bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A29: Dissecting the mechanisms of senescence immune surveillance in liver cancer
Authors: Chen Hsuan-An , Alonso-Curbelo Direna , Ho Yu-Jui , Morris John P. , Houlihan Shauna , Smolkin Ryan , Luan Wei , Hendrickson Ronald C. , Lowe Scott W. 
Published: June 2020

Abstract
Senescence is a cell cycle arrest program that limits the expansion of damaged cells and can trigger antitumor immunity that leads to their elimination in vivo, serving as a potent barrier to tumorigenesis. However, during tumor initiation, the effective clearance of senescent cells is compromised, warranting a deeper mechanistic understanding of this process. To define the critical immunomodulatory factors mediating senescence immune surveillance and how these mechanisms are bypassed during cancer development and progression, we exploited a genetic approach in which liver tumor cells can be triggered to senesce by restoration of tumor suppressor p53. p53 reactivation triggers cytostatic response in vitro, yet it drives robust regression of established liver tumors in immunocompetent mice. Profiling of the immune landscape upon senescence induction revealed that there is an accumulation of CD8 and CD4 T cells in the tumor microenvironment. Consistently, immune cell blockade through depleting antibodies blunts tumor regression, indicating a key role of adaptive immunity in this process. To gain mechanistic insight into how senescent cells are recognized by the immune system, RNA-seq and mass spectrometry were conducted on both proliferating and senescent tumor cells and revealed several senescence-enriched cell surface factors related to epithelial-immune cell interactions and MHC-I presentation. Ongoing work aims to functionally interrogate the role of these senescence-induced factors as novel senescence surveillance effectors. Our research will increase the current knowledge of the strategies to trigger senescence in advanced cancers that can restore immune surveillance programs lost during the course of tumor evolution.
Citation Format: Hsuan-An Chen, Direna Alonso-Curbelo, Yu-Jui Ho, John P. Morris IV, Shauna Houlihan, Ryan Smolkin, Wei Luan, Ronald C. Hendrickson, Scott W. Lowe. Dissecting the mechanisms of senescence immune surveillance in liver 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 A29.
Abstract A36: Organoid models for deciphering roles of the evolving landscape of epigenetic heterogeneity during aging in cancer development
Authors: Tao Yong , Kang Byunghak , Petkovich Daniel , Baylin Steve , Easwaran Hariharan 
Published: June 2020

Abstract
Background: Tumor initiation and development occur not necessarily by genetic changes alone, but in the context of the epigenome and cell microenvironment. Growing evidence indicate that cancer risk factors, such as aging and inflammation, may primarily modulate the epigenome, causing predisposition to cancer development by driver mutations. Thus, there is a need to study and model epigenetic changes preceding and associating with cancer development. We have developed ex vivo models for investigating the evolution and roles of DNA methylation changes during normal cell divisions and how these epigenetic changes play critical roles in early stages of tumor development.
Results: We showed that spontaneous epigenetic changes, specifically promoter-DNA hypermethylation, have a very important role in tumor initiation by oncogenic driver mutations. We addressed the precursor role of aging-like spontaneous promoter-DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show promoter hypermethylation spontaneously arises in cells mimicking the human “aging-like” phenotype. The silenced genes activate the Wnt pathway, causing a stemlike state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E producing the typical human proximal BRAFV600E-driven colon adenocarcinomas characterized by extensive, abnormal gene promoter CGI methylation or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitized to BrafV600E-induced transformation. We showed that “spontaneous” promoter hypermethylation, arising in an “aging-like” scenario, sufficiently affects genes with roles in negative regulation of Wnt pathway. Inactivation of these genes leads to increased stem cell state and defects in differentiation.
Conclusion: Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis. The organoid-based model opens up an opportunity to study mechanisms underlying epigenetic heterogeneity arising during normal cellular processes and their role in cancer predisposition.
Citation Format: Yong Tao, Byunghak Kang, Daniel Petkovich, Steve Baylin, Hariharan Easwaran. Organoid models for deciphering roles of the evolving landscape of epigenetic heterogeneity during aging in 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 A36.
Abstract A38: A critical role of Wnt5a-Axin2 axis in small-cell lung cancer development
Authors: Kim Kee-Beom , Kim Dong-Wook , Kim Youngchul , Park Jae-Il , Park Kwon-Sik 
Published: June 2020

