Cooperative Agreement U01CA289564

PROMOTION OF METASTASIS BY APOPTOTIC CELLS - PROJECT SUMMARY/ABSTRACT THE GOAL OF MOST CANCER TREATMENTS IS TO INDUCE THE APOPTOTIC DEATH OF TUMOR CELLS; IN MANY CASES THESE TREATMENTS ALSO INDUCE SUBSTANTIAL OFF-TARGET APOPTOSIS IN HEALTHY TISSUES. EVEN IN THE ABSENCE OF THERAPY, THE MAJORITY OF PROSPECTIVE METASTATIC CELLS DIE BY APOPTOSIS, RESULTING IN THE EARLY METASTATIC NICHE BEING RICH IN APOPTOTIC CELL MATERIAL. WHILE NUMEROUS STUDIES HAVE FOCUSED ON THE FEATURES OF TUMOR CELLS THAT ALLOW THEM TO SURVIVE AND METASTASIZE IN THE FACE OF SUCH TREATMENTS, LESS ATTENTION HAS BEEN PAID TO THE INFLUENCE OF DYING CELLS THEMSELVES ON CANCER PROGRESSION. THE WORK PROPOSED HERE WILL INVESTIGATE THE HYPOTHESIS THAT APOPTOTIC CELLS DRIVE EFFICIENT METASTATIC SPREAD OF HEALTHY CANCER CELLS, BECAUSE THEY INITIATE A CASCADE OF PLATELET RECRUITMENT, COAGULATION, AND MYELOID CELL REPROGRAMMING AT METASTATIC SITES. WE WILL ADDRESS THIS HYPOTHESIS BY FOCUSING ON THREE AIMS: FIRST, WE WILL ADDRESS THE ROLE OF PHOSPHATIDYLSERINE EXPOSURE ON APOPTOTIC CELLS IN RECRUITING PLATELETS AND PROMOTING TUMOR CELL SURVIVAL WITHIN THE INTRAVASCULAR NICHE UPON ARRIVAL OF METASTASIZING CELLS TO THE LUNG. SECOND, WE WILL EXAMINE THE INTERFACE BETWEEN APOPTOTIC CELLS, CANCER CELLS, AND THE MYELOID IMMUNE NETWORK OF THE LUNG, DURING EXTRAVASATION AND ESTABLISHMENT OF THE METASTATIC NICHE. THIRD, WE WILL STUDY THE EFFECTS OF APOPTOTIC CELLS ON SPONTANEOUS METASTASIS FROM A PRIMARY TUMOR, AND TEST WHETHER BLOCKING PRO-METASTATIC FEATURES OF APOPTOTIC CELLS CAN REDUCE METASTASIS IN THIS SETTING. WHILE OUR WORK IS FOCUSED ON THE FUNDAMENTAL PROCESSES BY WHICH APOPTOTIC CELLS INFLUENCE METASTASIS, WE SUGGEST THAT IT MAY POINT TOWARD THERAPEUTIC COMBINATIONS THAT PREVENT METASTASIS.