The Role that Lysosomes and Autophagy play in Alveolar soft parts Sarcoma, clear cell Sarcoma and Synovial Sarcoma

Sarcomas are cancer of the connective tissue and are very deadly group of cancers. Two of the sarcoma types, alveolar soft parts sarcoma (ASPS) and clear cell sarcoma (CCS) have a unique vacuolar morphology. This unique morphology is absent in synovial sarcoma (SS). We believe that the unusual morphology in ASPS and CCS is caused by the presence of abundant lysosomes. Lysosomes are the cell's digestive system and also play a crucial role in the programmed cell death process, autophagy. Autophagy is known to help tumor cells survive under stressful conditions. We hypothesize that ASPS and CCS upregulate autophagy related genes and use autophagy as a survival mechanism. Analysis of RNA sequencing data for the three sarcomas showed that Lamp1, Lamp2a, CathepsinD and Beclin1 genes are upregulated. Western blot data showed that the protein levels translated from all four genes were highest in ASPS and lowest in SS. Immunohistochemistry showed that the LAMP1, LAMP2A, BECLIN1 and CATHEPSIN D are localized outside the nucleus and in concentrated pockets. This supports the theory that ASPS and CCS have abundant lysosomes. We inhibited autophagy using chloroquine in vitro but that did not have an effect on the rate of survival in these cancer cells. We also investigated the role of Mitf in the regulation of Lamp1, Lamp2a, CathepsinD and Beclin1. Mitf did not affect the expression of the genes in vitro, however, Mitf KO mice lived longer than Mitf WT mice. The synergistic effects of inhibiting autophagy and another cancer therapy like chemotherapy or radiation therapy might be more effective than solely inhibiting autophagy.