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interactions, paracrine factors, and intracellular signaling events that govern the biology of the each signature are currentlyunderway. Ultimately, an important goal is to determine whether early detection of metastasis, similar to early detectionof primary cancer, can result in a biologically-definable period whereby immature tumor-microenvironmental interactionslimit metastatic colonization, spread, and resistance to therapy. If so, a subset of patients with metastasis may be amenable toaggressive and perhaps curative treatment.Carrie Rinker-Schaeffer, PhDAssociate Professor of SurgeryCell Signaling &Gene RegulationCancer metastasis is a complex, dynamic process that begins with dissemination of cells from the primary tumor andculminates in the formation of clinically detectable, overt metastases at one or more discontinuous secondary sites. Theprocess of invasion has been well studied, but the last steps in metastasis, metastatic colonization, remain largely unknown.Identifying pathways that control metastatic colonization may be critical for successful clinical management of cancerin both the metastatic and adjuvant settings. While genetic mutations or epigenetic changes may be required for cells toseparate and survive distant from the primary tumor, the environment within secondary tissues plays a substantial role indetermining whether disseminated cells survive and proliferate. Work in the Rinker-Schaeffer laboratory is focused on acritical unanswered question: Why do the majority of disseminated cells, which should be fully malignant, fail to proliferateimmediately at secondary sites, and how do these cells initiate growth and cause lethal disease? Over the past decade, thelaboratory has created unique model systems and developed biochemical tools to address this question mechanistically.This work is laying the foundation for the translational goal of identifying targets for inhibiting metastatic colonization andprolonging disease-free and overall survival.There is considerable interest in controlling the growth of cancer cells at metastatic sites. Therapeutic leads may be discernedby determining why disseminated cancer cells, which have molecular alterations that alter their growth properties, oftenlodge at target organs and persist as undetectable, or dormant disease. Many laboratories have worked on this question interms of angiogenesis, roles of oncogenes in conferring growth potential, or aspects of dormancy. The models used in thesestudies, however, did not enable the investigators to mechanistically interrogate effects on proliferation vs. apoptosis vs.quiescence in vivo. The Rinker-Schaeffer team chose to approach this problem from a different angle and use the unique toolsthey have developed over the past decade. The laboratory discovered that the stress-signaling kinase JNKK1/MKK4 cancontrol an early step in metastatic colonization and extended symptom-free survival in preclinical models of prostate andovarian cancers. Recent studies from the group support the hypothesis that activated JNKK1/MKK4 impairs proliferationof cells early in the course of metastatic colonization. It is remarkable that few, if any, studies have been conducted thatspecifically examine growth control of cells during metastatic colonization.The more intriguing question is how these cells ultimately bypass suppression and form overt metastases. Historically,fundamental tenets of metastasis biology dictate that acquisition of metastatic ability is the result of the “drive” of malignantcells towards growth. Thus it was predicted that bypass of suppression is simply the result of mutation-selection cycleswhich permanently inactivate JNKK1/MKK4 or members of its signaling cascade. Published data from the Rinker-Schaefferlaboratory challenge this paradigm and suggest that JNKK1-mediated suppression may be due to a reversible cell cycle arrestconcomitant with changes in JNKK1/MKK4 activation status. An exciting opportunity now exists to re-examine importantbut scattered literature on population-dependent behaviors of metastatic cells which have heretofore been refractory tomechanistic study. Understanding how a population of suppressed cells can adapt to its environment and initiate growthis critical to the development of adjuvant therapies that can be used in conjunction with local therapy to delay the onset ofmetastases. Ongoing studies are aimed at understanding how activated JNKK1/MKK4 regulates proliferation of disseminatedcells and the global mechanism(s) by which suppressed cells ultimately bypass suppression.UCCRC SCIENTIFIC REPORT 200913