bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A36: Characterizing the role of Egfr signaling in mediating the exacerbative effect of acute inflammation on tumor development in a mouse model for familial adenomatous polyposis
Authors: Li Wei , Yang Yu-Ping , Coffey Robert J. 
Published: May 2018

Abstract
Over the past decade a number of inducible mouse models of intestinal tumor formation have been developed to study the genetic and cellular changes that contribute to colorectal cancer (CRC) development. Among them, the Lrig1-Cre/+;Apcfl/+ mice serve as a good model to study familial adenomatous polyposis (FAP), as the targeted elimination of one copy of the Apc gene in the Lrig1-expressing (Lrig1+) intestinal progenitor cells leads to loss of heterozygosity of the remaining wild-type Apc allele in the intestinal epithelium and eventually the formation of multiple histologically advanced adenomas in the distal colon. However, adenomas formed in the Lrig1-Cre/+;Apcfl/+ mice do not progress to adenocarcinomas. In order to develop a mouse model that recapitulates the process of CRC development in its entirety, we treated the Lrig1-Cre/+;Apcfl/+ mice with the proinflammatory reagent dextran sodium sulfate (DSS) and found that a single cycle of DSS right after tamoxifen-induced initial loss of one Apc allele significantly exacerbated tumor formation in the distal colon. Interestingly, DSS-treated Lrig1-Cre/+;Apcfl/+ mice also developed highly dysplastic tumors in the proximal colon, which is normally spared from tumor formation in the untreated Lrig1-Cre/+;Apcfl/+ mice. Using a newly developed chimeric Egfr protein reporter mouse, we are interrogating the roles of dysregulated epithelial and stromal Egfr signaling in promoting tumor development in the DSS-treated Lrig1-Cre/+;Apcfl/+;EgfrEmGFP/+ mice.
Citation Format: Wei Li, Yu-Ping Yang, Robert J. Coffey, Jr. Characterizing the role of Egfr signaling in mediating the exacerbative effect of acute inflammation on tumor development in a mouse model for familial adenomatous polyposis [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 A36.
Abstract A38: Twist1-driven fatty pancreas formation facilitates pancreatitis and pancreatic ductal adenocarcinoma progression
Authors: Nguyen Thien Ly , Singh Purba , Parajuli Parash , Li Lianna , Prunier Celine , Kumar Santosh , Eragmerdi Sailaja , Ozkan Seval , Me Hao , Carmo Jussara do , Hall John , Atfi Azeddine 
Published: May 2018

Abstract
Fatty pancreas or pancreatic steatosis has been associated with a variety of debilitating diseases, such as obesity, diabetes, pancreatitis, and pancreatic ductal adenocarcinoma (PDAC). Currently, neither the mechanisms underlying the pathogenesis of fatty pancreas nor the physiopathologic impacts of this disorder are well established. Serendipitously, we found that conditional overexpression of Twist1 in pancreatic progenitor cells in mice resulted in fatty pancreas development, leading to pancreatic insufficiency, severe hyperglycemia, and growth retardation. Molecular and genetic studies demonstrated that Twist1 drives fatty pancreas formation by selectively reprogramming acinar cells towards the adipocyte lineage albeit without affecting islet or ductal cell fate. Moreover, loss-of-function genetic experiments demonstrated that Twist1 plays a causative role in glucose tolerance, pancreatitis genesis, and PDAC progression. Finally, high levels of Twist1 expression correlate with fatty pancreas formation in patients with pancreatitis or PDAC, implicating Twist1 as a prognostic marker and possible target for attenuating several lethal diseases associated with fatty pancreas development.
Citation Format: Thien Ly Nguyen, Purba Singh, Parash Parajuli, Lianna Li, Celine Prunier, Santosh Kumar, Sailaja Eragmerdi, Seval Ozkan, Hao Me, Jussara do Carmo, John Hall, Azeddine Atfi. Twist1-driven fatty pancreas formation facilitates pancreatitis and pancreatic ductal adenocarcinoma progression [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 A38.
Abstract A48: Ube2v1 promotes EMT and metastasis by suppression of autophagy
Authors: Shen Tong , Cai Lingdong , Liu Yuhong , Li Jianming 
Published: May 2018

