BackgroundIt is well established that inflammation and platelets promote multiple processes of cancer malignancy. Recently, platelets have received attention for their role in carcinogenesis through the production of microvesicles or platelet-derived microparticles (PMPs), which transfer their biological content to cancer cells. We have previously characterized a new subpopulation of these microparticles (termed mito-microparticles), which package functional mitochondria. The potential of mitochondria transfer to cancer cells is particularly impactful as many aspects of mitochondrial biology (i.e., cell growth, apoptosis inhibition, and drug resistance) coincide with cancer hallmarks and disease progression. These metabolic aspects are particularly notable in chronic lymphocytic leukemia (CLL), which is characterized by a relentless accumulation of proliferating, immunologically dysfunctional, mature B-lymphocytes that fail to undergo apoptosis. The present study aimed to investigate the role of PMPs on CLL metabolic plasticity leading to cancer cell phenotypic changes.MethodsCLL cell lines were co-incubated with different concentrations of human PMPs, and their impact on cell proliferation, mitochondrial DNA copy number, OCR level, ATP production, and ROS content was evaluated. Essential genes involved in metabolic-reprogramming were identified using the bioinformatics tools, examined between patients with early and advanced CLL stages, and then validated in PMP-recipient CLLs. Finally, the impact of the induced metabolic reprogramming on CLLs’ growth, survival, mobility, and invasiveness was tested against anti-cancer drugs Cytarabine, Venetoclax, and Plumbagin.ResultsThe data demonstrated the potency of PMPs in inducing tumoral growth and invasiveness in CLLs through mitochondrial internalization and OXPHOS stimulation which was in line with metabolic shift reported in CLL patients from early to advanced stages. This metabolic rewiring also improved CLL cells' resistance to Cytarabine, Venetoclax, and Plumbagin chemo drugs.ConclusionAltogether, these findings depict a new platelet-mediated pathway of cancer pathogenesis. We also highlight the impact of PMPs in CLL metabolic reprogramming and disease progression.
Circular RNAs (circRNAs) are a newly identified class of RNA which are highly expressed and conserved in mammalian cells. With the intrinsic property of being resistant to exonucleolytic activity due to their circular configuration, circRNAs are remarkably stable compared to their linear RNA species counterpart. CircRNAs regulate many biological processes and their aberrant expression is often associated with disease progression. Recently, we have characterized the expression of circRNAs of the potent Pax‐5 oncogene in B cell cancers. In this present study, we set out to identify and establish the expression profiles of Pax‐5 circRNAs in B cell cancers and also, to evaluate the potential of these non‐coding products to act as disease biomarkers. Using RT‐PCR in B cell lines, Pax‐5 circRNAs were amplified with divergent primers. PCR products were then sequenced and aligned for identification and validation. Pax‐5 circRNAs were also evaluated by qPCR from peripheral blood mononuclear cells (PBMCs) from healthy donors and clinical samples. Four circRNA isoforms of the Pax‐5 gene were isolated, sequenced and identified from various B cell models. These latter Pax‐5 circRNA variants consisted of a circular single RNA strand characterized with either exons 2, 3, 4; exons 2, 3, 4, 5; exons 2, 3, 4, 5, 6; or exons 2, 3, 4, 5, 6, 7, 8 of the human Pax‐5 gene. Profiling of Pax‐5 circRNA expression levels in clinical samples reveal an overexpression in chronic lymphocytic leukemia in comparison to other B cell cancer lesions and healthy donors. Altogether, we describe 4 novel gene products (i.e. circRNAs) of the Pax‐5 oncogene in B cell cancers. Preliminary results also support a potential role for Pax‐5 circRNAs as prognostic or diagnostic biomarkers for specific B cell cancers. Further studies are ongoing to validate the correlation between Pax‐5 circRNA levels and disease progression. In addition, the mechanistic elucidation of Pax‐5 circRNAs in cancer processes will also potentially identify new avenues for B cell cancer therapeutic interventions.Support or Funding InformationThis work was supported by grants from the New Brunswick (NB) Innovation Foundation, the Canadian Breast Cancer Foundation, the Canadian Breast Cancer Society/QEII Foundation, the NB Health Research Foundation and by the Beatrice Hunter Cancer Research Institute.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inflammation is an essential process of host defense against infections, illness, or tissue damage. Polymorphonuclear neutrophils (PMN) are among the first immune cells involved in acute inflammatory responses and are on the front line in the fight against bacterial infections. In the presence of bacterial fragments, PMN release inflammatory mediators, enzymes, and microvesicles in the extracellular milieu to recruit additional immune cells required to eliminate the pathogens. Recent evidence shows that platelets (PLTs), initially described for their role in coagulation, are involved in inflammatory responses. Furthermore, upon activation, PLT also release functional mitochondria (freeMitos) within their extracellular milieu. Mitochondria share characteristics with bacterial and mitochondrial damage‐associated molecular patterns, which are important contributors in sterile inflammation processes. Deep sequencing transcriptome analysis demonstrates that freeMitos increase the mitochondrial gene expression in PMN. However, freeMitos do not affect the mitochondrial‐dependent increase in oxygen consumption in PMN. Interestingly, freeMitos significantly induce the release of PMN‐derived microvesicles. This study provides new insight into the role of freeMitos in the context of sterile inflammation.
