Inflammation is a major driver of tumor progression and metastasis, although the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. Interleukin-6 (IL-6) is a potent proinflammatory cytokine that is elevated in individuals with pancreatic cancer (PDAC), is required for PDAC progression in mice, and increases tumor cell invasion Here, we provide insights into the mechanisms by which IL-6 activates tumor cell invasion. We found that IL-6 stimulation rapidly and robustly activates the small GTPase cell division cycle 42 (CDC42) in human PDAC cells and promotes the formation of premigratory filopodia. The CDC42 activation was required for IL-6-induced invasion as blocking CDC42 activity rendered the cells insensitive to IL-6's proinvasive effects. Loss of Janus kinase 2 (JAK2) or signal transducer and activator of transcription 3 (STAT3) prevented IL-6-mediated CDC42 activation, indicating that IL-6 activates CDC42 through both JAK2 and STAT3. However, the rapid activation of CDC42 suggested that this activation may be distinct from canonical STAT3-mediated transcriptional activation. Importantly, we observed an interaction between STAT3 and IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffolding platform that binds CDC42. STAT3 colocalized with CDC42 and IQGAP1 at the plasma membrane, suggesting cross-talk between IL-6-mediated STAT3 signaling and CDC42 activation. These results suggest that IL-6 promotes metastatic invasion, at least partially, through CDC42 and that, along with its pleiotropic effects on tumor growth and progression, IL-6 signaling also activates proinvasive GTPase signaling, priming tumor cells for metastatic invasion.

Dyn2 and α-actinin 4 interact directly to regulate invasive cell migration and the stabilization of invadopodia. Intriguingly, this is specific for α-actinin 4, and not the highly related protein α-actinin 1. These findings elucidate a novel mechanism of regulating cell migration, with important implications for invasive tumor cells.

The α-actinin family of actin cross-linking proteins have been implicated in driving tumor cell metastasis through regulation of the actin cytoskeleton; however, there has been little investigation into whether these proteins can influence tumor cell growth. We demonstrate that α-actinin 1 and 4 are essential for nutrient uptake through the process of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC) cells, and inhibition of these proteins decreases tumor cell survival in the presence of extracellular protein. The α-actinin proteins play essential roles throughout the macropinocytic process, where α-actinin 4 stabilizes the actin cytoskeleton on the plasma membrane to drive membrane ruffling and macropinosome internalization, and α-actinin 1 localizes to actin tails on macropinosomes to facilitate trafficking to the lysosome for degradation. In addition to tumor cell growth, we also observe that the α-actinin proteins can influence uptake of chemotherapeutics and extracellular matrix (ECM) proteins through macropinocytosis, suggesting that the α-actinin proteins can regulate multiple tumor cell properties through this endocytic process. In summary, these data demonstrate a critical role for the α-actinin isoforms in tumor cell macropinocytosis, thereby affecting growth and invasive potential of PDAC tumors. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

Statement of the Problem On November 17, 1873, the General Conference adopted George I. Butler’s leadership philosophy, which officially centralized ecclesiastical authority within one person. This statement on leadership and authority was deemed highly important and several resolutions, as well as a covenantal pledge, were voted and signed in promise that this new policy would be strictly followed. What led the Adventist Church to adopt such a policy and bind itself to it in this manner? What were the philosophical and theological tenets that the policy espoused? Since this position on leadership is no longer accepted in the Adventist Church today, what led the denomination to change its mind and how did the Leadership Controversy that erupted as a result of Butler’s philosophy impact the history of the church? The purpose of this thesis is to answer these questions in a threefold manner: (1) to set Butler’s “leadership doctrine” within its Adventist historical context and briefly chronicle the events that prompted him to write Leadership, (2) to analyze, evaluate and critique Butler’s philosophy of leadership, and (3) to chronicle the responses to Butler’s essay and note the impact the Leadership Controversy had on the Seventh-day Adventist Church in subsequent years. Methodology This study was conducted on the basis of primary source research. The documents referenced include church publications and periodicals as well as correspondence, diaries, church record books, and other germane documents. More recent studies by scholars are also cited on occasion as secondary sources, either for support or critique. Conclusion Between the 1840s and 1863, James White, in effect, led the Sabbatarian Adventist movement as one man. Evidently, this informal type of governance was appropriate for this small group of Sabbath-keepers during this time. When the denomination officially organized in 1863, however, the locus of authority officially broadened from one informal leader to the formally elected three-person General Conference Executive Committee. It was difficult for Adventists to make this transition and questions regarding leadership began to arise. This became particularly pronounced during the years following James White’s first stroke (1866-1877) as a controversy between leaders began to threaten denominational unity. In response, George I. Butler led Adventists to accept his philosophy of leadership and centralize power within one person for the sake of protection. This caused the Adventist Church to officially revert to its first (though unofficial) conceptualization of church governance that was practiced between the 1840s and 1863. Though this reversion came with great enthusiasm in 1873, it eventually sparked the Leadership Controversy of the 1870s as certain Adventists began to challenge Butler’s philosophy. This controversy concluded in 1877 when the Adventist Church officially reaffirmed the oligarchical understanding of leadership that it adopted in 1863. In this way, the Leadership Controversy was resolved by broadening the locus of authority from one person to a small group of persons. Within the next decade, however, Ellen G. White realized that the church had grown too large to be governed so closely by the small General Conference Executive Committee. Though she supported an oligarchical form of leadership and authority in 1875, she began calling for change after the General Conference session in 1888. Eventually, in 1901, the Adventist Church recognized the need to broaden the locus of authority once again. In order to affirm this final shift between practiced models of leadership, Ellen White gave her final response to the Leadership Controversy of the 1870s in 1909, stating explicitly that ecclesiastical authority should not be centralized in one person or a small group of persons.