bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1126: Exploring the roles of Suppressor of Fused in the postnatal neurogenic niche and tumorigenesis
Authors: Castillo Jesse Garcia , Gomez Hector G. , Aguilar David , Pleasure Samuel J. , Yabut Odessa 
Published: August 2018

Abstract
Isolated brain tumors consist of cells with stem cell features and a tissue microenvironment similar to the neurogenic niche, implying that tumors must require the same niche factors for tumor growth and progression. Thus, a better understanding of how neural stem cell (NSC) behavior is regulated can have significant therapeutic implications in brain cancers. To this end, we examined the roles of Suppressor of Fused (Sufu) in the postnatal neurogenic niche of the forebrain, the ventricular-subventricular zone (V-SVZ), a potential site of origin for forebrain tumors. Given that recent studies showed low expression of Sufu in gliomas, we wondered how conditional deletion of Sufu using the hGFAP-Cre driver (hGFAP-cre/+;Sufu-fl/fl) influences NSC behavior in the V-SVZ. We found that Sufu critically controls NSC proliferation, since loss of Sufu in the hGFAP-cre/+;Sufu-fl/fl mice resulted in abnormal expansion of the V-SVZ. These defects were due to the increased production of DCX+ Type A cells at the expense of transit amplifying Type C and oligodendrocyte precursor cells. Furthermore, many of these cells failed to migrate out of the V-SVZ, where they remained and continued to proliferate. Nevertheless, an increase in apoptotic cells was observed, which likely prevented the formation of brain tumors from loss of Sufu function alone. Indeed, our preliminary studies showed that the combined deletion of Sufu and the tumor suppressor p53 (hGFAP-Cre/+;Sufu-fl/fl;p53-fl/fl) resulted in a more severe and sustained cell expansion phenotype in the V-SVZ. We predict that these genetic conditions predispose NSCs within the V-SVZ to form tumors at later postnatal stages. We are now investigating this and the molecular mechanisms by which Sufu exerted this effect. Of particular focus is the role of Sufu as an inhibitor of the mitogenic Sonic hedgehog (Shh) signaling, which is highly active in various glioblastoma subtypes. Taken together, our findings point to a potential role for Sufu in preventing tumor development in the forebrain. Our studies also provide novel insights on how developmental and oncogenic signals converge to initiate tumorigenesis or tumor progression. We hope that these studies will lead to the identification of critical niche factors that may be targeted to treat brain cancers and improve patient outcome.
Citation Format: Jesse Garcia Castillo, Hector G. Gomez, David Aguilar, Samuel J. Pleasure, Odessa Yabut. Exploring the roles of Suppressor of Fused in the postnatal neurogenic niche and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1126.
Abstract 1138: LBH, a novel WNT effector in promoting basal-like breast cancer
Authors: Ashad-Bishop Kilan C. , Briegel Karoline J. 
Published: August 2018

Abstract
BACKGROUND: Clinically aggressive basal-like breast cancers (BLBC) disproportionally contribute to cancer deaths, but lack effective treatment options due to absence of expression of key therapeutic targets (ER, PR, HER2). New evidence suggests BLBC may originate from luminal breast epithelial cells through luminal-to-basal cell lineage conversion and dedifferentiation. However, the factors that reprogram cell fate and differentiation states during BLBC development remain poorly understood.
Our laboratory has identified a novel WNT/β-Catenin target transcriptional regulator, Limb-Bud-and-Heart (LBH), which is majorly overexpressed in aggressive BLBC harboring WNT hyperactivation. We previously showed in a conditional LBH knockout mouse model in vivo that LBH is a key stem cell and basal lineage regulator in normal mammary gland development. However, it's role in breast cancer remains elusive. Here, we crossed conditional LBH knockout (KO) mice with a mouse model for WNT-driven breast cancer (MMTV-Wnt1) to test if LBH is a critical effector of WNT-driven basaloid breast cancer, and whether its inhibition may affect BLBC tumorigenesis.
