bims-lycede Biomed News
on Lysosome-dependent cell death
Issue of 2024–12–29
two papers selected by
Sofía Peralta, Universidad Nacional de Cuyo
  1. TFEB triggers a matrix degradation and invasion program in triple-negative breast cancer cells upon mTORC1 repression.
  2. Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples.
  1. Dev Cell. 2024 Dec 21. pii: S1534-5807(24)00727-5. [Epub ahead of print]
    TFEB triggers a matrix degradation and invasion program in triple-negative breast cancer cells upon mTORC1 repression.
    David Remy, Sandra Antoine-Bally, Sophie de Toqueville, Célia Jolly, Anne-Sophie Macé, Gabriel Champenois, Fariba Nemati, Isabel Brito, Virginie Raynal, Amulya Priya, Adèle Berlioz, Ahmed Dahmani, André Nicolas, Didier Meseure, Elisabetta Marangoni, Philippe Chavrier.
      The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently hyperactivated in triple-negative breast cancers (TNBCs) associated with poor prognosis and is a therapeutic target in breast cancer management. Here, we describe the effects of repression of mTOR-containing complex 1 (mTORC1) through knockdown of several key mTORC1 components or with mTOR inhibitors used in cancer therapy. mTORC1 repression results in an ∼10-fold increase in extracellular matrix proteolytic degradation. Repression in several TNBC models, including in patient-derived xenografts (PDXs), induces nuclear translocation of transcription factor EB (TFEB), which drives a transcriptional program that controls endolysosome function and exocytosis. This response triggers a surge in endolysosomal recycling and the surface exposure of membrane type 1 matrix metalloproteinase (MT1-MMP) associated with invadopodia hyperfunctionality. Furthermore, repression of mTORC1 results in a basal-like breast cancer cell phenotype and disruption of ductal carcinoma in situ (DCIS)-like organization in a tumor xenograft model. Altogether, our data call for revaluation of mTOR inhibitors in breast cancer therapy.
    Keywords:  MT1-MMP; TFEB; extracellular matrix; invadopodia; mTOR inhibitors; mTORC1; patient-derived xenograft; triple-negative breast cancer; tumor invasion
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.005
  2. J Clin Invest. 2024 Dec 26. pii: e183592. [Epub ahead of print]
    Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples.
    Daniel Saarela, Pawel Lis, Sara Gomes, Raja S Nirujogi, Wentao Dong, Eshaan S Rawat, Sophie Glendinning, Karolina Zeneviciute, Enrico Bagnoli, Rotimi Fasimoye, Cindy Lin, Kwamina Nyame, Fanni A Boros, Friederike Zunke, Frederic Lamoliatte, Sadik Elshani, Matthew Jaconelli, Judith Jm Jans, Margriet A Huisman, Christian Posern, Lena M Westermann, Angela Schulz, Peter M van Hasselt, Dario R Alessi, Monther Abu-Remaileh, Esther M Sammler.
      Lysosomes are implicated in a wide spectrum of human diseases including monogenic lysosomal storage disorders (LSDs), age-associated neurodegeneration and cancer. Profiling lysosomal content using tag-based lysosomal immunoprecipitation (LysoTagIP) in cell and animal models has substantially moved the field forward, but studying lysosomal dysfunction in human patients remains challenging. Here, we report the development of the 'tagless LysoIP' method, designed to enable the rapid enrichment of lysosomes, via immunoprecipitation, using the endogenous integral lysosomal membrane protein TMEM192, directly from clinical samples and human cell lines (e.g., induced pluripotent stem cell derived neurons). Isolated lysosomes were intact and suitable for subsequent multimodal omics analyses. To validate our approach, we applied the tagless LysoIP to enrich lysosomes from peripheral blood mononuclear cells derived from fresh blood of healthy donors and patients with CLN3 disease, an autosomal recessive neurodegenerative LSD. Metabolic profiling of isolated lysosomes revealed massive accumulation of glycerophosphodiesters (GPDs) in patients' lysosomes. Interestingly, a patient with a milder phenotype and genotype displayed lower accumulation of lysosomal GPDs, consistent with their potential role as disease biomarkers. Altogether, the tagless LysoIP provides a framework to study native lysosomes from patient samples, identify disease biomarkers, and discover human-relevant disease mechanisms.
    Keywords:  Cell biology; Genetic diseases; Lysosomes; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1172/JCI183592
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒29 at 2:58.