bims-lymeca 2022-12-04 papers

bims-lymeca

Biomed News

on Lysosome metabolism in cancer

Issue of 2022‒12‒04
ten papers selected by
Harilaos Filippakis
University of New England

PTEN deficiency facilitates exosome secretion and metastasis in cholangiocarcinoma by impairing TFEB-mediated lysosome biogenesis.
Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.
Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2.
Altered Lysosomal Function Manipulates Cellular Biosynthetic Capacity By Remodeling Intracellular Cholesterol Distribution.
Functions of Nutrient-Sensing Nuclear Receptors in Health.
Saikosaponin a enhances Docetaxel efficacy by selectively inducing death of dormant prostate cancer cells through excessive autophagy.
Modified lipidomic profile of cancer-associated small extracellular vesicles facilitates tumorigenic behaviours and contributes to disease progression.
The lysosome as a novel therapeutic target of EGFR-mediated tumor inflammation.
Metabolic determinants of tumour initiation.

Gastroenterology. 2022 Nov 24. pii: S0016-5085(22)01301-4. [Epub ahead of print]

PTEN deficiency facilitates exosome secretion and metastasis in cholangiocarcinoma by impairing TFEB-mediated lysosome biogenesis.

Tian-Yi Jiang, Yuan-Yuan Shi, Xiao-Wen Cui, Yu-Fei Pan, Yun-Kai Lin, Xiao-Fan Feng, Zhi-Wen Ding, Chun Yang, Ye-Xiong Tan, Li-Wei Dong, Hong-Yang Wang.

  BACKGROUND & AIMS: In eukaryotes, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are essential for maintaining cellular proteostasis and associated with cancer progression. Our previous studies have demonstrated that phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, limits proteasome abundance and determines chemosensitivity to proteasome inhibitors in cholangiocarcinoma (CCA). However, whether PTEN regulates the lysosome pathway remains unclear.METHODS: We tested the effects of PTEN on lysosome biogenesis and exosome secretion using loss- and gain-of-function strategies in CCA cell lines. Using in vitro dephosphorylation assays, we explored the regulatory mechanism between PTEN and the key regulator of lysosome biogenesis, transcription factor EB (TFEB). Using the migration assays, invasion assays, and trans-splenic liver metastasis mouse models, we evaluated the function of PTEN deficiency, TFEB-mediated lysosome biogenesis, and exosome secretion on tumor metastasis. Moreover, we investigated the clinical significance of PTEN expression and exosome secretion by retrospective analysis.
RESULTS: PTEN facilitated lysosome biogenesis and acidification through its protein phosphatase activity to dephosphorylate TFEB at Ser211. Notably, PTEN deficiency increased exosome secretion by reducing lysosome-mediated degradation of multi-vesicular bodies (MVBs), which further facilitated the proliferation and invasion of CCA. TFEB agonist curcumin analog C1 restrained the metastatic phenotype caused by PTEN deficiency in mouse models, and we highlighted the correlation between PTEN deficiency and exosome secretion in clinical cohorts.
CONCLUSIONS: In CCA, PTEN deficiency impairs lysosome biogenesis to facilitate exosome secretion and cancer metastasis in a TFEB phosphorylation-dependent manner.

Keywords:  Cholangiocarcinoma; Exosome; Lysosome; MVB; PTEN; TFEB

DOI:  https://doi.org/10.1053/j.gastro.2022.11.025
Mol Genet Metab. 2022 Nov 12. pii: S1096-7192(22)00434-6. [Epub ahead of print]137(4): 382-387

Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.

Guy M Lenk, Miriam H Meisler.

