Scott D Findlay

The University of Western Ontario, London, Ontario, Canada

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Publications (8)21.46 Total impact

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    ABSTRACT: The progression of cancer from localized to invasive disease is requisite for metastasis, and is often characterized by epithelial-to-mesenchymal transition (EMT) and alterations in cellular adhesion and migration. Studies have shown that this transition is associated with an upregulation of embryonic stem cell-associated genes, resulting in a dedifferentiated phenotype and poor patient prognosis. Nodal is an embryonic factor that plays a critical role in promoting early invasive events during development. Nodal is silenced as stem cells differentiate; however, it re-emerges in adult life during placentation and mammary gland development, and is aberrantly expressed in many cancers. Here, we show that Nodal overexpression, in poorly invasive breast cancer and choriocarcinoma cells, causes increased invasion and migration in vitro. Furthermore, we show that Nodal overexpression in these epithelial cancer types induces an EMT-like event concomitant with the internalization of E-Cadherin. This ability of Nodal to promote cellular invasion and EMT-like phenomena is dependent upon the phosphorylation of ERK1/2. As Nodal normally signals through SMADs, these findings lend insight into an alternative pathway that is hijacked by this protein in cancer. To evaluate the clinical implications of our results, we show that Nodal inhibition reduces liver tumor burden in a model of spontaneous breast cancer metastasis in vivo, and that Nodal loss-of-function in aggressive breast cancer lines results in a decrease in invasive phenotypes. Our results demonstrate that Nodal is involved in promoting invasion in multiple cellular contexts, and that Nodal inhibition may be useful as a therapeutic target for patients with progressive disease.Oncogene advance online publication, 21 January 2013; doi:10.1038/onc.2012.608.
    Oncogene 01/2013; · 7.36 Impact Factor
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    ABSTRACT: The microenvironment acts as a conduit for cellular communication, delivering signals that direct development and sustain tissue homeostasis. In pathologies such as cancer, this integral function of the microenvironment is hijacked to support tumor growth and progression. Cells sense the microenvironment via signal transduction pathways culminating in altered gene expression. In addition to induced transcriptional changes, the microenvironment exerts its effect on the cell through regulation of post-transcriptional processes including alternative splicing and translational control. Here we describe how alternative splicing and protein translation are controlled by microenvironmental parameters such as oxygen availability. We also emphasize how these pathways can be utilized to support processes that are hallmarks of cancer such as angiogenesis, proliferation, and cell migration. We stress that cancer cells respond to their microenvironment through an integrated regulation of gene expression at multiple levels that collectively contribute to disease progression.
    Journal of Cell Communication and Signaling 10/2012;
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    ABSTRACT: Tumor vascularization is requisite for breast cancer progression, and high microvascular density in tumors is a poor prognostic indicator. Patients bearing breast cancers expressing human embryonic stem cell (hESC)-associated genes similarly exhibit high mortality rates, and the expression of embryonic proteins is associated with tumor progression. Here, we show that Nodal, a hESC-associated protein, promotes breast cancer vascularization. We show that high levels of Nodal are positively correlated with high vascular densities in human breast lesions (P = 0.0078). In vitro, we show that Nodal facilitates breast cancer-induced endothelial cell migration and tube formation, largely by upregulating the expression and secretion of proangiogenic factors by breast cancer cells. Using a directed in vivo angiogenesis assay and a chick chorioallantoic membrane assay, we show that Nodal promotes vascular recruitment in vivo. In a clinically relevant in vivo model, whereby Nodal expression was inhibited following tumor formation, we found a significant reduction in tumor vascularization concomitant with elevated hypoxia and tumor necrosis. These findings establish Nodal as a potential target for the treatment of breast cancer angiogenesis and progression.
    Cancer Research 08/2012; 72(15):3851-63. · 8.65 Impact Factor
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    Scott D Findlay, Paul Thagard
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    ABSTRACT: We propose a schema that characterizes how parts constitute wholes at diverse levels of organization, ranging from the atomic to the biological to the social. This schema of tags, organizers, attachers, and communicators provides a unified understanding of the structure, function, and dynamics of organization in physics, biology, and the cognitive and social sciences. We use this schema to identify and describe structures and processes at many levels of organization, and discuss its relevance for understanding the nature of constitution and emergence, especially the relation between individual humans and the social groups they constitute.
