bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C21: IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis
Authors: Pena Maria Marjorette O. , Zhang Yu , Davis Celestia , Ryan James C. , Altomare Diego , Shah Sapana , Hughes Daniel Titus 
Published: October 2016

Abstract
The major cause of death from colorectal cancer (CRC) is liver metastasis and understanding its mechanisms is necessary for early diagnosis and development of new therapies. Interleukin-33 (IL-33) is an IL-1 cytokine that functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or early danger signal. Its role in invoking type 2 immune response is firmly established; however, its role in tumor development and metastasis in only beginning to be elucidated. We identified IL-33 as a potently upregulated cytokine in highly metastatic CRC cells and examined its role in tumor growth and metastasis to the liver. We expressed IL-33 in murine and human CRC cell lines and their growth and spontaneous metastasis to the liver was assessed in orthotopic models of CRC in wild type and IL33 knockout mice. The results suggest that tumor- rather than host- derived IL-33 promoted growth and metastasis by inducing expression of cytokines that stimulated mobilization of CD11b+ GR1+ and CD11b+F4/80+ myeloid cells to remodel the tumor microenvironment, and increase tumor angiogenesis, potentially by activating endothelial cells. Conversely, pro-tumorigenic cytokines derived from the microenvironment induced IL-33 expression in tumor cells to create a sustained pro-tumorigenic loop that promotes tumor growth and metastasis. Our findings underscore the potential of IL-33 as a novel and viable therapeutic target for CRC and liver metastasis.
Citation Format: Maria Marjorette O. Pena, Yu Zhang, Celestia Davis, James C. Ryan, Diego Altomare, Sapana Shah, Daniel Titus Hughes. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C21.
Abstract C26: Melanoma brain metastasis is facilitated by instigation of reactive astrogliosis
Authors: Schwartz Hila , Blacher Eran , Amer Malak , Livneh Nir , Klein Anat , Ben-Shushan Dikla , Soffer Shelly , Stein Reuven , Satchi-Fainaro Ronit , Umansky Viktor , Pukrop Tobias , Erez Neta 
Published: October 2016

Abstract
Melanoma frequently metastasizes to the brain, resulting in dismal survival. A major obstacle for characterizing mechanisms of brain metastasis is the lack of tractable pre-clinical models that mimic the multi-stage process of brain metastasis. We established a novel model of spontaneous melanoma brain metastasis in immunocompetent mice. Aggressive local tumors are formed following orthotopic injection, and 3-4 months after surgical excision of the primary tumor, 50% of the mice develop brain macrometastases. By utilizing a unique ex-vivo modeling system, we detected brain micrometastases in 50-60% of the mice and quantified the metastatic load. Moreover, we show that the detection of melanoma transcripts in cerebrospinal fluid (CSF) is correlated with brain metastases. Interestingly, preliminary findings suggest that the melanoma-derived transcripts are found in exosomes. Astrocytes are glial cells that maintain brain homeostasis, and constitute a central part of the brain microenvironment. Reactive astrogliosis is the primary response of astrocytes to brain insult. While much data have accumulated on the contribution of astrogliosis to neurodegenerative diseases, the functional role of astrogliosis in promoting melanoma brain metastases is unknown. Utilizing our model we demonstrate early changes in the microenvironment and show that micrometastases are associated with activation of astrocytes and with hyperpermeability of the blood-brain-barrier. In-vitro, paracrine signaling by melanoma cells activated astrocytes to up-regulate a ‘wound healing program’ including Cxcl10 and Serpins. Reciprocally, astrocytes facilitated the invasion of melanoma cells and were necessary for primary outgrowth in 3D co-cultures. Finally, we show that intracranial co-injection of astrocytes with melanoma cells resulted in a 9 fold increase of tumor volume, and that the same gene-signature was up-regulated in astrocytes in-vivo. Studying spontaneous melanoma brain metastasis in a clinically relevant setting enables in-depth understating of the metastatic microenviromet which is the key to developing therapeutic approaches that may prevent brain metastatic relapse.
Citation Format: Hila Schwartz, Eran Blacher, Malak Amer, Nir Livneh, Anat Klein, Dikla Ben-Shushan, Shelly Soffer, Reuven Stein, Ronit Satchi-Fainaro, Viktor Umansky, Tobias Pukrop, Neta Erez. Melanoma brain metastasis is facilitated by instigation of reactive astrogliosis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C26.
Abstract IA04: Stromal regulation of pancreatic cancer epigenome and metabolome
Authors: Sherman Mara H. , Evans Ronald 
Published: October 2016

Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the dramatic accumulation of stromal components implicated in tumor growth, metastasis, and resistance to therapy. This creates a living chimera in which stroma-derived growth factors, matrix proteins and inflammatory cytokines are thought to nurture the nascent tumor. This study reveals that the stromal secretome exerts rapid epigenomic changes in the cancer cells that effectively marshals up metabolic and genomic networks needed to power cell growth.
To tackle the complexity of the tumor microenvironment (TME), we devised a three-dimensional culture system to dissect the adaptive impact of the stromal secretome on the cancer cell. This integrative approach identified the rapid mobilization of more than a dozen gene networks (cell cycle, steroid biosynthesis, metabolic pathways, DNA replication, etc.), as well as a commensurate adaptive metabolome. A major unanswered question relates to the sequence of events that result in the formation and ultimate function of these networks, in part generated by rapid changes in acetylation of histone H3 at lysines 9 and 27 (H3K9ac and H3K27ac).
Our work suggests the existence of a molecular and-gate such that tumor activation is the consequence of mutant Ras and the tumor micro-environment. To mediate this molecular hand-shake, we find that BRD2 acts in the epithelial compartment to transduce stromal cues at the genomic level. Based on the above, and consistent with recent Mazur PK et al Nat Med (2015), we show the BET bromodomain inhibitor JQ1 targets a key synergy point and reduces pancreatic tumor growth in vivo. Collectively, this work describes a novel connection between the stromal response and a driver oncogene and may offer new insights into the role of the TME in the treatment of ras-driven tumor.
Citation Format: Mara H. Sherman, Ronald Evans. Stromal regulation of pancreatic cancer epigenome and metabolome. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA04.
Abstract IA06: Influence of macrophage metabolism on vessel shape: Implications for cancer
Authors: Mazzone Massimiliano 
Published: October 2016

Abstract
Cancer typically has an inflammatory nature. Of all immune cells invading the tumor, the role of macrophages remains controversial because of their functionally distinct differentiation states. Classically activated (M1-like) macrophages and alternatively activated (M2-like) macrophages represent the two extremities of a continuum, in which the former are proinflammatory and tumoricidal, whereas the latter display pro-angiogenic and protumoral activities. This heterogeneity reflects the plasticity and versatility of these cells in response to microenvironmental signals. The tumor environment is constituted of cancer cells and stromal cells that coexist under different oxygen tensions and the influence of soluble factors. A plethora of (hypoxia-induced) cytokines and chemokines can define the macrophage phenotype and their positioning within the tumor. We have elucidated an elegant mechanism by which macrophages are recruited and retained in avascular hypoxic niches of the tumor, where they exert their immunosuppressive and pro-angiogenic activity. Hypoxia by itself indeed strongly affects macrophage function, as the cells are forced to adapt and alter their metabolism, which is accompanied by a drastic change in their transcriptome and proteome. We have found that the resultant metabolic changes drive macrophages towards a pro-angiogenic phenotype in an attempt to restore oxygenation. Soluble factors derived from the tumor exacerbate this macrophage shift by further enforcing this metabolic adaptation. As a consequence, tumor blood vessels are abnormal and dysfunctional, thus perpetuating hypoxia, which in turn fosters metastasis. By using genetic tools in mice, we show that inhibiting macrophage recruitment in hypoxic niches, or altering their metabolic and energetic state can break this feed-forward loop, resulting in normalized blood vessels and thus, strongly reducing metastatic dissemination.
Citation Format: Massimiliano Mazzone. Influence of macrophage metabolism on vessel shape: Implications for cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA06.
Abstract IA08: p62/SQSTM1 accumulation links chronic tissue damage to malignant progression in liver and pancreas
Authors: Karin Michael 
Published: October 2016