  Loss-of-function mutations of FIG4 impair the biosynthesis of PI(3,5)P2 and are responsible for rare genetic disorders including Yunis-Varón Syndrome and Charcot-Marie-Tooth Disease Type 4 J. Cultured cells deficient in FIG4 accumulate enlarged lysosomes with hyperacidic pH, due in part to impaired regulation of lysosomal ion channels and elevated intra-lysosomal osmotic pressure. We evaluated the effects of the FDA approved drug chloroquine, which is known to reduce lysosome acidity, on FIG4 deficient cell culture and on a mouse model. Chloroquine corrected the enlarged lysosomes in FIG4 null cells. In null mice, addition of chloroquine to the drinking water slowed progression of the disorder. Growth and mobility were dramatically improved during the first month of life, and spongiform degeneration of the nervous system was reduced. The median survival of Fig4 null mice was increased from 4 weeks for untreated mutants to 8 weeks with chloroquine treatment (p < 0.009). Chloroquine thus corrects the lysosomal swelling in cultured cells and ameliorates Fig4 deficiency in vivo. The improved phenotype of mice with complete loss of Fig4 suggests that chloroquine could be beneficial FIG2 in partial loss-of-function disorders such as Charcot-Marie-Tooth Type 4 J.

Keywords:  CMT4J; Chloroquine; FIG4; Lysosomal disorder; Neurodegeneration; PI(3,5)P(2)

DOI:  https://doi.org/10.1016/j.ymgme.2022.11.004
Nat Commun. 2022 Nov 28. 13(1): 7338

Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.

Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G Gutierrez.

Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.

DOI: https://doi.org/10.1038/s41467-022-34632-8
Theranostics. 2022 ;12(17): 7431-7449

Elevated ITGA5 facilitates hyperactivated mTORC1-mediated progression of laryngeal squamous cell carcinoma via upregulation of EFNB2.

Dapeng Li, Anjiang Sun, Liang Zhang, Zhao Ding, Fangzheng Yi, Xue Yang, Zixi Wang, Xu Chen, Weiwei Liu, Shixian Liu, Hailong Shen, Manli Miao, Ling Zhang, Ping Liu, Yuchen Liu, Shihong Su, Hailiang Huang, Can Huang, Zhongdong Hu, Hongbing Zhang, Xiaojun Zha, Yehai Liu.

  Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck, and it has shown increasing incidence and mortality. The mechanistic target of rapamycin complex 1 (mTORC1) is frequently dysregulated in LSCC, but its underlying mechanisms remain unclear. Methods: Establishment of a novel LSCC cell line using primary LSCC tumor tissues with dysregulated mTORC1 activity and then stable knockdown of Raptor (an mTORC1 specific component) in this cell line. Transcriptomic sequencing, quantitative real-time PCR, western blot analysis, and immunofluorescence assays were used to identify the crucial downstream effector of mTORC1. A series of experiments were conducted to investigate the functions and underlying mechanisms of the mTORC1 target gene in LSCC progression. Clinical LSCC samples were used to evaluate the association of mTORC1 and its downstream targets with clinicopathological features and patient prognosis. Finally, the influence on cisplatin (CDDP) sensitivity upon depletion of the mTORC1 target gene was assessed using a cell culture system, a cell line-derived xenograft (CDX) model, and a patient-derived xenograft (PDX) model. Results: We successfully established a novel LSCC cell line with hyperactivated mTORC1 activity and then identified integrin subunit alpha 5 (ITGA5) as a novel functional downstream effector of mTORC1 in the progression of LSCC. Elevated ITGA5 promotes LSCC progression through augmentation of ephrin-B2 (EFNB2). Clinical data analysis indicated that the activation of the mTORC1-ITGA5-EFNB2 signaling pathway is associated with malignant progression and poor prognosis of LSCC patients. Inhibition of ITGA5 significantly sensitized LSCC cells to CDDP. Conclusions: Our findings highlight a novel molecular mechanism for the tumorigenesis driven by deregulated mTORC1 signaling in LSCC, suggesting that the ITGA5-EFNB2 axis may be a therapeutic target for the treatment of mTORC1-related LSCC.

Keywords:  EFNB2; ITGA5; LSCC; mTOR; tumorigenesis

DOI:  https://doi.org/10.7150/thno.76232
Cell Biochem Biophys. 2022 Dec 02.

Altered Lysosomal Function Manipulates Cellular Biosynthetic Capacity By Remodeling Intracellular Cholesterol Distribution.

Sudarshana Rajasekaran, Anand Ramaian Santhaseela, Shamila Ragunathan, Sangita Venkataraman, Tamilselvan Jayavelu.