    Frontiers in Physiology 01/2012; 3:455.
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    ABSTRACT: Breast cancers expressing human embryonic stem cell (hESC)-associated genes are more likely to progress than well-differentiated cancers and are thus associated with poor patient prognosis. Elevated proliferation and evasion of growth control are similarly associated with disease progression, and are classical hallmarks of cancer. In the current study we demonstrate that the hESC-associated factor Nodal promotes breast cancer growth. Specifically, we show that Nodal is elevated in aggressive MDA-MB-231, MDA-MB-468 and Hs578t human breast cancer cell lines, compared to poorly aggressive MCF-7 and T47D breast cancer cell lines. Nodal knockdown in aggressive breast cancer cells via shRNA reduces tumour incidence and significantly blunts tumour growth at primary sites. In vitro, using Trypan Blue exclusion assays, Western blot analysis of phosphorylated histone H3 and cleaved caspase-9, and real time RT-PCR analysis of BAX and BCL2 gene expression, we demonstrate that Nodal promotes expansion of breast cancer cells, likely via a combinatorial mechanism involving increased proliferation and decreased apopotosis. In an experimental model of metastasis using beta-glucuronidase (GUSB)-deficient NOD/SCID/mucopolysaccharidosis type VII (MPSVII) mice, we show that although Nodal is not required for the formation of small (<100 cells) micrometastases at secondary sites, it supports an elevated proliferation:apoptosis ratio (Ki67:TUNEL) in micrometastatic lesions. Indeed, at longer time points (8 weeks), we determined that Nodal is necessary for the subsequent development of macrometastatic lesions. Our findings demonstrate that Nodal supports tumour growth at primary and secondary sites by increasing the ratio of proliferation:apoptosis in breast cancer cells. As Nodal expression is relatively limited to embryonic systems and cancer, this study establishes Nodal as a potential tumour-specific target for the treatment of breast cancer.
    PLoS ONE 01/2012; 7(11):e48237. · 3.73 Impact Factor
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    Paul Thagard, Scott Findlay
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    ABSTRACT: This chapter shows that belief revision about global warming can be modeled by a theory of explanatory coherence that has previously been applied to many cases of scientific belief change. We present a computer simulation of how current evidence supports acceptance of important conclusions about global warming on the basis of explanatory coherence. In addition, we explain resistance to these conclusions using a computational model of emotional coherence, which shows how political and economic goals can bias the evaluation of evidence and produce irrational rejection of claims about global warming. Finally, we argue that explanatory coherence gives a better account of belief revision than major alternatives including logicist and Bayesian theories.
    10/2010: pages 329-345;
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    Scott D. Findlay, Paul Thagard
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    ABSTRACT: This paper uses a new diagramming method, cognitive-affective mapping, to analyze the emotional changes in the 1978 Camp David negotiations that led to a breakthrough accord between Egypt and Israel. We use the technique to model the mental states of the two primary negotiators, Anwar Sadat and Menachem Begin, based on detailed descriptions provided in Jimmy Carter’s memoirs. From Carter’s account of the emotional states of the Egyptian and Israeli leaders, we generate maps that show how the attitudes of both Sadat and Begin shifted over the course of the deliberations, eventually leading to resolution of a major conflict. Such methods for facilitating recognition and reconciliation of emotional differences between disputants may contribute to movement toward peaceful and satisfying settlements. KeywordsEmotion–Negotiation–Camp David accords–Cognition–Diagrams–Conflict resolution–Attitudes
    Group Decision and Negotiation · 1.02 Impact Factor
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    Paul Thagard, Scott Findlay
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    ABSTRACT: Darwin’s theory of evolution by natural selection is central to modern biology, but is resisted by many people. This paper discusses the major psychological obstacles to accepting Darwin’s theory. Cognitive obstacles to adopting evolution by natural selection include conceptual difficulties, methodological issues, and coherence problems that derive from the intuitiveness of alternative theories. The main emotional obstacles to accepting evolution are its apparent conflict with valued beliefs about God, souls, and morality. We draw on the philosophy of science and on a psychological theory of cognitive and emotional belief revision to make suggestions about what can be done to improve acceptance of Darwinian ideas.
    Science & Education 19(6):625-636. · 0.71 Impact Factor