The acquisition of highly malignant traits by carcinoma cells enables their invasion and metastatic dissemination. In many, and possibly all carcinomas, these traits are conferred by a cell-biological program termed the epithelial-mesenchymal transition (EMT). The EMT program is induced in carcinoma cells, usually reversibly, by contextual signals that they receive, largely if not entirely from the adjacent reactive stroma that is present in many highly progressed tumors. While the intracellular signaling circuits that enable activation of EMT programs have come into view, the nature of the extracellular, contextual signals that activate these programs in carcinoma cells is still obscure as are the cellular origins of these signals. This Indicates that the ultimate governors of malignant progression - the stromal cells and the signals that they release - are still poorly understood. The proposed research derives from the convergence of two lines of research in the Pi's laboratory. First. Twist - an EMT-inducing transcription factor - is responsible for the malignant behavior of highly aggressive 4T1 mouse mammary carcinoma cells;its expression is induced in vivo, ostensibly by signals that the implanted 4T1 cells receive from the stromal cells that they recruit. Second, these carcinoma cells induce splenomegaly in tumor-bearing syngeneic mouse hosts. Rather than being an epiphenomenon of tumor pathogenesis, this splenomegaly plays a causal role in 4T1 tumor formation, since in the absence of a functional spleen (achieved by splenectomy), the expression of the Twist and Snail EMT-TFs and their ability to spawn metastases are all significantly reduced. Hence, the local malignant state of these tumors, and likely many other tumors, is controlled by systemic factors, in this case myeloid cells recruited from the spleen. These dynamics suggest that certain carcinomas, such as the 4T1 tumors studied here, induce splenomegaly;the myeloid cells that collect In the spleen may then be recruited via the circulation into the tumor-associated stroma, where these cells proceed to release heterotypic signals that induce an EMT in the 4T1 cells, enabling the latter to metastasize. Importantly for the proposed research, the spleens of these mice should represent a rich source of the myeloid cells that participate in the induction of the EMT and thus in the triggering of metastatic relapse. The research that is proposed will examine these cells as well as others that are recruited into the tumor-associated stroma in order to develop a list of the functionally important, malignancy-promoting cells in the tumor-associated stroma and to uncover the EMT-inducing paracrine signals that they release.
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