With the short latency and anatomically restricted tumor location in the neck, we sought to leverage this model to explore the cell of origin of ERMS. Lineage tracing experiments identified aP2-Cre labeled cells are distinctly nonmyogenic and were identified as endothelial cells found in the interstitium between muscle fibers. We illustrate that aP2-Cre is not expressed in the quiescent or activated muscle stem cells or satellite cells. Expression of oncogenic SmoM2 with aP2-Cre results in proliferation and expansion of the aP2-Cre labeled muscle interstitial endothelial cells and myogenic transdifferentiation resulting in ERMS. Activation of the hedgehog pathway in aP2-Cre labeled endothelial progenitors results in expression of skeletal muscle specification factors specific in the head and neck development, including TBX1, PITX2, TCF21, and MSC. We illustrate that endothelium and skeletal muscle within the head and neck arise from KDR (VEFGR2)-expressing progenitors. Hedgehog pathway activation in committed KDR+ endothelial progenitors results in Tbx1 expression and subsequent MYOD1 expression driving a partially myogenic program characteristic of ERMS. Our work identifies reprogramming cell fate as a mechanism of transformation in pediatric sarcoma and illustrates that it is dangerous to assume the cell of origin from the characteristics of the tumor cell.
Citation Format: Catherine J. Drummond, Kathrine E. Gadek, Madeline Bush, Matthew R. Garcia, Mark E. Hatley. Developmental reprogramming via Hedgehog pathway activation in nonmyogenic endothelial progenitors drives fusion-negative rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR01.
Blockade of PAR‐1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin‐Overexpressing Hypertensive Mice
Authors: Yokono Yoshikazu , Hanada Kenji , Narita Masato , Tatara Yota , Kawamura Yousuke , Miura Naotake , Kitayama Kazutaka , Nakata Masamichi , Nozaka Masashi , Kato Tomo , Kudo Natsumi , Tsushima Michiko , Toyama Yuichi , Itoh Ken , Tomita Hirofumi 
Published: June 2020

Background

Although PAR‐1 (protease‐activated receptor‐1) exerts important functions in the pathophysiology of the cardiovascular system, the role of
PAR
‐1 signaling in heart failure development remains largely unknown. We tested the hypothesis that
PAR
‐1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin–angiotensin system activation using renin‐overexpressing hypertensive (Ren‐Tg) mice.

Methods and Results

We treated 12‐ to 16‐week‐old male wild‐type (
WT
) mice and Ren‐Tg mice with continuous subcutaneous infusion of the
PAR
‐1 antagonist
SCH
79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren‐Tg mice than in
WT
mice, and
SCH
79797 treatment significantly decreased these thicknesses in Ren‐Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren‐Tg mice than in
WT
mice, and both conditions were attenuated by
SCH
79797 treatment. Cardiac
mRNA
expression levels of
PAR
‐1, TNF‐α (tumor necrosis factor‐α), TGF‐β1 (transforming growth factor‐β1), and COL3A1 (collagen type 3 α1 chain) and the ratio of β‐myosin heavy chain (β‐
MHC
) to α‐
MHC
were all greater in Ren‐Tg mice than in
WT
mice;
SCH
79797 treatment attenuated these increases in Ren‐Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren‐Tg mice than in
WT
mice, and both conditions were unaffected by
SCH
79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal‐regulated kinase 1/2) phosphorylation, and
SCH
79797 pretreatment abolished this enhancement. Furthermore, gene expression of
PAR
‐1,
TGF
‐β1, and
COL
3A1 were enhanced by factor Xa, and all were inhibited by
SCH
79797.

Conclusions

The results indicate that
PAR
‐1 signaling is involved in cardiac remodeling induced by renin–angiotensin system activation, which may provide a novel therapeutic target for heart failure.
Cactodera solani n. sp. (Nematoda: Heteroderidae), a new species of cyst-forming nematode parasitising tomato in Mexico
Authors: Escobar-Avila Ilia Mariana , Subbotin Sergei A. , Tovar-Soto Alejandro 
Published: June 2020

Summary
A new species of cyst-forming nematode, Cactodera solani n. sp., from Mexico is described. The new species was found in a glasshouse in Mexico City parasitising tomato and common lambsquarter. This cyst nematode has light brown to almost black cysts, presents a small vulval cone with circumfenestra and morphologically it most resembles C. milleri. Cactodera solani n. sp. can be differentiated from C. milleri by having smaller cysts that are 417 (291-581) × 324 (204-505) vs 632 (515-730) × 506 (419-598) μm in size and a longer stylet in the second-stage juveniles of 25 (24-27) vs 22 (21-23) μm. Phylogenetic relationships within populations and species of Cactodera are given based on the analysis of the ITS rRNA and the partial COI gene sequences. The ITS rRNA and COI gene sequences clearly differentiated C. solani n. sp. from other Cactodera species. This new cyst-forming nematode has several generations per year and its life cycle can be completed in 49 days on tomato and in 40 days on common lambsquarter at 20-25°C.
The Terror of Time: The Festival of Dionysus and Saturnalia in Jewish Responses to Foreign Rule
Authors: Bonesho Catherine E. 
Published: June 2020

Abstract
Proper observance of festivals is a major concern in early Jewish literature, but the festivals of the gentiles also figure prominently in this period. Two such festivals are the Greek Festival of Dionysus, described in Second Maccabees, and the Roman festival of Saturnalia, described in the Palestinian Talmud. I show the varied ways in which the authors of these texts, members of different groups, with different textual practices, and living centuries apart, problematize foreign holidays in their responses to imperial rule. Though the polemic against gentiles is heightened in both texts, the epitomator primarily problematizes the Festival of Dionysus because its observance is a violation of ancestral law, while the Palestinian Amoraim stress Saturnalia’s status as a Roman holiday. The different emphases in these discussions of gentile festivals distinguish the prerogatives of these two Jewish communities, their understandings of gentile festivals, and their respective responses to Greek and Roman hegemony.
The New and the Old: A Qualitative Analysis of Modes of Conflict Resolution in the Kingdom of Saudi Arabia
Authors: Pilotti Maura A. E. , El Alaoui Khadija , Salameh Muamar Hasan , Singh Sukhsimranjit , Al Mulhem Huda 
Published: June 2020

Abstract
Using a case study method, we examine how practitioners, including judges, arbitrators and community mediators, view dispute resolution in the Kingdom of Saudi Arabia (KSA). The goal of this study is to assess whether traditional approaches to dispute resolution coexist with or are discarded for imported modes. Participants were selected through convenience sampling. Structured interviews involved (a) participants’ general theoretical foundations, (b) key principles that govern their professional role, (c) their views of different roles, and (d) the extent to which traditional modi operandi persist. The results highlight the dominance of principles and practices of Sharia law over common law. Although the use of formal Western procedures was reported in commercial disputes and rarely in family and tribal matters, implementation was undeniably shaped by religious and kin-based social habits and values.