Abstract
The paucity of readily actionable alterations in the small-cell lung cancer (SCLC) genome necessitates exploration of alternative targets for clinical intervention, including reactivated developmental signaling pathways. Despite the widespread implication of deregulated WNT signaling in cancer, its role in the pathogenesis of SCLC remains unknown. In this study, we observe selective induction of Axin2, a target of WNT pathway, and its genetic reporter in the lung tumors developed in genetically engineered mouse models (GEMM) of SCLC. Intriguingly, however, other transcription targets of b-catenin-dependent “canonical” pathway are downregulated in tumors relative to normal lung, and knockout of Ctnnb1 encoding b-catenin does not affect tumor development in the GEMM. On the other hand, Axin2 knockout, which enhances b-catenin level, suppresses the tumor development. These findings suggest not only the dispensability of b-catenin-dependent pathway but also the significant role of Axin2 in SCLC. Meanwhile, we observe that tumors and cell lines express significantly higher levels of ligands for b-catenin-independent “noncanonical” pathway, including Wnt5a, than precancerous cells (preSC) as well as whole lung. Ectopic Wnt5a in preSC enhances cell proliferation in culture and tumorigenic capacity in athymic nude mice while increasing Axin2 expression. Depletion of Wnt5a suppresses cell proliferation and tumor development. Taken together, these results suggest a critical role of the Wnt5a-Axin2 axis in SCLC development.
Citation Format: Kee-Beom Kim, Dong-Wook Kim, Youngchul Kim, Jae-Il Park, Kwon-Sik Park. A critical role of Wnt5a-Axin2 axis in 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 A38.
Abstract B08: High-resolution positron emission microscopy of patient-derived tumor organoids
Authors: Khan Syamantak , Shin June Ho , Cheng Ning , Kuo Calvin , Sunwoo John , Pratx Guillem 
Published: June 2020

Abstract
Tumor organoids are self-organizing three-dimensional tumor models grown in vitro from patient-derived tumor tissue. They closely recapitulate the structural and functional microenvironment of solid tumors. Rapid translation of biomedical information from preclinical models to patients requires imaging biomarkers that span the full scale of tumor models. However, a key limitation is that, unlike human patients or preclinical mouse models, the tiny organoids are incompatible with the suite of radiologic tools used in oncology clinics. Here, we present 18F-fluorodeoxyglucose positron-emission microscopy (FDG-PEM), a radioluminescence-based technique for imaging glucose metabolism in patient-derived tumor organoids with spatial resolution 100-fold better than that of clinical positron emission tomography (PET). Tumor organoids derived from head-and-neck cancer patients were imaged to reveal metabolic maps that, in combination with brightfield imaging, functionally mirror the PET/CT images from the clinic. Tumor organoids were fed with FDG and mounted on a thin CdWO4 scintillator plate. Scintillator flashes were directly imaged by a single-photon-sensitivity electron-multiplying charge-coupled devices (EMCCD) camera. The EMCCD signal was calibrated with known radioactivity of FDG for accurate quantification of PEM images. Dual-modality PEM/fluorescence imaging found that FDG uptake occurred mainly in the viable region of tumor organoids and was more specific than staining by 2-NBDG, a fluorescent glucose mimetic. The influx rate constant (Ki) of FDG into the tumor organoids was calculated and found to be similar to the patient tumor from which the organoids were grown. This positive correlation of FDG influx between patient and organoid tumor suggests that PEM can be a preclinical tool to bridge the gap between laboratory and clinical cancer imaging. Finally, organoids treated with cisplatin displayed a dose-dependent decrease in the metabolic activity, while organoids derived from cisplatin-resistant patients retained high metabolic activity despite cisplatin treatment. Our results suggest that PEM imaging of patient-derived organoids could be used to predict individual patient response to different treatments to provide a more personalized approach to cancer care.
Citation Format: Syamantak Khan, June Ho Shin, Ning Cheng, Calvin Kuo, John Sunwoo, Guillem Pratx. High-resolution positron emission microscopy of patient-derived tumor organoids [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 B08.
Abstract B13: A novel mouse model for small-cell carcinoma of bladder
Authors: Xu Dongbo , Cao Qiang , Wang Li , Wang Yanqing , Zhang Xiaojing , Wu Yue , Smith Gary , Xu Bo , Goodrich David , Li Qiang 
Published: June 2020