RESULTS: In our in vivo mouse model, epithelial-specific LBH inactivation using a Keratin 14/K14-Cre significantly attenuated Wnt1-induced mammary gland hyperplasia and delayed tumor onset. Yet, tumor volumes and burden were not changed, indicating that LBH is not essential for WNT-induced tumorigenesis. However, LBH-deficient MMTV-Wnt1-transgenic tumors exhibited pronounced histopathological differences compared to LBH WT MMTV-Wnt1-transgenic tumors. Whereas Wnt1+;K14CreLbh WT tumors were highly vascularized, disorganized, with mixed basal and luminal cell identity; tumors from Wnt1+;K14CreLbh KO mice were more organized, differentiated, and predominantly luminal Keratin 8 positive. We are currently investigating if the attenuated hyperplasia and tumor onset caused by LBH loss may be due to a deficiency in cancer stem cells in this breast cancer model.
CONCLUSION: Our data indicate that LBH is an essential cell fate regulator downstream of WNT signaling that maintains basal lineage identity and the undifferentiated nature of BLBC. Thus, LBH inhibition may be a novel strategy to reduce the high mortality of BLBC patients through differentiation therapy.
Citation Format: Kilan C. Ashad-Bishop, Karoline J. Briegel. LBH, a novel WNT effector in promoting basal-like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1138.
Abstract 1139: An shRNA screening reveals that the tumorigenic effect of FBXO11 is inversely correlated with EMT profiles in breast cancer
Authors: Kim Jiyoung , Bagger Sofie O. , Hopkinson Branden B. , Villadsen René , Petersen Ole W. 
Published: August 2018

Abstract
Over the last decade a trend to study cancer stem cells (CSCs) has become synonymous to studying epithelial to mesenchymal transition (EMT), and has emerged in the field of breast cancer research. In turn, tumorigenesis of epithelial luminal-like breast cancer has been largely overlooked. Recently however, we and others have provided evidence that tumorigenic capacity is not always restricted to EMT-like cancer cells. Furthermore, the metastatic feature is conveyed by subclones of phenotypically differentiated non-EMT cancer cells. In this study, we aimed to identify the differential tumorigenic mechanisms of more aggressive non-EMT cells against the less aggressive EMT cells in breast cancer. By using loss of function screening, we found that a member of the E3 ubiquitin ligase complexes, FBXO11, facilitates tumor formation of non-EMT like cells by inhibiting the p53/p21 pathway. More importantly, our data showed that roles of FBXO11 in tumorigenesis are highly cell-type dependent. In conclusion, our study empathizes that it is important to understand the complexities of individual tumors in the development of personalized therapy.
Citation Format: Jiyoung Kim, Sofie O. Bagger, Branden B. Hopkinson, René Villadsen, Ole W. Petersen. An shRNA screening reveals that the tumorigenic effect of FBXO11 is inversely correlated with EMT profiles in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1139.
Abstract 114: Basal-like breast cancer engages tumor-supportive macrophages via cytokines triggered by extracellular S100A4
Authors: Prasmickaite Lina , Tenstad Ellen M. , Egeland Eivind Valen , Pettersen Solveig , Jabeen Shakila , Nord Silje , Haugen Mads Haugland , Juell Siri , Øyjord Tove , Engebråten Olav , Mælandsmo Gunhild Mari 
Published: August 2018

Abstract
Recently the biological and therapeutic perspective on cancer has evolved from focusing on tumor cells only, to include the complex impact of the tumor microenvironment (TME). The TME appears to have a strong influence on both tumor progression and response to treatment. In breast cancer, and in particular the triple-negative subgroup, patient outcome together with the therapeutic response are strongly linked to the tumor's inflammatory profile: presence of tumor-infiltrating leukocytes and their regulatory cytokine. Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the TME, and expression of such cells has been strongly correlated with both poor outcome and development of resistance.
In this study we explored the effect of the pro-metastatic, inflammation-associated, TME factor S100A4 on breast cancer cells (BCCs) of different subtypes, and their further interactions with inflammatory cells. We show that S100A4 activates BCCs, stimulating secretion of pro-inflammatory cytokines, which, in turn, promotes monocyte conversion into TAM-like cells. This was in particular prominent for cytokines secreted from basal-like BCCs. The TAM-like cells possess pro-tumorigenic activities, including increased resistance and ability to migrate. In conclusion, we demonstrate that S100A4 instigate an inflammatory microenvironment, involving a network of cytokines and TAMs, which is particularly pronounced in basal-like BC and could facilitate aggressive phenotypes of this subtype.