Abstract
Despite extensive genomic exploration, the mechanisms that initiate malignancy remain obscure. We addressed this issue by studying how chronic liver diseases progress to hepatocellular carcinoma (HCC). We focused our studies on the role of p62/SQSTM1, whose accumulation is a hallmark of premalignant liver disease. Using mice, we found that hepatocyte-specific p62 ablation inhibits HCC development in four distinct models, with strongest effect exerted in etiologies involving mTORC1 activation. Forced p62 expression in autophagy-competent livers suffices for HCC induction. Amongst p62 activities including aggregate formation, binding ubiquitinated proteins, mTORC1 stimulation and transcription factor activation, most critical is the NRF2 pathway, which is mutationally activated in 14% of human HCCs. We propose that environmentally-induced p62-dependent NRF2 signaling is a key early event inHCC pathogenesis that together with mTORC1 promotes survival and expansion of superoxide-accumulating HCC-initiating cells. Indeed, high p62 expression in preneoplastic human liver predicts rapid HCC recurrence after curative ablation.
Citation Format: Michael Karin. p62/SQSTM1 accumulation links chronic tissue damage to malignant progression in liver and pancreas. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA08.
Abstract IA20: Hypoxic influences on the tumor microenvironment
Authors: Simon M. Celeste 
Published: October 2016

Abstract
Solid tumors typically develop hostile microenvironments characterized by irregular vascularization and poor oxygen (O2) and nutrient supply. Whereas normal cells modulate anabolic and catabolic pathways in response to changes in nutrient availability, cancer cells exhibit unregulated growth even under nutrient scarcity. Recent studies have demonstrated that constitutive activation of growth-promoting pathways results in dependence on unsaturated fatty acids for survival under O2 deprivation. In cancer cells, this dependence represents a critical metabolic vulnerability that could be exploited therapeutically. Here I will review how this dependence on unsaturated lipids is affected by the microenvironmental conditions faced by cancer cells, particularly in the setting of sarcomas.
Citation Format: M. Celeste Simon. Hypoxic influences on the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA20.
Abstract IA23: Deconvolution of the triple-negative breast cancer microenvironment
Authors: Saleh Sadiq , Gruosso Tina , Gigoux Mathieu , Bertos Nicholas , Omeroglu Atilla , Zuo Dongmei , Meterissian Sarkis , Hallett Michael , Park Morag 
Published: October 2016

Abstract
Breast cancer heterogeneity is one of the principal obstacles both to predicting outcome and to determining an effective course of treatment for this disease. Although genomic technologies have been used to gain a better understanding, by identifying gene expression signatures associated with clinical outcome and breast cancer subtypes, relatively little is known about heterogeneity in the tumor microenvironment. It is now accepted that changes in the normal cells that constitute the tumor microenvironment (TME) play important roles in determining cancer progression and ultimate outcome. We and others have established that an immune gene expression signature correlates with good outcome in triple negative breast cancer (TNBC), yet fails to accurately predict outcome in all patients. Examining stromal heterogeneity in TNBC has identified four distinct stromal clusters, three of which are prognostic, contain distinct immune signatures and a signature of fibrosis. Lymphocytic infiltration and access to tumor parenchyma is not well understood due to high levels of spatial heterogeneity within tumors. We show that location of CD8+T cells is strongly influenced by TME subtypes and identify gene expression signatures predictive of distinct CD8+T cell localization and patient outcome. Since mounting evidence suggests that immune-checkpoint inhibitor immunotherapies may be promising for only a subset of TNBC patients, highlights the importance of understanding how the TME influences CD8+T cell location.
Citation Format: Sadiq Saleh, Tina Gruosso, Mathieu Gigoux, Nicholas Bertos, Atilla Omeroglu, Dongmei Zuo, Sarkis Meterissian, Michael Hallett, Morag Park. Deconvolution of the triple-negative breast cancer microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA23.
Abstract IA26: Regulation of epithelial versus mesenchymal polarity and malignant progression
Authors: Pattabiraman Diwakar , Pattabiraman Diwakar , Shibue Tsukasa , Shibue Tsukasa , Ye Xin , Ye Xin , Weinberg Robert A. , Weinberg Robert A. , Weinberg Robert A. 
Published: October 2016