  Lysosomes are known to influence cholesterol trafficking into endoplasmic reticulum (ER) membranes. Though intracellular cholesterol levels are known to influence the lipid biosynthetic responses in ER, the specific effects of lysosomal modulation on these outcomes is not known. To demonstrate this, C2C12 cells were treated with chloroquine, a lysosomotropic agent, and its effects on cellular biosynthetic capacity, structural and functional status of ER was determined. In addition to its known effects on autophagy reduction, chloroquine treatment induced accumulation of total cellular lipid and ER-specific cholesterol content. It was also observed that chloroquine caused an increase in smooth-ER content with defects in overall protein turnover. Further, since ER and mitochondria function in close association through ER membrane contact sites, it is likely that lysosomal modulation also brings about associated changes in mitochondria. In this regard, we found that chloroquine reduces mitochondrial membrane potential and mitochondrial dynamics. Collectively, the differential biosynthetic response of rise in lipid content, but not protein content, cannot be accounted by merely considering that chloroquine induced suppression of autophagy causes defects in organelle function. In this defective autophagy scenario, both biosynthetic responses such as lipid and protein synthesis are expected to be reduced rather than only the latter, as observed with chloroquine. These findings suggest that cholesterol trafficking/distribution within cellular organelles could act as an intracellular mediator of differential biosynthetic remodelling in interconnected organelles.

Keywords:  Chloroquine; Cholesterol; Endoplasmic reticulum; Lysosome; Mitochondria

DOI:  https://doi.org/10.1007/s12013-022-01123-y
J Nutr Sci Vitaminol (Tokyo). 2022 ;68(Supplement): S14-S16

Functions of Nutrient-Sensing Nuclear Receptors in Health.

Ryoichi Yamaji.

  Nutrients play important roles in the regulation of physiological and pathophysiological events in higher animals. Nuclear receptors (NRs) share a common modular functional structure and constitute a transcription factor superfamily consisting of 48 members in humans. Some NRs are activated by the binding of small lipophilic molecules such as food components including fat-soluble vitamins (vitamins A, K, and D) or lipids (phosphatidylcholine, oleoylethanolamide, or fatty acids). NRs contribute to cell growth, differentiation, or metabolic regulation. Generally, NRs bound to their ligands function as a transcription factors targeting specific DNA sequences in genes. Additionally, ligand-bound NRs mediate the activation of specific intracellular signal transduction pathways. On the other hand, some NRs are functional without binding a ligand. Information on the roles and functions of nutrient-sensing NRs in physiological or pathophysiological events not only leads to an understanding of the need for nutrients, but also contributes to the prevention and amelioration of nutrition-related diseases.

Keywords:  farnesoid X receptor; peroxisome proliferator-activated receptor α; retinoic acid receptor; steroid and xenobiotic receptor; vitamin D receptor

DOI:  https://doi.org/10.3177/jnsv.68.S14
Cancer Lett. 2022 Nov 25. pii: S0304-3835(22)00498-0. [Epub ahead of print] 216011

Saikosaponin a enhances Docetaxel efficacy by selectively inducing death of dormant prostate cancer cells through excessive autophagy.

Jiling Feng, Zhichao Xi, Xue Jiang, Yang Li, Wan Najbah Nik Nabil, Mengfan Liu, Zejia Song, Xiaoqiong Chen, Hua Zhou, Qihan Dong, Hongxi Xu.

  Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence when QCCs resume cell cycle progression. However, drugs selectively targeting QCCs are lacking. Saikosaponin A (SSA) derived from Bupleurum DC., is highly potent in eradicating multidrug-resistant prostate QCCs compared with proliferative prostate cancer cells. By further exacerbating the already increased autophagy through inactivation of Akt-mTOR signaling, SSA triggered cell death in QCCs. Contrarily, inhibition of autophagy or activation of Akt signaling pathway prevented SSA-induced cell death. The multicycle of Docetaxel treatments increased the proportion of QCCs, whereas administering SSA at intervals of Docetaxel treatments aggravated cell death in vitro and led to tumor growth arrest and cell death in vivo. In conclusion, SSA is posed as a novel QCCs-eradicating agent by aggravating autophagy in QCCs. In combination with the current therapy, SSA has potential to improve treatment effectiveness and to prevent cancer recurrence.