Citation Format: Lina Prasmickaite, Ellen M. Tenstad, Eivind Valen Egeland, Solveig Pettersen, Shakila Jabeen, Silje Nord, Mads Haugland Haugen, Siri Juell, Tove Øyjord, Olav Engebråten, Gunhild Mari Mælandsmo. Basal-like breast cancer engages tumor-supportive macrophages via cytokines triggered by extracellular S100A4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 114.
Abstract 1143: Prox1 and Notch mark distinct colorectal cancer stem cell populations
Authors: Högström Jenny , Heino Sarika , Kallio Pauliina , Lähde Marianne , Leppänen Veli-Matti , Kaijalainen Seppo , Balboa Diego , Otonkoski Timo , Robine Sylvie , Wiener Zoltan , Alitalo Kari 
Published: August 2018

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality. Signaling pathways, such as the Wnt and Notch pathways, are essential for the maintenance and differentiation of wild-type intestinal stem cells. We have shown that the Prox1 transcription promotes expansion of the colorectal cancer stem cell pool and that a subpopulation of the Prox1+ CRC cells display stem cell activity. Because of these results we have further analyzed the role of Prox1 in the regulation of CRC stem cell. Here, we report that Prox1 regulates CRC stem-like cells via bidirectional interaction with Notch1 during CRC initiation and progression. Using genetic in vivo models and ex vivo 3D organoid cultures, we show that Notch inhibition decreases the number of Lgr5+ stem cells whereas it increases expression of the Prox1. Although Notch inhibition led to increased proliferation of the Prox1 positive cells, it did not affect their ability to give rise to differentiated Prox1 negative progeny. Ectopic overexpression of the active fragment of Notch1 suppressed Prox1 expression and inhibited stem cell activity in the CRC cells. On the other hand, the PROX1-NuRD complex suppressed the Notch signaling pathway and Prox1 deletion increased Notch target gene expression and promoter activity, indicating reciprocal regulation between Prox1 and Notch1. Thus, although Prox1 and Notch suppress each other in colorectal cancer cells, Prox1+ cells can function as a stem cell population without the need for Notch pathway activity.
Citation Format: Jenny Högström, Sarika Heino, Pauliina Kallio, Marianne Lähde, Veli-Matti Leppänen, Seppo Kaijalainen, Diego Balboa, Timo Otonkoski, Sylvie Robine, Zoltan Wiener, Kari Alitalo. Prox1 and Notch mark distinct colorectal cancer stem cell populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1143.
Abstract 1144: Building Kras (G12D)/Trp53 null/Pdx1-cre (KPC) mouse allograft tumor model for efficacy evaluation of combinatory immunotherapies
Authors: Song Yanrui , Liu Benqi , An Annie Xiaoyu , Zhang Likun , Cai Jie , Shi Qian , Li Henry Qixiang , Ouyang Davy Xuesong 
Published: August 2018

Abstract
Pancreas ductal adenocarcinoma (PDAC) has dreadful 5-year survival of 6% and remains one of the most difficult to treat cancers with very few standard-of-care options. Fueled by the clinical success of immune checkpoint inhibitors in other solid tumors, several clinical trials have been conducted in PDAC patients. Unfortunately, those attempts have achieved limited clinical benefits as single-agent treatment. Now investigators are eager to test combinatory therapies of chemotherapies, small-molecule immune modulators, and immune checkpoint antibodies. Highly relevant preclinical models are very much needed for proof-of-principle efficacy evaluation. KPC model, first described by Tuveson and colleagues as LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre, and later established in a variety of derivatives by several labs with Trp53 heterozygous or homozygous knockouts, recapitulates human PDAC tumors in many aspects including morphologic small ductal tumors with enriched stromal contents; key features of immune microenvironment of PDAC representing robust inflammatory reactions, like high levels of B cells and macrophages and exclusion of effector T cells; and most importantly, is nonresponsive to a series of chemotherapies and immune checkpoint inhibitors, including PD1 and CTLA4 antibodies. These features make KPC model an ideal model to test combinatory therapies for PDAC. However, parental KPC model is difficult to use for pharmacologic studies due to the spontaneous nature of tumor onset and progression. The compound mutant mice are also costly to breed. We have generated a transplantable KPC tumor model by passaging the primary tumor subcutaneously in the C57BL/6 mice. These KPC allografts retain morphologic similarity to human PDAC. Immune profiling of both subcutaneously and orthotopically grafted tumors demonstrated highly enriched CD45+ lymphocytes, particularly B cells and macrophages, in the tumor. The tumor is also nonresponsive to gemcitabine treatment, in line with the data from parental line. Orthotopically engrafted tumor leads to lethality of the host with the median survival time of 25 days. We are now testing a variety of combinatory therapies with chemotherapies, immune modulators and immune checkpoint antibodies. The results will be presented at the meeting.