Abstract
Ubiquitination is one of the basic post-translational modifications for cellular homeostasis. The conjugating enzyme (E2) family plays as a bridge linking the first step mediated by E1 with the final step mediated by E3 in the ubiquitin-proteasome system. However, the role of Ube2v1, one of ubiquitin-conjugating E2 enzyme variant proteins (Ube2v), in colorectal cancer (CRC) and autophagy is unclear. Here, we found that Ube2v1 is elevated in tumor samples of CRC patients and correlated with poorer survival of CRC patients. Furthermore, Ube2v1 promotes migration and invasion of CRC cells in vitro and boosts tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1 suppresses autophagy program and promotes EMT and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, rapamycin attenuates the enhanced in vitro migration and invasion and in vivo lung metastasis of Ube2v1 overexpression by inducing the autophagy pathway. Mechanistically, Ube2v1 increases histone H4 lysine 16 acetylation by downregulating expression of Sirt1 and epigenetically suppresses gene expression of autophagy genes in colorectal cancer. In conclusion, Ube2v1 functions as a global regulator for autophagy by epigenetically transcriptional suppression of autophagy, and consequently promotes EMT and metastasis of CRC. Our study functionally links Ube2v1, one member of E2 family in the ubiquitin-proteasome system to autophagy program in CRC progression and metastasis.
Citation Format: Tong Shen, Lingdong Cai, Yuhong Liu, Jianming Li. Ube2v1 promotes EMT and metastasis by suppression of autophagy [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 A48.
Abstract A50: Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells in vivo and in vitro
Authors: Fan Hong , Sun Zheng 
Published: May 2018

Abstract
Oral squamous cell carcinoma (OSCC) is the most common epithelial cancer worldwide. Despite improvements and innovations in diagnostic techniques and treatments, the survival rate of patients with oral cancer has not increased. We previously demonstrated that activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a vital role in OSCC. However, the underlying mechanism of Nrf2 is unclear in OSCC. This study aimed to clarify the mechanism of Nrf2 regulating the tumorigenesis and progression of OSCC in vivo and in vitro. We confirmed that overexpression of Nrf2 promotes cell growth, migration, invasion, and colony formation in established stable Nrf2 overexpression OSCC cell lines. Quantitative real-time reverse transcription-PCR and Western blotting assays revealed that silencing the endogenous Nrf2 markedly reduced the expression levels of Notch1, the Notch1 intracellular domain (NICD1), and Hairy and enhancer of split-1 (Hes1) in OSCC cells. As expected, the transcriptional levels of Notch1 and Hes1 and the protein expression level of NICD1 and Hes1 were increased in Nrf2-overexpressing OSCC cell lines. In addition, we demonstrated that the expression of Notch1, NICD1 and Hes1were increased in the tongue tissues of 4NQO induced dysplasia and OSCC mouse model by immunohistochemistry, but their expression was lower in Nrf2-/- mice than in wild-type mice. In conclusion, Nrf2 may play a role in promoting cancer through regulating the Notch signaling pathways in oral cancer in vivo and in vitro.
Citation Format: Hong Fan, Zheng Sun. Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells in vivo and in vitro [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 A50.
Abstract A51: Nicotine induces cervical lymph node metastasis of mouse tongue cancer by regulating Prx1 /EMT signaling
Authors: Wang Min , Niu Wenwen , Qi Moci , Tang Xiaofei 
Published: May 2018