Abstract
The ability of carcinoma cells to acquire cell-biological phenotypes associated with advanced malignancies is increasingly associated with activation of the EMT (epithelial-mesenchymal transition) program. Among the acquired phenotypes are those of motility, invasiveness, the ability to disseminate, and the ability to form increased numbers of tumor-initiating cells/cancer stem cells (CSCs). We have investigated the regulation of the EMT program and found that a key intracellular determinant is the levels of the cAMP second messenger molecule. When elevated, it causes exit of more mesenchymal carcinoma cells into an epithelial state. The formation of the CSCs within tumors has long been posited to arise following the conversion of normal tissue SCs into CSCs. However, in our hands, in a transgenic model of breast carcinoma formation, the SCs reside in one cell layer of the mammary ducts while the CSCs arise in another, making the direct derivation of CSCs from normal SCs unlikely, at least in this experimental model of mammary carcinogenesis. Once the EMT program is activated, carcinoma cells are able to acquire attributes that not only enable their dissemination from the primary tumor but also affect their subsequent post-extravasation proliferation in the lung parenchyma. The basis of this proliferation derives from the EMT-induced ability of extravasated carcinoma cells to form mature focal adhesions and activate the mitogenic signaling pathway via focal adhesion kinase (FAK). Additional consequences of EMT action will be discussed.
Citation Format: Diwakar Pattabiraman, Diwakar Pattabiraman, Tsukasa Shibue, Tsukasa Shibue, Xin Ye, Xin Ye, Robert A. Weinberg, Robert A. Weinberg, Robert A. Weinberg. Regulation of epithelial versus mesenchymal polarity and malignant progression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA26.
Abstract PR06: Reciprocal prostate cancer signaling with its microenvironment mediates castrate-resistant disease progression
Authors: Tripathi Manisha , Nandana Srinivas , Huang Jen-Ming , Kato Manabu , Chung Leland W. K. , Mishra Rajeev , Xin Li , Bhowmick Neil 
Published: October 2016