Citation Format: Yanrui Song, Benqi Liu, Annie Xiaoyu An, Likun Zhang, Jie Cai, Qian Shi, Henry Qixiang Li, Davy Xuesong Ouyang. Building Kras (G12D)/Trp53 null/Pdx1-cre (KPC) mouse allograft tumor model for efficacy evaluation of combinatory immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1144.
Abstract 115: Crosstalk between breast cancer cells and macrophages in tumor microenvironment induces inflammasome activation
Authors: Jang Jeong-Hoon , Kim Do-Hee , Park Sin-Aye , Kim Su-Jung , Surh Young-Joon 
Published: August 2018

Abstract
The inflammasome is a multiprotein complex that is composed of NOD-like receptor, ASC and caspase-1. During the activation of the inflammasome, pro-interleukin (IL)-1β is cleaved by active caspase-1 to produce mature IL-1β. Although the inflammasome plays a controversial role in many types of tumor, emerging evidence indicates that the inflammasome functions as a negative regulator of breast cancer progression. Notably, high levels of IL-1β in breast cancer tissues are associated with a more virulent tumor phenotype and poor prognosis. However, it remains unresolved how IL-1β is accumulated in breast tumor microenvironment. In the present study, we have found that various human breast cancer cells (MDA-MB-231, MDA-MB-468, SKBr3, MCF-7 and T47D) retain cleaved-IL-1β whereas secretion of IL-1β into the culture medium was not observed. However, IL-1β was detected in the medium when human breast cancer cells were co-cultured with human monocytic (THP-1) cells. Among the various human breast cancer cells, triple-negative breast cancer cells (MDA-MB-231 and MDA-MB-468) effectively stimulated secretion of IL-1β. When co-cultured with MDA-MB-231 cells, THP-1 cells exhibited the elevated levels of pro- and cleaved-IL-1β. Consistent with this result, there was a marked increase in the secretion of IL-1β from THP-1 cells treated with the conditioned media of triple-negative breast cancer cells. Both triple-negative MDA-MB-231 and MDA-MB-468 breast cancer cells induced ASC oligomerization, which is a hallmark of inflammasome activation. Thus, it is likely that soluble factors from breast cancer cells promote IL-1β secretion from macrophages through activation of inflammasomes. In conclusion, breast cancer cells drive inflammasome activation in macrophages, thereby stimulating the accumulation of IL-1β in the tumor microenvironment. The secreted-IL-1β, in turn, promotes breast cancer progression.
Citation Format: Jeong-Hoon Jang, Do-Hee Kim, Sin-Aye Park, Su-Jung Kim, Young-Joon Surh. Crosstalk between breast cancer cells and macrophages in tumor microenvironment induces inflammasome activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 115.
