Lysosomes and Cancer Progression: A Malignant Liaison

Abstract

During primary tumorigenesis isolated cancer cells may undergo genetic or epigenetic changes that render them responsive to additional intrinsic or extrinsic cues, so that they enter a transitional state and eventually acquire an aggressive, metastatic phenotype. Among these changes is the alteration of the cell metabolic/catabolic machinery that creates the most permissive conditions for invasion, dissemination, and survival. The lysosomal system has emerged as a crucial player in this malignant transformation, making this system a potential therapeutic target in cancer. By virtue of their ubiquitous distribution in mammalian cells, their multifaced activities that control catabolic and anabolic processes, and their interplay with other organelles and the plasma membrane (PM), lysosomes function as platforms for inter- and intracellular communication. This is due to their capacity to adapt and sense nutrient availability, to spatially segregate specific functions depending on their position, to fuse with other compartments and with the PM, and to engage in membrane contact sites (MCS) with other organelles. Here we review the latest advances in our understanding of the role of the lysosomal system in cancer progression. We focus on how changes in lysosomal nutrient sensing, as well as lysosomal positioning, exocytosis, and fusion perturb the communication between tumor cells themselves and between tumor cells and their microenvironment. Finally, we describe the potential impact of MCS between lysosomes and other organelles in propelling cancer growth and spread.

E-Cadherin Modulation and Inter-Cellular Trafficking in Tubular Gastric Adenocarcinoma: A High-Resolution Microscopy Pilot Study

“…Drugs that diffuse into the cytoplasm are trapped in lysosomes and are rapidly effluxed by cancer cells that express multidrug resistance transporters. Doxorubicin, cisplatin, vincristine, vinblastine, sorafenib, and sunitinib are some examples of lysosomotropic chemotherapeutics [34][35][36].…”

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling

“…Lysosomes have recently emerged as important players in cancer development or progression, while targeting their function has been proposed as a promising strategy in cancer treatment (Machado et al, 2021;Tang et al, 2020). Recently, we showed that components of the ESCRT machinery could serve as potential therapeutic targets against colorectal cancer (CRC) (Kolmus et al, 2021;Szymanska et al, 2020), but whether modulation of ESCRT activity would affect lysosomal function in CRC cells has not been tested.…”

“…Yet, whether ESCRTs are implicated in the physiological regulation of lysosomal morphology, function or signaling in the absence of induced lysosomal damage has not been thoroughly addressed. This question is important for human health, as lysosomal function and signaling contribute to development or progression of cancer (Machado et al, 2021;Tang et al, 2020), including colorectal cancer (CRC) in which ESCRT machinery has been proposed as a promising therapeutic target (Kolmus et al, 2021;Szymanska et al, 2020).…”

Ion Interference Therapy of Tumors Based on Inorganic Nanoparticles

“…In particular, the acidic organelle in cells, the lysosome, as a proton store, is the center responsible for degradation, nutrient sensing and immunity [ 18 ]. At the same time, lysosomes are also closely related to the growth, proliferation and migration of tumor cells [ 19 ]. Targeting lysosomes to achieve H + -mediated ion interference therapy is also an effective means to treat cancers.…”