Richard Miallot

Bio: Richard Miallot is an academic researcher from French Institute of Health and Medical Research. The author has contributed to research in topics: Mitochondrion & Medicine. The author has co-authored 1 publications.

Metabolic landscapes in sarcomas.

Abstract: Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.

An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity

Abstract: This work describes how a mutation affecting mitochondrial metabolism in a sarcoma model induces protective immunity against the tumor and how this result might be relevant for sarcoma patients. Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell–deficient, mice. These cells prime CD8+ lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity.

Application of Multi-Omics Approach in Sarcomas: A Tool for Studying Mechanism, Biomarkers, and Therapeutic Targets

Abstract: Sarcomas are rare, heterogeneous mesenchymal neoplasms with various subtypes, each exhibiting unique genetic characteristics. Although studies have been conducted to improve the treatment for sarcomas, the specific development from normal somatic cells to sarcoma cells is still unclear and needs further research. The diagnosis of sarcomas depends heavily on the pathological examination, which is yet a difficult work and requires expert analysis. Advanced treatment like precise medicine optimizes the efficacy of treatment and the prognosis of sarcoma patients, yet, in sarcomas, more studies should be done to put such methods in clinical practice. The revolution of advanced technology has pushed the multi-omics approach to the front, and more could be learnt in sarcomas with such methods. Multi-omics combines the character of each omics techniques, analyzes the mechanism of tumor cells from different levels, which makes up for the shortage of single-omics, and gives us an integrated picture of bioactivities inside tumor cells. Multi-omics research of sarcomas has reached appreciable progress in recent years, leading to a better understanding of the mutation, proliferation, and metastasis of sarcomas. With the help of multi-omics approach, novel biomarkers were found, with promising effects in improving the process of diagnosis, prognosis anticipation, and treatment decision. By analyzing large amounts of biological features, subtype clustering could be done in a better precision, which may be useful in the clinical procedure. In this review, we summarized recent discoveries using multi-omics approach in sarcomas, discussed their merits and challenges, and concluded with future perspectives of the sarcoma research.

On the Relevance of Soft Tissue Sarcomas Metabolic Landscape Mapping

Abstract: Soft tissue sarcomas (STS) prognosis is disappointing, with current treatment strategies being based on a “fit for all” principle and not taking distinct sarcoma subtypes specificities and genetic/metabolic differences into consideration. The paucity of precision therapies in STS reflects the shortage of studies that seek to decipher the sarcomagenesis mechanisms. There is an urge to improve STS diagnosis precision, refine STS classification criteria, and increase the capability of identifying STS prognostic biomarkers. Single-omics and multi-omics studies may play a key role on decodifying sarcomagenesis. Metabolomics provides a singular insight, either as a single-omics approach or as part of a multi-omics strategy, into the metabolic adaptations that support sarcomagenesis. Although STS metabolome is scarcely characterized, untargeted and targeted metabolomics approaches employing different data acquisition methods such as mass spectrometry (MS), MS imaging, and nuclear magnetic resonance (NMR) spectroscopy provided important information, warranting further studies. New chromatographic, MS, NMR-based, and flow cytometry-based methods will offer opportunities to therapeutically target metabolic pathways and to monitorize the response to such metabolic targeting therapies. Here we provide a comprehensive review of STS omics applications, comprising a detailed analysis of studies focused on the metabolic landscape of these tumors.

An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity

Abstract: This work describes how a mutation affecting mitochondrial metabolism in a sarcoma model induces protective immunity against the tumor and how this result might be relevant for sarcoma patients. Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell–deficient, mice. These cells prime CD8+ lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity.

The coenzyme A precursor pantethine restrains sarcoma growth through promotion of type 1 immunity

Abstract: Abstract The tumor microenvironment is a dynamic network of stromal, cancer and immune cells that interact and compete for resources. Mitochondria play an essential role in the control of metabolic plasticity and contribute to tumor progression and immune cell functionality. We previously identified the Vanin1 pathway as a tumor suppressor of sarcoma development via vitamin B5 and coenzyme A regeneration. Using an aggressive sarcoma cell line that lacks Vnn1 expression, we showed that administration of pantethine, a vitamin B5 precursor, impairs tumor growth in immunocompetent mice. Pantethine boosts anti-tumor type 1 immunity including polarization of myeloid and dendritic cells towards enhanced IFNγ-driven antigen presentation pathways and improved development of hypermetabolic effector CD8 + T cells endowed with potential anti-tumor activity. At later stages of treatment, the effect of pantethine is limited by the development of immune cell exhaustion. Nevertheless, its activity is comparable to that of anti-PD1 treatment in sensitive tumors. In humans, VNN1 expression correlates with improved survival and immune cell infiltration in soft tissue sarcomas but not osteosarcomas. Pantethine could be a potential therapeutic immunoadjuvant for the development of anti-tumor immunity.