Cancer is one of the leading causes of morbidity and mortality among women worldwide. Although mortality rates have been declining for years, metastasis accounts for the majority of deaths associated with the disease. An increasing number of studies show that platelets as well as platelet‐derived microparticles (PMPs) play a significant role in cancer malignancy and disease progression. PMPs are small vesicles released into the circulatory system and the extracellular environment during platelet activation. PMP generation involves a process where bioactive material is transferred from platelets to the PMPs. Interestingly, PMPs have the capacity to interact with target recipient cells and transfer their bioactive cargo into these cells upon internalization. Accordingly, studies have shown that PMPs allow intercellular exchange and trafficking of bioactive material to modulate signaling and activation processes of recipient cells. We believe that PMPs represent an important source of breast cancer modulators leading to malignant features and disease progression. The objective of this study was to evaluate the impact of PMPs on breast cancer processes. More specifically, we investigated the modulating effects of PMPs on breast cancer metabolism and phenotypic processes involved in breast cancer metastasis. First, we characterized and validated the capacity of breast cancer models to internalize PMPs and their cargo using confocal microscopy and flow cytometry. Interestingly, we observed that the levels of PMPs internalization vary and are dependent of the type of breast cancer recipient cells. Using a series of biochemical and cell‐based assays, we also demonstrated that the cargo of PMPs is biologically active which results in the modulation of breast cancer cell metabolism, viability and migration properties of recipient cells. Overall, we demonstrate that PMPs modulate cancer cell processes reminiscent of disease malignancy. These findings provide a better understanding of the role of PMPs and their influence as cancer disease modulators. The knowledge gained from these studies will thus foster the development of potentially new strategic interventions to help mitigate the morbidity and mortality associated with cancer disease.
Breast cancer is one of the leading causes of morbidity and mortality among women, where metastasis accounts for the majority of deaths associated with this disease. Thus, the potential to effectively target tumor malignancy offers hope to mitigate disease progression and improve patient outcomes. It is well established that platelets promote multiple processes of metastasis cascade. Recently, platelets have received new attention for their impact in cancer through the production of platelet-derived microparticles (PMPs). Interestingly, PMPs allow intercellular exchange and trafficking of bioactive material through the internalization of these vesicles into recipient cells. As a result, the delivery of the intravesicular cargo can modulate signaling and activation processes of recipient cells. We recently identified a new subpopulation of these vesicles (termed mitoMPs) containing functional mitochondria. Given the predominant role of mitochondria in cancer malignancy, we believe that mitoMPs provide an important source of foreign mitochondria to support recipient breast cancer cells in malignancy and disease progression. We therefore set out to study the impact of mitoMPs on breast cancer metabolic and phenotypic processes involved in metastasis. Technically, PMPs were generated and purified from human blood platelets and co-incubated with various breast cell models (MB231, MCF7 and MCF10A). The physiological significance of mitoMPs in breast cancer disease was then assessed using various cellular and molecular assays. We demonstrate that the level of PMP internalization is highly dependent upon the type of breast cancer recipient cells. Furthermore, we show that the cargo of mitoMPs (notably mitochondria) is biologically active where recipient breast cancer cells acquired mitochondria-dependent functions, such as increased oxygen consumption rates and intracellular ATP production. Finally, we observe that mitoMPs promote malignant features such as cancer cell migration and invasion. Overall, we demonstrate that PMPs can modulate cancer cell activation and behaviour. These findings provide a better understanding of the extracellular tumor environment and the contribution of mitoMPs in supporting breast cancer cells through the metastatic landscape. The knowledge gained will further provide new avenues for therapeutic strategies in breast cancer patients. Citation Format: Vanessa Veilleux, Nicolas Pichaud, Luc H. Boudreau, Gilles A. Robichaud. Platelet-derived microparticles modulate breast cancer malignant processes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3708.