Keywords:  Akt; Induce autophagy; Prostate cancer; Quiescent cancer cells; SSA

DOI:  https://doi.org/10.1016/j.canlet.2022.216011
Adv Biol Regul. 2022 Nov 21. pii: S2212-4926(22)00075-6. [Epub ahead of print] 100935

Modified lipidomic profile of cancer-associated small extracellular vesicles facilitates tumorigenic behaviours and contributes to disease progression.

Jordan Fyfe, Pratibha Malhotra, Marco Falasca.

  Metabolic rewiring is a key feature of cancer cells, which involves the alteration of amino acids, glucose and lipids to support aggressive cancer phenotypes. Changes in lipid metabolism alter cancer growth characteristics, membrane integrity and signalling pathways. Small extracellular vesicles (sEVs) are membrane-bound vesicles secreted by cells into the extracellular environment, where they participate in cell-to-cell communication. Lipids are involved in the formation and cargo assortment of sEVs, resulting in their selective packaging in these vesicles. Further, sEVs participate in different aspects of cancer development, such as proliferation, migration and angiogenesis. Various lipidomic studies have indicated the enrichment of specific lipids in sEVs derived from tumour cells, which aid in their pathological functioning. This paper summarises how the modified lipid profile of sEVs contributes to carcinogenesis and disease progression.

Keywords:  Cancer biomarkers; Cancer progression; Extracellular vesicles; Lipid metabolism; Lipidomic

DOI:  https://doi.org/10.1016/j.jbior.2022.100935
Front Pharmacol. 2022 ;13 1050758

The lysosome as a novel therapeutic target of EGFR-mediated tumor inflammation.

Woo Jung Sung, Dohyang Kim, Anlin Zhu, Namki Cho, Hee Min Yoo, Ji Heon Noh, Kyoung Mi Kim, Hyun-Su Lee, Jaewoo Hong.

  EGFR-mediated tumors have been targeted to overcome several different malignant cancers. EGFR overexpression and mutations are directly related to the malignancy, which makes the therapy more complicated. One reason for the malignancy is the induction of AP1 followed by inflammation via IL-6 secretion. Current therapeutic strategies to overcome EGFR-mediated tumors are tyrosine kinase inhibitors (TKIs), anti-EGFR monoclonal antibodies, and the combination of these two agents with classic chemotherapy or immune checkpoint inhibitors (ICIs). Although the strategies are straightforward and have shown promising efficacy in several studies, there are still hurdles to overcoming the adverse effects and limited efficacy. This study reviews the current therapeutic strategies to target EGFR family members, how they work, and their effects and limitations. We also suggest developing novel strategies to target EGFR-mediated tumors in a novel approach. A lysosome is the main custodial staff to discard unwanted amounts of EGFR and other receptor tyrosine kinase molecules. Targeting this organelle may be a new approach to overcoming EGFR-mediated cancers.

Keywords:  EGFR; ErbB; TKI; combination therapy; lysosome

DOI:  https://doi.org/10.3389/fphar.2022.1050758
Nat Rev Endocrinol. 2022 Nov 29.

Metabolic determinants of tumour initiation.

Julia S Brunner, Lydia W S Finley.

Tumours exhibit notable metabolic alterations compared with their corresponding normal tissue counterparts. These metabolic alterations can support anabolic growth, enable survival in hostile environments and regulate gene expression programmes that promote malignant progression. Whether these metabolic changes are selected for during malignant transformation or can themselves be drivers of tumour initiation is unclear. However, intriguingly, many of the major bottlenecks for tumour initiation - control of cell fate, survival and proliferation - are all amenable to metabolic regulation. In this article, we review evidence demonstrating a critical role for metabolic pathways in processes that support the earliest stages of tumour development. We discuss how cell-intrinsic factors, such as the cell of origin or transforming oncogene, and cell-extrinsic factors, such as local nutrient availability, promote or restrain tumour initiation. Deeper insight into how metabolic pathways control tumour initiation will improve our ability to design metabolic interventions to limit tumour incidence.

DOI: https://doi.org/10.1038/s41574-022-00773-5