Abstract
Our lab has previously reported that the mouse model knocked out for TGF-beta receptor type II in fibroblasts results in castrate resistance of prostate tissues, mediated by paracrine Wnt signaling. We found that antagonizing androgen signaling leads to Wnt ligand expression by prostatic fibroblasts, interestingly dependent on cell-cell contact. This led us to hypothesize that a juxtacrine action within the stromal compartment was important to the development of castrate resistance. Building upon this observation, we found that Notch signaling was upregulated in prostate cancer associated fibroblasts (CAFs) compared with normal tissue associated fibroblasts (NAFs). Further, inhibition of Notch signaling in CAFs, using DAPT, resulted in decrease in Wnt2b and decreased expression of Notch target genes. Similarly, castration or androgen receptor antagonism (i.e. bicalutamide or enzalutamide) resulted in increased Notch signaling and downstream Wnts 2 and 2b up regulation. The further generation of chimeric tissue recombinant xenografts with human RV1 prostate cancer epithelia with mouse prostate stromal cells with activated Notch signaling, derived from NICD transgenic mice resulted in increased tumor size compared with wild type control stromal recombinants. Conversely, recombinants derived from prostatic fibroblasts having a loss of Notch signaling, from RBPJ-knockout mice, had diminished tumorigenesis, compared to xenografts with the wild type fibroblasts counterpart. In trying to determine the mediator of Wnt-associated paracrine prostate epithelial expansion, we found downstream YAP activation in the RV1 cells. In a reciprocal epithelial-to-fibroblast communication we found that the RV1 cells treated with conditioned media from NICD fibroblasts showed increased IL-6 expression. Conversely, conditioned media from prostate cancer cells increased Notch target gene expression in CAFs, which was blocked upon addition of IL-6 neutralizing antibody. Taken together there is a stromal-derived signaling cascade involving Notch and Wnt ligands, that activates YAP in the epithelia for paracrine IL-6-dependent Notch activity back in the stromal fibroblasts. Critically, disruption of this cross-talk in the fibroblasts can limit the gain of stem features and castrate resistance of the adjacent epithelia in halting lethal progression of prostate cancer.
This abstract is also presented as Poster A44.
Citation Format: Manisha Tripathi, Srinivas Nandana, Jen-Ming Huang, Manabu Kato, Leland W. K. Chung, Rajeev Mishra, Li Xin, Neil Bhowmick. Reciprocal prostate cancer signaling with its microenvironment mediates castrate-resistant disease progression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR06.
Abstract PR13: Understanding the systemic interactions between primary tumors and disseminated tumor initiating cells
Authors: Castano Zafira , Chaffer Christine L. , Spiegel Asaf , Pant Ayush , Richardson Andrea L. , Reinhardt Ferenc , Marsh Timothy , Janssen Susanne , Gifford Ann M. , Weinberg Robert A. , McAllister Sandra S. 
Published: October 2016

Abstract
The causes for breast cancer recurrence in the form of metastatic disease and the reasons why less than 1% of disseminated tumor cells form metastases are unknown. A number of studies have demonstrated that the aggressive cancer cell population capable of driving metastasis feature properties of the epithelial-mesenchymal transition (EMT) and tumor initiation (TI). We previously reported novel mechanisms by which systemic and microenvironmental factors enrich tumors for EMT and TI genes and demonstrated that recurrence rates are not strictly due to tumor cell intrinsic properties (Castano et al., Cancer Discovery 2013). Using a preclinical model of breast cancer during the early phases of metastatic disease, when patients harbor disseminated tumor initiating cells (TICs) in the periphery at the time of their primary diagnosis (McAllister SS et al., Cell 2008), we recently made a surprising, and seemingly contrasting discovery. Specifically, we found that certain primary tumors can inhibit progression of disseminated TICs into overt tumors, maintaining them in the TI state and slowing their proliferation and differentiation to form tumor tissue mass. We established that the primary tumor induce mobilization of IL1beta-expressing monocytes that are recruited to sites where TICs reside. At those sites, signaling via the IL1 receptor maintains the EMT/TI state of the disseminated cells, thus promoting disease indolence. Importantly, surgical removal of the primary tumor enables TICs at the secondary sites to exit the EMT/TI state and to produce robustly growing tumors. Confirming our xenograft results, we established that stromal expression of IL1β in patient tumors is associated with poor outcome. Collectively, these data highlight the profound impact a primary tumor can exert on metastasizing cells - in this case, by altering the systemic environment to the detriment of secondary tumor growth. Moreover, our data highlight a central role for IL1β in modulating tumor cell plasticity and suggest it may provide a novel avenue for targeting recurrent disease.
Citation Format: Zafira Castano, Christine L. Chaffer, Asaf Spiegel, Ayush Pant, Andrea L. Richardson, Ferenc Reinhardt, Timothy Marsh, Susanne Janssen, Ann M. Gifford, Robert A. Weinberg, Sandra S. McAllister. Understanding the systemic interactions between primary tumors and disseminated tumor initiating cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR13.