Poster Presentation 36th Lorne Cancer Conference 2024

Understanding how Cancer Cells Exploit Lysosomal Biogenesis to Promote Survival (#130)

Tara A Tigani 1 2 , Andrew G Cox 1 2 3 , Kristin K Brown 1 2 3
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  3. Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, Australia

Cancer cells depend on an adequate nutrient supply to fuel the biosynthetic processes that drive their uncontrolled growth. However, nutrient availability in the tumour microenvironment is frequently compromised due to poor vascularisation and competition for resources between different cell types occupying the tumour niche. Therefore, cancer cells often employ alternative approaches to acquire nutrients. Central to many of these nutrient acquisition pathways is the lysosome, an organelle that breaks down macromolecules (e.g. proteins) into their constituent parts (e.g. amino acids). Malignant transformation is associated with a variety of changes to lysosomes/lysosomal function including increased lysosomal biogenesis. Lysosomal biogenesis is regulated by TFEB/TFE3, transcription factors that regulate key proteins in lysosomal function. Emerging evidence suggests that cancer cells may exploit TFEB/TFE3 to fuel their growth and promote survival. However, the specific molecular signals that contribute to lysosomal biogenesis are poorly understood. Using physiologically relevant cell culture models, we have demonstrated that amino acid deprivation and exposure to chemotherapeutic agents promote lysosomal biogenesis. Moreover, we have shown that genetic depletion of TFEB/TFE3 sensitises cells to these perturbations. We have performed a targeted metabolic CRISPR screen, to identify genes that contribute to the regulation of lysosomal biogenesis under these stress conditions. The mechanisms by which genes identified in the screen contribute to lysosomal regulation are currently being explored. Our studies will not only contribute to a greater understanding of the regulation of lysosomal biogenesis but have the potential to identify novel strategies for cancer therapy.