bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A43: Loss of Keap1 promotes KRAS-driven lung cancer and results in genotype-specific vulnerabilities
Authors: Romero Rodrigo , Sayin Volkan I. , Shawn Davidson M. , Bauer Matthew , Singh Simranjit X. , LeBoeuf Sarah , Karakousi Triantafyllia R. , Ellis Donald C. , Bhutkar Arjun , Sanchez-Rivera Francisco , Subbaraj Lakshmipriya , Martinez Britney , Bronson Roderick T. , Prigge Justin R. , Schmidt Edward E. , Thomas Craig J. , Davies Angela , Dolgalev Igor , Heguy Adriana , Allaj Viola , Piorier John T. , Moreira Andre L. , Rudin Charles M. , Pass Harvey I. , Heiden Matthew G. Vander , Jacks Tyler , Papagiannakopoulos Thales 
Published: May 2018

Abstract
Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1)2-4, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response5-10. The high frequency of mutations in KEAP1, which would be predicted to result in activation of the NRF2 pathway, suggests an important role for the oxidative stress response in lung tumorigenesis. To test this directly, we used a CRISPR/Cas9-based approach in a mouse model of Kras-driven LUAD to examine the effects of loss of KEAP1 function in lung cancer progression. We show that loss of KEAP1 hyper-activates Nrf2 and promotes Kras-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we also show that KEAP1/NRF2 mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacologic inhibition of glutaminase. Finally, we provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2 mutant tumors as likely to respond to glutaminase inhibition.
Citation Format: Rodrigo Romero, Volkan I. Sayin, Davidson M. Shawn, Matthew Bauer, Simranjit X. Singh, Sarah LeBoeuf, Triantafyllia R. Karakousi, Donald C. Ellis, Arjun Bhutkar, Francisco Sanchez-Rivera, Lakshmipriya Subbaraj, Britney Martinez, Roderick T. Bronson, Justin R. Prigge, Edward E. Schmidt, Craig J. Thomas, Angela Davies, Igor Dolgalev, Adriana Heguy, Viola Allaj, John T. Piorier, Andre L. Moreira, Charles M. Rudin, Harvey I. Pass, Matthew G. Vander Heiden, Tyler Jacks, Thales Papagiannakopoulos. Loss of Keap1 promotes KRAS-driven lung cancer and results in genotype-specific vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A43.
Abstract A49: Using IL10-/- mouse model to assess heavy-ion radiation exposure-associated colitis and colorectal cancer incidence
Authors: Suman Shubhankar , Moon Bo-Hyun , Fornace Albert J. , Datta Kamal 
Published: May 2018

Abstract
Underlying risk of γ-ray-induced colitis and colorectal cancer incidence is emphasized by the studies on atom bomb survivors and also in patients undergoing radiotherapy. However, uncertainties in colitis and CRC risk prediction after exposure to high-LET space (particle) radiation exposure has not been realized due to lack of reliable in vivo data. Here we report IL10-/- mice as a suitable mouse model for assessment of colitis and CRC risk after exposure to space radiation.
Male mice (n=12 mice/group) were whole-body exposed to sham-radiation, γ-rays (137Cs-source, 2.0 Gy), and 28Si-ion (300 MeV/n; 70 keV/μm; 1.4 Gy). We used γ-ray equitoxic doses using relative biologic effectiveness (RBE) values determined earlier. Mice were sacrificed 90 days after irradiation, and colon swiss rolls were prepared and histopathologic assessment of colitis score and CRC grade was noted. Further, inflammation-associated gene-expression analysis was conducted in both radiation-induced tumor and adjoining normal tissue area. Immunohistochemistry (β-catenin, Cyclin-D1, and phospho-histone H3) was also performed to assess HZE-induced proliferative signaling.
Relative to controls and γ-ray, colitis score, colon tumor incidence, size, and grade were significantly higher after space (28Si-ion) radiation exposure. Additionally, tumor incidence per unit of radiation (per cGy) was also higher after 28Si-ion radiation relative to γ radiation. Higher number of phospho-histone H3-positive cells in 28Si-ion exposed mouse colon demonstrated increased proliferative index resulting in increased intestinal tumors of larger size and grade was due to greater activation of β-catenin and its downstream effector cyclin D1. Inflammatory gene signature was more pronounced after 28Si-ion exposure. Significant upregulation of GATA4, ICAM1, ITGA2, and EGFR was exclusive to 28Si-ion exposed mouse colon; however, PTGES and TGFβ1 were upregulated in both γ and 28Si-ion exposed mice.
Overall, our findings suggest that IL10-/- mice are a suitable model to assess IR-induced colitis and CRC risk and space radiation carries higher risk of colitis and CRC incidence, relative to γ-rays at comparable doses. This study has implications for risk prediction in astronauts planning for deep-space missions and also for cancer patients planning to undergo particle radiotherapy.
Citation Format: Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Jr., Kamal Datta. Using IL10-/- mouse model to assess heavy-ion radiation exposure-associated colitis and colorectal cancer incidence [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A49.
Abstract A52: Arid1a exerts context-dependent oncogenic and tumor suppressor functions in liver cancer
Authors: Sun Xuxu , Wang Sam , Zhang Shuyuan , Zhu Hao 
Published: May 2018

