Abscisic Acid Regulates Dormancy of Disseminated Tumor Cells in Bone Marrow Prostate cancer (PCa) preferentially metastasizes to the bone marrow. Paget's ?seed and soil hypothesis? in 1889 has been used to describe tumor cells (i.e. seed) metastasize to bone marrow (i.e. soil), which have specific factors conducive to metastatic growth. Recently, abscisic acid (ABA), a phytohormone, regulates the dormancy of plant seeds and other stress responses was demonstrated to be expressed in mammals where it inhibits proliferation of many cell types. Our data shows that ABA induces PCa cell cycle arrest in G0, regulates PCa survival in response to chemotherapy, and ABA receptors (LANCL2, PPAR?) are expressed by DTCs recovered from human marrow. Further ABA expression may represent a common pathway for dormancy mediators (e.g. TGF, GAS6, BMP4). The central hypothesis is: Abscisic acid induces dormancy of metastatic DTCs in the bone marrow.
Aim 1 : Determine the extent to which ABA induces PCa dormancy in bone marrow. Subhypothesis: ABA is critical for establishing DTC dormancy. Approach: Coculture studies and in vivo metastasis model s will explore the role of ABA in establishing DTC dormancy and how regulates cancer stem cell (CSC)-like activities. In vivo studies will be examine the role that niche-produced ABA plays in the maintenance of DTC dormancy. We will validate these observations with DTCs isolated from marrow of PCa patients.
Aim 2 : Determine the extent to which ABA signaling through LANCL2 or PPAR? receptors induces dormancy of PCa cells in the marrow. Subhypothesis: The binding of ABA to its receptors are critical for DTCs to become dormant. Approach:
In Aim 2 A: we will defined the role that each ABA receptor plays in regulating dormancy and what are the downstream signals, and in Aim 2B, we will determine what transcription pathways are activated by ABA to induce DTC Aim 3: Define the role of ABA signaling in resistance of PCa to chemotherapy in bone marrow. Subhypothesis: Dormant PCa cells are resistant to chemotherapy. Approach: We will to evaluate whether the disruption of DTC dormancy by ABA or ABA signaling will improve treatment outcomes by sensitizing dormant PCa cells to current chemotherapies.
DTCs may lie dormant for years prior to becoming activated to generate a lethal metastatic disease. This project aims to understand the molecular mechanisms which regulate dormancy. This knowledge will be used to develop a rationale for therapeutic targets focused on dormancy signaling to either prevent relapse or specifically activate tumor growth in an adjuvant setting so that conventional chemotherapeutic agents targeting proliferating cells may be used as adjuvant therapy to eradicate DTCs in marrow.
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