Abstract
Oral squamous cell carcinoma (OSCC) represents one of the most common malignant neoplasms worldwide, while tobacco is a major risk factor for OSCC. Nicotine has been reported to induce EMT and promote the progression in several malignant tumors. Our previous study showed that upregulation of Peroxiredoxin 1(PRX1) expression was observed and associated with nicotine-induced oxidative stress in OSCC. However, the effects of nicotine and the underlying molecular mechanisms on the development of OSCC metastases are not completely understood. Here, we established the cervical metastasis mouse models of tongue cancer by orthotopic transplantation of OSCC cell line siControl CAL 27 cells and siPRX1 CAL 27 cells labeled with GFP into the tongues of nude mice, in order to investigate the roles and mechanisms of nicotine in OSCC metastasis. Fluorescence stereomicroscopy was used to confirm the tumor formation and the development of cervical metastases, which the tumor cells showed distinct green fluorescence in mouse tongues and lymph nodes. The results showed that at day 13 after CAL 27 cell implantation, nicotine promoted OSCC growth in the tongues and metastatic rates of cervical lymph node in mice compared with control. Histologic examination and immunohistochemical staining with anti-keratin antibody further confirmed tumor formation and lymph node metastases. Nicotine treatment was shown to promote the downregulation of expression levels of E-cadherin, and upregulation of vimentin and Snail expression in tongues and lymph nodes, compared with those in the control mice. PRX1 knockdown led to the reduction in the metastasis rate, upregulation of E-cadherin expression, and downregulation of vimentin and Snail expression in tongues and lymph nodes. No significant differences were seen in the cervical lymph node metastatic rates and the expression of EMT-related markers between nicotine-treated and vehicle-treated mice after PRX1 knockdown. These results suggest that nicotine may induce cervical lymph node metastases through the regulation of Prx1/EMT signal pathway during OSCC pathogenesis. PRX1 plays a critical role in nicotine-induced metastasis of OSCC.
Citation Format: Min Wang, Wenwen Niu, Moci Qi, Xiaofei Tang. Nicotine induces cervical lymph node metastasis of mouse tongue cancer by regulating Prx1 /EMT signaling [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 A51.
Abstract B06: A SOX9+ bile duct progenitor as a cell of origin of hepatocellular carcinoma
Authors: Viatour Patrick 
Published: May 2018

Abstract
Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer and its associated mortality is increasing. Most HCC patients are diagnosed at an advanced stage of the disease, which is not eligible for curative surgery and for which efficient drugs remain elusive. Consequently, the prognosis of these patients is particularly poor, begging for a revolution in our therapeutic approach of the disease.
Our in-depth understanding of HCC etiology suggests that patients at risk could be regularly screened for the early detection and treatment of nascent neoplastic lesions. This strategy requires a detailed knowledge of the early events that initiate HCC since their nature shapes the features of the developing lesions. However, the identity of cells that can serve as a cell of origin for HCC as well as the molecular events that transform them remain unknown, hampering the development of an early-intervention strategy.
To address this important gap in our knowledge, we have taken advantage of a tractable model of HCC initiated upon Rb family loss of function, which is an almost universal event in cancer and particularly in HCC. The Cre/Lox-mediated inactivation of Rb family genes in distinct liver cell populations (cholangiocytes, hepatocytes, and various populations of bipotential and committed progenitors) reveals that most tested cell types, while displaying aberrant cell cycle activity, are resistant to transformation upon Rb pathway alteration. However, Rb family inactivation in Sox9-expressing bile duct progenitor cells initiates HCC that recapitulates the human disease. Interestingly, these committed cholangiocyte progenitors rapidly lose their canonical markers to adopt markers that are specific of the hepatocyte lineage, suggesting that Rb gene family inactivation potentiates their cellular plasticity. Importantly, analysis of human HCC array reveals that expansion of Sox9-expressing cells is a common feature of premalignant lesions and early-stage HCC.
Despite its almost universal alteration in cancer, our mouse genetic approach demonstrates that only rare cell populations are susceptible to transformation upon Rb pathway inactivation. In addition, our data show that a cholangiocyte-restricted progenitor population can serve as the cell of origin for a hepatocyte-based type of cancer. This model will enable us to deconstruct the molecular mechanisms that initiate and drive early HCC development and ultimately allow us to shift the clinical management of the disease towards its early steps.
Citation Format: Patrick Viatour. A SOX9+ bile duct progenitor as a cell of origin of hepatocellular carcinoma [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 B06.
Abstract B10: The polyploid state plays a tumor-suppressive role in the liver
Authors: Zhang Shuyuan , Zhou Kejin , Luo Xin , Li Lin , Nguyen Liem , Zhang Yu , Tarlow Branden , Siegwart Daniel , Zhu Hao 
Published: May 2018