Circular RNAs (circRNAs) represent a new class of gene products involved in many biological processes. Due to their ability to bind and modulate co-interacting proteins and microRNAs (miRs), circRNAs represent new signaling mediators in cell biology and cancer processes. Recently, we identified circRNAs from the PAX5 oncogene (circPAX5) in B-cells. Given that PAX5 gene products are well established as potent oncogenic regulators of B-cell cancer lesions, we hypothesized that circPAX5 may also be potentially involved in pathogenic processes of B-cell malignancies. In this study, we wanted to understand the role of circPAX5 in B-cell cancer processes and elucidate new potential targets for diagnostic and therapeutic avenues. Using a series of B-cell cancer models and clinical samples, we sequenced, mapped, and profiled circPAX5 expression profiles and found that circPAX5 products are indeed overexpressed in various cancer cell types where the predominant expressed isoform consisted of exons 2 to 5 (circPAX5_2-5) of the PAX5 locus. In addition, we isolated circPAX5 complexes from cancer cells and identified co-interacting small non-coding RNAs, notably microARNs (miRs) by deep sequencing. To further elucidate the functional role of circPAX5 and miR co-interactions, selected miRs from the list were then conditionally overexpressed in B-cells followed by cellular phenotypic assays. Altogether, our results characterize new signaling products and pathways in B-cells. Our data also suggests that circPAX5 products are involved in B-cell cancer processes and could potentially represent new cancer pathways targeted for strategic therapeutic and/or diagnostic strategies in B-cell cancer lesions Citation Format: Danick M. Martin, Brandon Hannay, Alexis Martin, Vanessa Veilleux, Nicholas Finn, Gilles A. Robichaud. Circular RNAs from the PAX5 oncogene are overexpressed in B-cell malignancies and modulate cancer processes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3812.
The incidence of breast cancer among women far exceeds those of other cancers where metastasis accounts for the majority of deaths associated with the disease. It is well established that platelets play a prominent role in breast cancer malignancy and disease progression. Recently, activated platelets have been characterized to release platelet-derived microparticles (PMPs), which can also package functional mitochondria of platelet origin (termed mitoMPs). We recently demonstrated that mitoMPs can interact with breast cancer cells where they transfer their cargo (i.e., mitochondria) to recipient cancer cells upon their internalization. Given that metabolic reprogramming through mitochondrial dynamics represents a hallmark trait of cancer progression, the intercellular trafficking of foreign mitochondria provided by mitoMPs represent a new mechanistic avenue for cancer cell metabolic plasticity and disease progression.Therefore, the aim of this study was to evaluate the impact of mitoMP-packaged mitochondria on recipient breast cancer cell mitochondrial dynamics upon internalization. Technically, a series of breast cancer cell models (MB231, MCF7 and MCF10A) were co-cultured with mitoMPs and profiled for mitochondrial dynamics and function using complementing experimental approaches, such as flow cytometry, confocal microscopy, and RT-qPCR. We show that mitoMPs and their mitochondria cargo internalize primarily into the malignant MB231 cell model. To investigate the impact of mitoMP uptake by cancer cells on the mitochondrial dynamics, RT-qPCR and Western blot analyses were performed to profile the expression levels of several fusion and fission proteins, including OPA1, MFF, DRP1, MitoFusin 1 and MitoFusin 2. Finally, using fluorescent-based assays, we confirmed that mitoMPs modulated ATP production in MB231 breast cancer cells through upregulation of the OXPHOS pathway. Our research provides a new mechanism by which extracellular vesicles (mitoMPs) play an important role in cancer cell mitochondrial dynamics and function to support metabolic plasticity during the metastatic journey of cancer cells. The knowledge gained from these studies will further provide new avenues for strategic intervention to mitigate the morbidity and mortality associated with breast cancer disease. Citation Format: Vanessa L. Gauvin, Vanessa Veilleux, Nicolas Pichaud, Gilles A. Robichaud, Luc H. Boudreau. Mitochondria packaged from platelet-derived microvesicles modulate the metabolism and mitochondrial dynamics of breast cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4846.
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