Abstract
Background: Molecular characterization studies suggest the neuronal subtype muscle invasive bladder cancer (MIBC) is associated with a high response rate to immune checkpoint inhibitor. We sought to establish a mouse model for small-cell carcinoma of bladder.
Materials and Methods: Three canonical signaling pathways (TP53, RB1, and RTK/PI3K/AKT) are commonly altered in small-cell bladder cancer. Keratin 5 promoter-driven adenovirus Cre (Ad-K5-Cre, University of Iowa) was instilled into the bladder of female triple floxed (Trp53f/f:Pten f/f:Rb1 f/f) mice for 30 min. The mice were monitored for hematuria and bladder mass using ultrasound.
Results: One Ad-K5-Cre:Trp53-/-: Pten-/-: Rb1-/- mouse died from urinary obstruction at 22 weeks. An obstructive tumor was noted in bladder trigone. Immunohistochemistry analysis of bladder tumor demonstrated negative cytokeratin 7 (CK7) expression and strong synaptophysin expression. Disseminated metastatic foci in lung were noted with positive synaptophysin expression as of primary tumor in the bladder. PCR demonstrated Cre mediated recombined alleles of the Trp53, Pten, and Rb1 in the tumor DNA but not in the tail DNA. The bladder tumor was dissociated to generate an organoid line. The organoid after 5 passages was tested for drug response of standard chemotherapy regimens. IC50 of cisplatin, etoposide, and gemcitabine were 3.1 μM, 0.8 μM, and 92.3 nM, respectively. Further characterization of more mice will address the limitation of small sample size.
Conclusion: Inactivation of Trp53, Pten, and Rb1 is sufficient to induce metastatic small-cell carcinoma of bladder. This mouse model provides a powerful tool to study molecular mechanism of neuroendocrine differentiation and screen novel therapeutic drugs for small-cell carcinoma of bladder.
Citation Format: Dongbo Xu, Qiang Cao, Li Wang, Yanqing Wang, Xiaojing Zhang, Yue Wu, Gary Smith, Bo Xu, David Goodrich, Qiang Li. A novel mouse model for small-cell carcinoma of bladder [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 B13.
Abstract B38: Impact of nongenetic intratumor heterogeneity on phenotypic characteristics and ongoing evolutionary dynamics in lung tumors
Authors: Sharma Anchal , Merritt Elise , Hu Xiaoju , Cruz Angelique , Malhotra Jyoti , Riedlinger Greogory , De Subhajyoti 
Published: June 2020

Abstract
Impacts of genetic and nongenetic intratumor heterogeneity (ITH) on tumor phenotypes and evolvability remain debated. We analyzed ITH in lung squamous cell carcinoma at the levels of genome, transcriptome, tumor-immune interactions, and histopathologic characteristics by multiregion bulk and single-cell sequencing. Genomic heterogeneity alone was a weak indicator of intratumor nongenetic heterogeneity at immune and transcriptomic levels that impacted multiple cancer-related pathways, including those related to proliferation and inflammation, which in turn contributed to intratumor regional differences in histopathology and subtype classification. Tumor subclones had substantial differences in proliferation score, suggestive of non-neutral clonal dynamics. Proliferation and other cancer-related pathways also showed intratumor regional differences, sometimes even within the same subclones. Neoepitope burden negatively correlated with immune infiltration, indicating immune-mediated purifying selection on somatic mutations. Taken together, our observations suggest that nongenetic heterogeneity is a major determinant of heterogeneity in histopathologic characteristics and impacts evolutionary dynamics in lung cancer.
Note: This abstract was not presented at the conference.
Citation Format: Anchal Sharma, Elise Merritt, Xiaoju Hu, Angelique Cruz, Jyoti Malhotra, Greogory Riedlinger, Subhajyoti De. Impact of nongenetic intratumor heterogeneity on phenotypic characteristics and ongoing evolutionary dynamics in lung tumors [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 B38.
Abstract B48: STAT3 pathway in fibroblasts aggravates invasiveness of lung cancer cells in the tumor microenvironment
Authors: Kang Ju-Hee , Lee Ha Jung , Jung Hyun Jin , Kim Min Woo , Oh Seung Hyun 
Published: June 2020

Abstract
Cancer-associated fibroblasts (CAF), as one of the major components of tumor microenvironment, have a significant role in cancer development and progression. CAF also supports the survival and chemo-induced resistance of cancer cells. Among various signaling pathways involved in cancer cell and CAF interaction, the signal transducers and activators of transcription (STAT3) pathway has been investigated a lot, but its own role in CAF itself is not yet clearly defined. In this paper, we established CAF using MRC5, which is a stable lung fibroblast cell line, by culturing with conditioned medium from lung cancer cells. Then, by using a STAT3 inhibitor, STX-0119, and STAT3 siRNA, we examined whether the blocking of STAT3 pathway in MRC5 affects chemotherapeutic resistance or invasiveness of A549 lung cancer cells. We found out that STAT3 inhibition in fibroblasts did not prevent CAF-induced resistance of A549 cells on proliferation, but it did attenuate the invasiveness and migration of A549 cells. These results suggest that the combination of a low dose of a STAT3 inhibitor, which would be high enough to inactivate the CAF around the tumor cells, and an anticancer drug can be taken as an approach to cancer treatment.
Citation Format: Ju-Hee Kang, Ha Jung Lee, Hyun Jin Jung, Min Woo Kim, Seung Hyun Oh. STAT3 pathway in fibroblasts aggravates invasiveness of lung cancer cells in the tumor microenvironment [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 B48.
Abstract IA05: Signaling networks in small-cell lung cancer
Authors: Sage Julien 
Published: June 2020