Abstract 1153: Development and validation of a novel in vitro model of the tumor immune microenvironment
Authors: ZHOU RUOLAN , Weathered Rachel , Alonzo Luis , Mezyk-Kopec Renata , Swartz Melody 
Published: August 2018

Abstract
Tumor-associated lymphatics and their connection to the tumor-draining lymph node (TDLN) play important roles in cancer metastasis as well as in modulating the immune microenvironment. They bathe the TDLN in cytokines, exosomes, antigens, and suppressive factors from the tumor microenvironment to alter the anti-tumor immune response. These interactions are difficult to study in vivo, yet currently, these interactions cannot be readily explored in vitro. Here, we developed a perfused paper-based cell culture platform which can recreate the 3-dimensional architecture, stromal component and physiological levels of interstitial flow of the native tissue environment, while keeping the device high-throughput, easy to use, and inexpensive. This platform can sustain the long-term cultures (&gt;3 weeks) of a number of tumor cell lines, which form complex architectures reminiscent of actual tumors, as well as of excised tumor tissue. The platform also supports the function and viability of immune cells (such as T lymphocytes and dendritic cells) and stromal cells (such as lymphatic endothelial cells and fibroblasts). To model the tumor interaction with its TDLN, we created a model in which tumor cells and lymph node stromal cells (LNSC) are cultured in separate but connected compartments under perfusion. To validate this, we have demonstrated preferential tumor migration to preconditioned (vs. unconditioned) LN stroma. The LN stroma compartment also supports co-culture of dendritic cells and T lymphocytes. To validate the modeling of the crosstalk between the tumor and TDLN, we show that tumor conditionioning of the LN primes the LN microenvironment to dampen cytotoxic T cell function. Together, these data highlight the potential of this system for studying complex tumor-host cell interactions in the tumor microenvironment over long periods of time, and paves the way towards an in vitro screening platform for drug screening for drugs that target cells or factors in the tumor microenvironment that serve as barriers to both chemotherapy as well as immunotherapies.
Citation Format: RUOLAN ZHOU, Rachel Weathered, Luis Alonzo, Renata Mezyk-Kopec, Melody Swartz. Development and validation of a novel in vitro model of the tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1153.
Abstract 116: IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma
Authors: Sun Longhao , Liu Liang , Tian Weijun , Zhang Zhixiang , Kang Ya'an , Wang Huamin , Fleming Jason B. , Pasche Boris C. , Zhang Wei 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal and aggressive malignancy. Tumor-associated macrophages (TAMs) mainly represent the M2-like phenotype, with potent immunosuppressive activity, and play a pro-tumor role in nearly all aspects of PDAC biology. Elevated infiltration of M2 TAMs is associated with poor prognosis in PDAC. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogene that induces PDAC progression and is involved in the regulation of immune responses. Our recent study demonstrated that IGFBP2 potentiates signal transducer and activator of transcription 3 (STAT3) transactivation activities in glioma. Considering the essential role of IGFBP2 in governing tumor progression and immune evasion of PDAC, we hypothesized that IGFBP2 promotes tumor progression by inducing alternatively activated macrophages in PDAC. In this study, immunohistochemical (IHC) staining for human PDAC clinical samples was used to reveal the relationship among IGFBP2 expression, M2 TAM accumulation and patient survival. The function of IGFBP2 in inducing alternative polarization of macrophages and promoting tumor progression in PDAC through the STAT3 pathway were evaluated using in vitro and in vivo assays. Ingenuity pathway and gene set enrichment analyses were used to identify the correlation of IGFBP2 gene expression with all other genes in the genome and enriched pathways associated with IGFBP2 gene expression. Our results provide evidence that IGFBP2 expression is associated with M2 macrophage accumulation in the tumor microenvironment and with poor prognosis in PDAC. IGFBP2 augments the production and secretion of IL-10 through activation of STAT3 in PDAC cells, thus reprogramming the TAMs polarization toward an M2 phenotype and promoting tumor progression. These findings established IGFBP2 as an immune-suppressor in the PDAC microenvironment and suggested a strategy for targeting IGFBP2 to improve PDAC immunotherapy.
Citation Format: Longhao Sun, Liang Liu, Weijun Tian, Zhixiang Zhang, Ya'an Kang, Huamin Wang, Jason B. Fleming, Boris C. Pasche, Wei Zhang. IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 116.