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Mitochondrial Ca²⁺ signaling is a hallmark of specific adipose tissue-cancer crosstalk.

ABSTRACT: Obesity is associated with increased risk and worse prognosis of many tumours including those of the breast and of the esophagus. Adipokines released from the peritumoural adipose tissue promote the metastatic potential of cancer cells, suggesting the existence of a crosstalk between the adipose tissue and the surrounding tumour. Mitochondrial Ca²⁺ signaling contributes to the progression of carcinoma of different origins. However, whether adipocyte-derived factors modulate mitochondrial Ca²⁺ signaling in tumours is unknown. Here, we show that conditioned media derived from adipose tissue cultures (ADCM) enriched in precursor cells impinge on mitochondrial Ca²⁺ homeostasis of target cells. Moreover, in modulating mitochondrial Ca²⁺ responses, a univocal crosstalk exists between visceral adipose tissue-derived preadipocytes and esophageal cancer cells, and between subcutaneous adipose tissue-derived preadipocytes and triple-negative breast cancer cells. An unbiased metabolomic analysis of ADCM identified creatine and creatinine for their ability to modulate mitochondrial Ca²⁺ uptake, migration and proliferation of esophageal and breast tumour cells, respectively.

SUBMITTER: De Mario A

PROVIDER: S-EPMC11009327 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Mitochondrial Ca<sup>2+</sup> signaling is a hallmark of specific adipose tissue-cancer crosstalk.

De Mario Agnese A Trevellin Elisabetta E Piazza Ilaria I Vindigni Vincenzo V Foletto Mirto M Rizzuto Rosario R Vettor Roberto R Mammucari Cristina C

Scientific reports 20240411 1

Obesity is associated with increased risk and worse prognosis of many tumours including those of the breast and of the esophagus. Adipokines released from the peritumoural adipose tissue promote the metastatic potential of cancer cells, suggesting the existence of a crosstalk between the adipose tissue and the surrounding tumour. Mitochondrial Ca<sup>2+</sup> signaling contributes to the progression of carcinoma of different origins. However, whether adipocyte-derived factors modulate mitochondr ...[more]

PMID: 38605098

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Project description:BackgroundUterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker ryanodine receptor 1 (RYR1) identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment.MethodsTCGA USC dataset was analyzed to identify top genes that are associated with patient survival or disease stage, and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models.ResultsHigh expression level of RYR1 in the tumors is associated with advanced stage of the disease. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through Ca2+-dependent activation of AKT/CREB/PGC-1α and AKT/HK1/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression and survival in mouse models.ConclusionsThese findings provided insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival.

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Mitochondrial Ca²⁺ signaling is a hallmark of specific adipose tissue-cancer crosstalk.

Publications

Mitochondrial Ca<sup>2+</sup> signaling is a hallmark of specific adipose tissue-cancer crosstalk.

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Mitochondrial Ca2+ signaling is a hallmark of specific adipose tissue-cancer crosstalk.

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Mitochondrial Ca<sup>2+</sup> signaling is a hallmark of specific adipose tissue-cancer crosstalk.

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OmicsDI is part of the ELIXIR infrastructure

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Mitochondrial Ca²⁺ signaling is a hallmark of specific adipose tissue-cancer crosstalk.