Live analysis of tumor-host cells interactions

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Tissue homeostasis is a highly dynamic process, which requires a strict regulation of cell growth, cell proliferation, and cell death within the tissue. During development and adult life of the organism, cell proliferation and cell death are precisely coordinated to ensure the integrity of the epithelium. However, due to genetic alteration(s) some cells can uncouple their proliferation and death cues from the rest of the epithelium and thus acquire an autonomous ability to proliferate uncontrollably. If not corrected, this deregulation of cell proliferation and/or cell death can in turn lead to tumor formation within the tissue, potentially causing tissue/organ malfunction and subsequent death of the individual/animal. For tumor cells to effectively grow they must overcome several challenges, including anti-cell proliferation and/or pro-apoptotic signals within their environment. However, our understanding of how tumors interact with the host, specifically with neighboring wild type cells is incomplete. Furthermore, deregulation of additional signaling pathway(s) in primary benign tumors can transform these tumors into malignant tumors, which have the ability to spread to distant organs and precipitate the patient<s death. Carcinomas account for ~90% of human malignancies and metastasis is associated with poor patients prognosis. Our understanding of the nature of these malignant transforming signaling pathways and how these cues are internalized in tumor cells to cause such transformation is unclear. Moreover, it is now evident that tumors are functionally heterogeneous. For example, in any given tumor, cells have differing potential to initiate tumor metastasis. A characterization of these metastasis-initiating tumor cells is lacking. Using a Drosophila tumor model, the objectives of this research proposal are 1) to investigate how cell proliferation and cell death cues are regulated in benign versus malignant tumors, 2) to test a role for TGF2 signaling in the benign to malignant tumor transformation, and 3) To characterize the cytokinetic properties of metastasis initiating tumor cells. Aim1. To examine cell death and cell proliferation of benign versus malignant tumor cells Using live imaging techniques in a Drosophila fly tumor model, I will monitor tumor cell proliferation and cell death in benign or malignant tumors. Similarly, the behavior of wild type cells neighboring tumor cells will be concomitantly analyzed. Aim2. To investigate a role for TGF2 signaling in the benign to malignant tumor transformation, A role for TGF2 signaling in converting benign tumors into malignant tumors will be examined using immuno- staining and somatic genetic approaches. Aim3. To characterize the cytokinetic properties of metastasis initiating tumor cells. Tracking experiments will be performed to trace metastatic tumor cells back to their position within the primary tumor relative to neighboring wild type cells. Their cell proliferation behaviors will subsequently be analyzed. PUBLIC HEALTH RELEVANCE: Carcinomas account for ~90% of human malignancies and metastatic tumors are often associated with poor patient prognosis. Understanding how tumors interact with host cells to facilitate tumor growth and metastasis could potentially provide novel insights for clinical interventions