Regulated lysosomal exocytosis mediates cancer progression

Machado, Eda; White‐Gilbertson, Shai; Vlekkert, Diantha van de; Janke, Laura J.; Moshiach, Simon; Campos, Yvan; Finkelstein, David; Gomero, Elida; Mosca, Rosario; Qiu, Xiaohui; Morton, Christopher L.; Annunziata, Ida; d’Azzo, Alessandra

doi:10.1126/sciadv.1500603

Cited by 126 publications

(146 citation statements)

References 59 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…17 The spatial and temporal control of membrane dynamics is essential for cellular processes and may underly pathologies, as for example lysosomes are distributed toward the plasma membrane to promote invasion and metastasis in some cancer cells. 18 Our findings provide insight into Klp98A as a novel player in autophagic vesicle movement and maturation, which acts as a scaffold protein though its interdependent domains. Klp98A may act as a focal point for multiple regulatory signals.…”

mentioning

confidence: 79%

Autophagosomes take the Klp98-A train

Neufeld

2016

Small GTPases

View full text Add to dashboard Cite

The intracellular movement of membrane-bound vesicles is closely tied to their formation, maturation and ultimate function within the cell. Motor proteins and their associated cytoskeletal networks are critical for vesicle transport, but whether these factors play a more direct role in vesicle biogenesis is unclear. In recent work, we found that the Drosophila kinesin proteins Khc and Klp98A are both required for the normal anterograde movement of autophagosomes and autolysosomes during starvation-induced autophagy. In addition, Klp98A has a transport-independent function of promoting autophagosome-lysosome fusion, a key step in the maturation of autophagic vesicles. This function correlates with the association of Klp98A with the autophagosomal protein Atg8 and with the endolysosomal protein Rab14, suggesting that Klp98A may promote vesicle fusion by physically linking these vesicle surface proteins. These findings demonstrate how the delivery of vesicles to their proper destination can be coordinated with additional steps in their life cycle through molecular motor-based interactions.

show abstract

mentioning

confidence: 79%

Autophagosomes take the Klp98-A train

Neufeld

2016

Small GTPases

View full text Add to dashboard Cite

show abstract

“…In another study on rhabdomyosarcoma, data showed that lysosomal exocytosis, which is positively correlated with the release of exosomes, could be induced to transform tumor cells to an invasive and drug-resistant phenotype by downregulation of NEU1 (target of sialidase) and accumulation of LAMP1 (sialylated membrane glycoprotein) [67]. To determine the mechanism of NEU1-LAMP1 controlling lysosomal exocytosis in sarcoma, human rhabdomyosarcoma cell lines RH41 with higher-NEU1 and lower-LAMP1 expression and RH30 with lower-NEU1 and higher-LAMP1 expression were examined and compared [67].…”

Section: Roles Of Exosomes In Sarcomamentioning

confidence: 99%

“…To determine the mechanism of NEU1-LAMP1 controlling lysosomal exocytosis in sarcoma, human rhabdomyosarcoma cell lines RH41 with higher-NEU1 and lower-LAMP1 expression and RH30 with lower-NEU1 and higher-LAMP1 expression were examined and compared [67]. In both RH41 and RH30 cells, exosomes were isolated through ultracentrifugation and detected by positive expression of exosomal markers flotillin-1, CD81, syndecan-1, and syntenin-1; however, more exosomes were observed to be secreted by RH30 cells [67]. In RH30 cells, more lysosomes were found tethered to or docked at the plasma membrane and showed a stronger trend for exocytosis [67].…”

Section: Roles Of Exosomes In Sarcomamentioning

confidence: 99%

“…In both RH41 and RH30 cells, exosomes were isolated through ultracentrifugation and detected by positive expression of exosomal markers flotillin-1, CD81, syndecan-1, and syntenin-1; however, more exosomes were observed to be secreted by RH30 cells [67]. In RH30 cells, more lysosomes were found tethered to or docked at the plasma membrane and showed a stronger trend for exocytosis [67]. For further confirmation, scientists knocked down and overexpressed the NEU1 or LAMP1 genes respectively in RH41 and RH30 cells, and indicated that lysosomal exocytosis and release of exosomes were both enhanced by silencing NEU1 or upregulating LAMP1 [67].…”