Abstract
ARID1A, an ATP-dependent SWI/SNF chromatin remodeling complex component, is hypothesized to be one of the most commonly mutated tumor suppressors in human cancer. Using mouse liver cancer models, we sought to elucidate the functional consequences of ARID1A gain and loss. Surprisingly, mice with liver-specific Arid1a deficiency were resistant to chemical- and MYC-induced liver carcinogenesis, while ARID1A overexpression accelerated tumorigenesis when combined with a variety of oncogenes, indicating an important role during tumor initiation. Mechanistically, Arid1a promoted tumor initiation by increasing cytochrome P450-mediated oxidative stress. In human HCCs, late ARID1A loss has been observed upon metastatic spread, suggesting that deleterious mutations do occur after tumor initiation. Indeed, both homozygous and heterozygous loss after liver tumor formation in mice were sufficient to drive progression and metastasis. Intriguingly, the Arid1a haploinsufficient state was sufficient to globally increase chromatin occupancy and downregulate metastasis suppressor genes within tumors. In summary, ARID1A can play both tumor-suppressive and oncogenic roles in liver cancer in a temporally dependent manner, explaining the expression and mutation patterns seen in human HCC.
Citation Format: Xuxu Sun, Sam Wang, Shuyuan Zhang, Hao Zhu. Arid1a exerts context-dependent oncogenic and tumor suppressor functions in liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A52.
Abstract B07: Role of lysyl hydroxylases in metastatic lung cancer
Authors: Liu Wei , Zhang Ting , Guo Lixia , Wang Yuanyuan , Yang Yanan 
Published: May 2018

Abstract
Lung cancer remains the leading cause of cancer-related death, partly due to the fact that most patients are diagnosed with metastatic disease, which is the main cause of death, yet effective therapeutics are lacking. Utilizing mouse models of metastatic lung adenocarcinomas, we report that the transcription factor GATA3 and its cofactor FOG2 play critical roles in lung adenocarcinoma metastasis by promoting the expression of the lysyl hydroxylase (LH) family members, which in turn regulate the tumorigenicity and motility of lung tumor cells through both EMT and EMT-independent mechanisms. In vivo, LHs are elevated in human lung adenocarcinomas and are associated with worse patient survival. Collectively, our data suggest that targeting LHs may be useful for treating metastatic lung cancer.
Citation Format: Wei Liu, Ting Zhang, Lixia Guo, Yuanyuan Wang, Yanan Yang. Role of lysyl hydroxylases in metastatic lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B07.
Abstract B13: The prevention of lymphoproliferative lesions arising in patient-derived cancer xenografts by anti-graft-versus-host-disease agents
Authors: Chijiwa Tsuyoshi , Noguchi Akira , Komura Daisuke , Katayama Makoto , Haraguchi Mizuha , Hashimoto Haruo , Suemizu Hiroshi , Nakamura Yoshiyasu , Furukawa Daisuke , Isagawa Takayuki , Katoh Hiroto , Moriya Takashi , Ishikawa Shumpei , Nakamura Masato , Miyagi Yohei 
Published: May 2018