Abstract
SCLC is a lethal neuroendocrine (NE) cancer that accounts for ~15% of all lung cancers and causes ~250,000 deaths worldwide each year. SCLC is linked to heavy cigarette smoking and exposure to carcinogens. Unfortunately, the number of SCLC-related deaths continues to rise. A major clinical challenge is that ~70% of SCLC patients have disseminated disease at the time of diagnosis; these patients have a 5-year survival of &lt;1%. Even patients with localized disease at diagnosis have dismal survival rates. A second major challenge is that treatments for SCLC are inefficient and have remained mostly unchanged for the past 30 years, with no new approved treatments since 1996 and no approved targeted therapies. SCLC is managed with first-line chemoradiation. Patients usually respond well initially, but almost all relapse within months. There is a need to better understand the mechanisms underlying the aggressive growth and spread of SCLC and its rapid chemoresistance. At a gross level, SCLC tumors are quite “homogeneous” histologically (with fields of similar-looking small, blue, round cancer cells) and genetically (with near-ubiquitous loss of the Rb and p53 tumor suppressors). However, accumulating evidence has recently highlighted several levels of heterogeneity, and it has become clear that a better characterization and understanding of both genetic and epigenetic heterogeneity during SCLC progression will be critical to identify new therapeutic options. We have used mouse genetics combined with genomic and proteomic approaches to identify key signaling pathways that are implicated in the expansion of SCLC cell populations. In particular, we have recently identified kinases and phosphatases that control the expansion of long-term propagating cells (aka cancer stem cells) in SCLC.
Citation Format: Julien Sage. Signaling networks in small-cell lung 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 IA05.
Abstract IA08: Organoid modeling of tumor and tissue microenvironments
Authors: Kuo Calvin J. 
Published: June 2020

Abstract
Within the tumor microenvironment are diverse populations including fibroblasts, vasculature, and immune cells, all of which critically regulate cancer progression. A major historical impediment to basic and translational cancer studies has been the lack of in vitro methods that allow tumor epithelium to be robustly cultured together with stromal components. This talk will describe advances in 3D tumor organoid culture that allow tumor cells to be grown in a manner that preserves their native interaction with diverse tumor-infiltrating immune cells and allows analysis of immune checkpoint inhibition. Such organoid modeling of the tumor immune microenvironment within human clinical cancer biopsies will facilitate basic and translational immune-oncology studies. Additional applications to nonmalignant diseases will also be discussed.
Citation Format: Calvin J. Kuo. Organoid modeling of tumor and tissue microenvironments [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 IA08.
Abstract IA11: The use of GEM tumor models to identify effective therapies against KRAS mutant tumors
Authors: Barbacid Mariano 
Published: June 2020

Abstract
KRAS oncogenes are responsible for one fourth of all human tumors, including lung and pancreatic adenocarcinomas, two tumor types with some of the worse prognoses. Unfortunately, development of suitable therapies to treat these tumors has remained elusive for the last 35 years. Although KRAS remains an undruggable target (with the possible exception of the KRASG12C isoform), most of its downstream effectors are druggable kinases. Indeed, pharma and biotech companies have already developed dozens of selective inhibitors against these kinases. Yet none of them has been approved by the FDA, mostly due to unacceptable toxicities at antitumor effective doses. Hence, patients are still treated with old chemotherapy drugs. To address this important health issue, we have used a new generation of genetically engineered mouse (GEM) tumor models of KRas/Tp53 driven lung and pancreatic tumors to deconstruct oncogenic KRas signaling to identify those effectors whose systemic ablation/inactivation in tumor-bearing mice will result in therapeutic responses without inducing unacceptable toxicities. We have used this experimental strategy to interrogate the effect of ablating/inactivating each of the members of the MAPK cascade, including the Raf, Mek, and Erk kinases, as well as key effectors of the PI3K pathway, including PI3K p110alpha and mTOR. We have also evaluated additional downstream signaling elements such as the cell cycle Cdks. This systematic approach has revealed that most of the KRas signaling effectors are not suitable therapeutic targets due to either lack of therapeutic activity, such as Cdk2, Cdk6 A-Raf, or B-Raf, or to the induction of unacceptable toxicities such as the Mek1/2 and Erk1/2 kinases, PI3K p110alpha, mTOR, and Cdk1. Only Raf1 and Cdk4 turned out to be suitable therapeutic targets, based not only on their antitumor properties but also on the well-tolerated toxicities. Surprisingly, EGFR, an upstream effect of KRas, also has suitable therapeutic activity in pancreatic but not in lung tumors. We are now combining these targets to define more efficacious therapeutic strategies that could be eventually translated to the clinic. Moreover, we are using these experimental GEM tumor models to identify potential resistance mechanisms to these therapies.
Citation Format: Mariano Barbacid. The use of GEM tumor models to identify effective therapies against KRAS mutant tumors [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 IA11.