Section: Roles Of Exosomes In Sarcomamentioning

confidence: 99%

“…In RH30 cells, more lysosomes were found tethered to or docked at the plasma membrane and showed a stronger trend for exocytosis [67]. For further confirmation, scientists knocked down and overexpressed the NEU1 or LAMP1 genes respectively in RH41 and RH30 cells, and indicated that lysosomal exocytosis and release of exosomes were both enhanced by silencing NEU1 or upregulating LAMP1 [67]. Intriguingly, communication between exosomes and cells was observed.…”

Section: Roles Of Exosomes In Sarcomamentioning

confidence: 99%

See 2 more Smart Citations

The roles and implications of exosomes in sarcoma

Shen

et al. 2016

Cancer Metastasis Rev

View full text Add to dashboard Cite

Better diagnostic biomarkers and therapeutic options are still necessary for patients with sarcomas due to the current limitations of diagnosis and treatment. Exosomes are small extracellular membrane vesicles that are released by various cells and are found in most body fluids. Tumor-derived exosomes have been proven to mediate tumorigenesis, intercellular communication, microenvironment modulation, and metastasis in different cancers, including in sarcomas. Recently, exosomes have been considered as potential biomarkers for sarcoma diagnosis, prognosis, and possible targets for sarcoma therapy. Moreover, due to their specific cell-tropism and bioavailability, exosomes can also be engineered as vehicles for drug delivery. In this review, we discuss recent advances in the roles of tumor-derived exosomes in sarcoma and their potential clinical applications.

show abstract

Necroptosis is associated with Rab27‐independent expulsion of extracellular vesicles containing RIPK3 and MLKL

Gupta

Brown

Hsieh

et al. 2022

J of Extracellular Vesicle

View full text Add to dashboard Cite

Extracellular vesicle (EV) secretion is an important mechanism used by cells to release biomolecules. A common necroptosis effector—mixed lineage kinase domain like (MLKL)—was recently found to participate in the biogenesis of small and large EVs independent of its function in necroptosis. The objective of the current study is to gain mechanistic insights into EV biogenesis during necroptosis. Assessing EV number by nanoparticle tracking analysis revealed an increased number of EVs released during necroptosis. To evaluate the nature of such vesicles, we performed a newly adapted, highly sensitive mass spectrometry‐based proteomics on EVs released by healthy or necroptotic cells. Compared to EVs released by healthy cells, EVs released during necroptosis contained a markedly higher number of unique proteins. Receptor interacting protein kinase‐3 (RIPK3) and MLKL were among the proteins enriched in EVs released during necroptosis. Further, mouse embryonic fibroblasts (MEFs) derived from mice deficient of Rab27a and Rab27b showed diminished basal EV release but responded to necroptosis with enhanced EV biogenesis as the wildtype MEFs. In contrast, necroptosis‐associated EVs were sensitive to Ca2+ depletion or lysosomal disruption. Neither treatment affected the RIPK3‐mediated MLKL phosphorylation. An unbiased screen using RIPK3 immunoprecipitation‐mass spectrometry on necroptotic EVs led to the identification of Rab11b in RIPK3 immune‐complexes. Our data suggests that necroptosis switches EV biogenesis from a Rab27a/b dependent mechanism to a lysosomal mediated mechanism.

show abstract

Regulated lysosomal exocytosis mediates cancer progression

Abstract: LAMP1 oversialylation results in excessive lysosomal exocytosis, promoting tumor invasion and drug resistance.

Cited by 126 publications

References 59 publications

Autophagosomes take the Klp98-A train

Autophagosomes take the Klp98-A train

The roles and implications of exosomes in sarcoma

Necroptosis is associated with Rab27‐independent expulsion of extracellular vesicles containing RIPK3 and MLKL

Contact Info

Product

Resources

About