Abstract
Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization normally occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate the function of polyploidy while avoiding irreversible manipulations of essential cell cycle genes, we developed multiple orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as in vivo knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no impact of ploidy alterations on liver function, metabolism, or regeneration, hyperpolyploid mice suppressed and hyperdiploid mice accelerated tumorigenesis in mutagen and high fat induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that ploidy differentially protected the liver from distinct genomic aberrations. Our work suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury.
Citation Format: Shuyuan Zhang, Kejin Zhou, Xin Luo, Lin Li, Liem Nguyen, Yu Zhang, Branden Tarlow, Daniel Siegwart, Hao Zhu. The polyploid state plays a tumor-suppressive role in the liver [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 B10.
Abstract B32: Targeting WNT signaling in vivo via Tankyrase inhibition
Authors: Schatoff Emma M. , Leach Benjamin I. , Foronda Miguel , Zafra Maria Paz , Dow Lukas 
Published: May 2018

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 95% of CRCs show hyperactive WNT signaling, yet there are no targeted therapies that effectively suppress the WNT pathway. The majority (~80%) of these tumors harbor a mutation in APC, a scaffold component of the “destruction complex,” which is a critical negative regulator of WNT.
Using genetically defined mouse models of CRC, we recently showed that restoring Apc function can induce WNT suppression and rapid and sustained disease regression. While there is no way to restore normal APC protein in human CRCs, it may be possible to restore the function of the APC-associated destruction complex by inhibiting Tankyrase (TNKS) enzymes. Tankyrase inhibitors have been shown to stabilize AXIN, prevent degradation of the destruction complex, and decrease levels of WNT signaling. While in vitro studies have shown promise, it is unclear whether TNKS inhibition could provide a therapeutic benefit in vivo. Some published work reports significant antitumor activity, while others suggest overt dose-limiting toxicity. Thus, while TNKS inhibition holds significant potential, it is not clear whether TNKS enzymes are a viable target for CRC therapy.
To circumvent the limitations of drug delivery, potency, and specificity, we generated mice with inducible, fluorescent reporter-linked shRNAs targeting Tnks and its redundant family member Tnks2. Here we show that potent, simultaneous shRNA-mediated knockdown of both genes is sufficient to stabilize Axin in vivo, similar to treatment with a pan-TNKS inhibitor, XAV939. We show that Tnks1/2 knockdown stabilizes Axin and suppresses WNT signaling, but surprisingly, does not disrupt intestinal architecture. Importantly, Tnks1/2 silencing blocks hyperproliferation and tumor development in mice following Apc disruption. In contrast to current studies using small-molecule TNKS inhibitors, our work suggests that there is a viable therapeutic window of TNKS1/2 inhibition in vivo, and that this strategy enables control of hyperactive WNT signaling in CRC and other WNT-associated cancers.
Citation Format: Emma M. Schatoff, Benjamin I. Leach, Miguel Foronda, Maria Paz Zafra, Lukas Dow. Targeting WNT signaling in vivo via Tankyrase inhibition [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 B32.
Abstract B42: Targeting cancer cell CCR2 enhances synergistic immune surveillance in breast cancer
Authors: Fein Miriam R. , He Xue-Yan , Almeida Ana S. , Pommier Arnaud , Bružas Emilis , Eberhardt Anaïs , Wilkinson John Erby , Santos Camila dos , Egeblad Mikala 
Published: May 2018