Abstract
Xenografts derived from engrafting fresh surgical specimens directly onto immunodeficient mice have enabled the development of more relevant in vivo models for human cancers. Such patient-derived xenograft (PDX) models retain similar morphology, heterogeneities, and molecular signatures with the original cancers. We reported the rapid and efficient establishment of PDXs using super-immunodeficient NOG mice (PDX/NOG models). During the establishment process, a transplantable lymphoproliferative lesion (LPL) that replaces the original tumor cells sometimes occurs. The occurrence of LPL is the most problematic aspect of the establishment of PDX. This phenomenon may arise because of the Epstein-Barr virus due to the severely immunodeficient nature of the animal model; however, the mechanisms underlying LPL have not yet been elucidated in detail. In the present study, we histologically analyzed and tried to prevent the occurrence of LPL in PDX/NOG.
Over 100 lines of cancer xenografts were established in our previous studies. Throughout these processes, we also established 10 LPL-PDX lines. Some LPL-PDX lines consist of B cells, T cells, and differentiated plasma cells. These LPL lymphocytes exhibited negligible proliferative potency in vitro. The invasions of LPL in the liver, lung, and pancreas were observed immunohistochemically.
NOG mice bearing LPL-PDX (LPL-PDX/NOG) were treated with the anti-graft-versus-host-disease (anti-GVHD) drugs FK506 (1.0 mg/kg/day) and mycophenolate mofetil (MMF, 120 mg/kg/day) for 4 weeks using intraperitoneal injections. The LPL proliferations were significantly suppressed with FK506 (p=0.011) and MMF (p=0.014) compared with the control.
The occurrence of LPL during establishment of PDX may be based on the GVHD-like mechanism. This phenomenon can be prevented by using anti-GVHD agents in the severely immunodeficient mice. The LPL-PDX/NOG models are also proposed for the utilization of GVHD mouse models with organic damage, particularly chronic GVHD mouse models.
Citation Format: Tsuyoshi Chijiwa, Akira Noguchi, Daisuke Komura, Makoto Katayama, Mizuha Haraguchi, Haruo Hashimoto, Hiroshi Suemizu, Yoshiyasu Nakamura, Daisuke Furukawa, Takayuki Isagawa, Hiroto Katoh, Takashi Moriya, Shumpei Ishikawa, Masato Nakamura, Yohei Miyagi. The prevention of lymphoproliferative lesions arising in patient-derived cancer xenografts by anti-graft-versus-host-disease agents [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B13.
Abstract B24: Stem cell lineage infidelity drives wound repair and cancer
Authors: Ge Yejing , Fuchs Elaine 
Published: May 2018

Abstract
Human adult tissues harbor resident stem cells (SCs) responsible for homeostasis and wound repair. Tumorigenesis arises when normal SCs accumulate mutations that cause them to derail, shifting their homeostatic balance to favor tissue growth at the expense of differentiation. In contrast to wound repair, where the growth:differentiation imbalance is transient, cancers are refractory to tissue restoration cues, seemingly hijacking these normal cellular programs to fuel their molecular thirst for uncontrolled growth.
The notion that a “cancer is a wound that never heals” has origins dating back to Rudolf Virchow in the 1800s. Since then, intimate connections between wounds and tumors have also been drawn at the molecular level. Although intriguing, it remains unclear which of the normal SC remodeling pathways are exploited by tumor SCs and how cancers rewire preinstalled regulatory networks to support malignancy.
Here, we investigate such a phenomenon in the skin, where during homeostasis, stem cells of epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement--granting privileges associated with both fates--is not only a hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Probing the mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate new oncogenic enhancers that distinguish cancers from wounds.
Citation Format: Yejing Ge, Elaine Fuchs. Stem cell lineage infidelity drives wound repair and cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B24.
Abstract B28: Development of estrogen-dependent and estrogen receptor-negative cervical cancer in HPV transgenic mice
Authors: Son Jieun , Chung Sang-Hyuk 
Published: May 2018

Abstract
Estradiol (E2) and human papillomavirus (HPV) cooperate to cause cervical cancer. The role of estrogen receptor α (ERα) in cervical cancer has been underappreciated. Chronic treatment with E2 promotes the development of cervical cancer in K14E7 transgenic mice expressing HPV16 E7 oncoprotein. In the present study, we bred K14E7 to mice with conditional ablation of Esr1 (ERα-coding gene) in the cervical epithelial cells (Wnt7aCre/Esr1f/f; Esr1ed/ed). We found that E2 promoted the development of ERα cervical cancer in K14E7/Esr1ed/ed mice. In addition, proliferation and apoptotic indices of ERα cancer in K14E7/Esr1ed/ed mice were similar to those of ERα+ cancer in K14E7/Esr1f/f mice. We also found that E2 increased the epithelium thickness and epithelial cell proliferation in the cervix of Esr1ed/ed mice. Our published results have demonstrated that deletion of Esr1 in the cervical stroma promotes the regression of cervical precancer lesions in K14E7 mice. In patients, ERα is expressed in the cancer stroma but not cancer epithelial cells. These observations support that stromal ERα, rather than epithelial ERα, mainly mediates oncogenic E2 signaling for cervical cancer. They also suggest that stromal ERα might be an effective therapeutic target for cervical cancer.
Note: This abstract was not presented at the conference.
Citation Format: Jieun Son, Sang-Hyuk Chung. Development of estrogen-dependent and estrogen receptor-negative cervical cancer in HPV transgenic mice [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B28.
Abstract B29: A carcinogen-induced mouse model recapitulates the molecular alterations of human muscle-invasive bladder cancer
Authors: Fantini Damiano , Glaser Alexander P. , Kalen Rimar J. , Yiduo Wang , Yu Yanni , Meeks Joshua J. 
Published: May 2018