Abstract
High expression of the C-C chemokine receptor type 2 (CCR2) in tumor samples and serum correlates with poor prognosis in human breast cancer, which has sparked interest in targeting the CCR2 pathway for therapeutic benefit. Importantly, a human CCR2 inhibitor (PF-04136309) has been investigated in clinical trials, and is currently being studied in a phase 1b/2 trial for pancreatic cancer (NCT02732938). Previous studies have focused on the protumor effects of CCR2 signaling in inflammatory monocytes. However, CCR2 is also expressed in breast cancer cells, but its potential function in cancer cells is poorly understood.
To determine the specific roles of CCR2 in cancer and host cells, respectively, we established an orthotopic breast cancer mouse model by injecting primary cancer cells from MMTV-PyMT; Ccr2+/+ or MMTV-PyMT; Ccr2-/- mice into the mammary glands of wide-type or Ccr2 null hosts. In this cancer model, deleting Ccr2 in host cells, including monocytes, did not alter tumor growth. However, when tumor cells had lost Ccr2, immune surveillance was much more efficient, with greater infiltration and expansion of cytotoxic CD8+ T cell lymphocytes (CTLs) that efficiently recognized and destroyed the cancer cells, resulting in significant inhibition of tumor growth. Consistently, the delayed tumor growth of Ccr2 null cancer cells was fully reversed when these same cancer cells were transplanted into athymic (immunodeficient) mice. The reduced growth of tumors derived from Ccr2-/- cancer cells was associated with upregulation of IFN-γ response genes and genes involved in MHC class I presentation, as well as decreased expression of checkpoint inhibitor PD-L1 in cancer cells. Finally, greater infiltration of CD103+ dendritic cells (DCs) in Ccr2-/- tumor microenvironment also contributed to increased CTL function by cross presentation.
Taken together, our results show that CCR2-expressing breast cancer cells orchestrated global changes in the infiltration of CTLs and DCs, leading to effective immune suppression. This suggests that CCR2 may be an immunotherapeutic target in breast cancer.
Citation Format: Miriam R. Fein, Xue-Yan He, Ana S. Almeida, Arnaud Pommier, Emilis Bružas, Anaïs Eberhardt, John Erby Wilkinson, Camila dos Santos, Mikala Egeblad. Targeting cancer cell CCR2 enhances synergistic immune surveillance in breast 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 B42.
Abstract B46: Varying the inoculation site of mouse syngeneic tumors can result in aberrant inclusion of lymph node tissue at tumor harvest
Authors: Clift Renee , Blouw Barbara , Zimmerman Susan , Rosengren Sanna , Thompson Curt , Thompson Benjamin 
Published: May 2018

Abstract
In recent years, growing interest in immunotherapies for the treatment of cancer has led to increased reliance on murine syngeneic tumor models for preclinical study in immunocompetent animals. These studies typically examine changes in the quantities and phenotypes of tumor-infiltrating immune cells; thus, it is crucial to distinguish between these cells and extratumoral immune cells during tumor harvest. Here, we show that 4T1 breast tumors inoculated in mammary fat pads (MFP) numbers 4 or 9 (4/9) contained greater frequencies of B cells and naïve T cells than tumors inoculated in MFP numbers 5 or 10 (5/10). Immunohistochemical analysis for B-cell presence demonstrated that MFP 4/9 tumors encroached on, and often encapsulated, inguinal lymph nodes, such that lymph node tissue was unknowingly collected during tumor harvest. This prevented accurate enumeration and phenotyping of infiltrating immune cells by flow cytometry, as the majority of lymphocytes in the affected samples derived from lymph nodes, and had not infiltrated the tumor per se. We observed the same phenomenon in peritibial tumors using immunohistochemical analysis, which began to encapsulate popliteal lymph nodes at large tumor volumes (&gt;1500 mm3). Our data highlight the importance of choosing an appropriate inoculation site for obtaining accurate and consistent results when evaluating immune cell infiltration in syngeneic tumor models.
Citation Format: Renee Clift, Barbara Blouw, Susan Zimmerman, Sanna Rosengren, Curt Thompson, Benjamin Thompson. Varying the inoculation site of mouse syngeneic tumors can result in aberrant inclusion of lymph node tissue at tumor harvest [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 B46.