Abstract
Bladder cancer is the fourth most common cancer in men and fifth most common malignancy in the United States. Survival of patients with muscle-invasive or metastatic bladder cancer is poor, with only 35% survival at 5 years. Developing innovative anticancer drugs relies on the availability of model systems that closely recapitulate the corresponding human disease at both the histologic and molecular levels. One of the major limitations in the field of bladder cancer research is the limited availability of such models.
The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) since it recapitulates the complex histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level.
In our study, we analyzed the mutational landscape of the BBN model by whole-exome sequencing followed by a bioinformatic comparison to human MIBC using genomic data from The Cancer Genome Atlas and other repositories. Similar to human MIBC, BBN tumors had a high mutation burden. Next, we extracted mouse-specific mutational signatures that correspond to different genetic instability processes operating in BBN tumors. Interestingly, one of these de novo extracted signatures aligned to a human mutational signature previously associated to DNA-repair deficiencies in human bladder cancers. We further analyzed the most commonly mutated genes and their intratumor mutation frequencies with the aim of identifying potential driver mutations. Our analyses converged on three genes that seem crucial in the process of tumorigenesis in both mouse and human bladder cancers: the tumor suppressor Trp53 as well as the genes Kmt2c and Kmt2d. These encode for methyltransferases involved in the methylation of histone H3K4 and play a key role in the epigenetic regulation of enhancer activity. Also, many of the putative driver mutations found in the BBN genomes corresponded to human cancer hotspot mutations, supporting their role as driver mutations.
Together, our study revealed several similarities between human MIBC and the BBN mouse model. Our results highlighted the contribution of aberrations to chromatin regulators and genetic instability in both human and BBN bladder tumors, thus providing a strong rationale for the use of this mouse model in molecular and drug discovery studies.
Citation Format: Damiano Fantini, Alexander P. Glaser, Rimar J. Kalen, Wang Yiduo, Yanni Yu, Joshua J. Meeks. A carcinogen-induced mouse model recapitulates the molecular alterations of human muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B29.
Abstract IA03: Cancer modeling in the CRISPR age
Authors: Ventura Andrea 
Published: May 2018

Abstract
The widespread use of high-throughput genomic methods is profoundly changing the way we understand, classify, and treat cancers, and provides unprecedented opportunities to design therapeutic approaches tailored to individual patients. The success of these efforts is contingent on our ability to identify, among the hundreds of different genetic lesions, those that actively drive tumorigenesis.
The recent development of powerful genome editing methods promises to greatly speed up this process and allows us, for the first time, to model a wide range of previously inaccessible cancer-associated mutations.
I will discuss how CRISPR-based gene editing methods are revolutionizing cancer. I will also show how my group is combining computational methods and in vivo somatic genome editing approaches to generate and characterize novel mouse models of human cancers and to explore the noncoding fraction of the cancer genome.
Citation Format: Andrea Ventura. Cancer modeling in the CRISPR age [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA03.
Abstract IA08: Somatic p53 mutations drive development of triple-negative breast cancer with evolutionarily distinct metastases
Authors: Zhang Yun , Xiong Shunbin , Lozano Guillermina 
Published: May 2018

Abstract
Breast cancer is a heterogeneous disease generally comprising four molecular subtypes: luminal A, luminal B, HER-2 enriched, and basal-like. Basal-like breast cancers, the majority of which are triple-negative breast cancers (TNBCs), are the most aggressive with the poorest prognosis and no targeted therapies. The majority of these tumors (80-88%) have mutations in the TP53 tumor suppressor, which suggests an important role for TP53 mutations in tumor initiation and progression. We have created two novel conditional mutant p53 alleles in the mouse, p53wm-R172H and p53wm-R245W. These alleles are wild type, but in response to Cre-mediated recombination, they produce p53R172H and p53R245W proteins that correspond to p53R175H and p53R248W hot spot mutants in human TNBCs. In a somatic breast cancer model, p53 mutations in a few mammary epithelial cells were generated using intraductal injection of Ad-Cre. Importantly, the stroma and immune cells retain wild type p53. p53wm-R172H/+ mice rarely developed breast cancer while p53wm-R172H/fl (includes the p53R172H mutation and a p53-null allele) and p53wm-R245W/+ readily developed breast carcinomas, a subset of which are TNBCs that metastasized to the lung and liver, common sites of human breast cancer metastasis. Whole-exome sequencing of p53R245W tumors revealed different evolution patterns for metastases. These models most closely simulate the genesis of TNBCs and will thus be invaluable in testing novel therapeutic combinations.
Citation Format: Yun Zhang, Shunbin Xiong, Guillermina Lozano. Somatic p53 mutations drive development of triple-negative breast cancer with evolutionarily distinct metastases [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA08.