Etude de la dissémination du cancer colorectal

The colorectal cancer (CRC) dissemination is an extremely inefficient multistep, but despite this, metastasis can be successfully formed. Dissemination starts by few cells that leave the primary tumor and use different type of migration individually or collectively. Once they enter into blood vessels, cancer cells become circulating tumors cells (CTCs). CTCs use the blood stream circulation to disseminate to distant organs. However, in each of the dissemination step, CTCs can face a new microenvironment that can give them advantages or disadvantages. Some of these disseminated tumor cells (DTCs) transform the microenvironment to a pro-tumoral microenvironment. If not, they can enter in dormancy and wait until that the microenvironment changes and became permissive. Each of these steps could be used to develop a targeted therapeutic strategy in order to impede the colorectal cancer dissemination. We face thus an urgent need to better understand the tumoral heterogeneity and their microenvironmental interactions. Furthermore, the dissemination process is a dynamic phenomenon and it must be considered earlier in order to integrate the early dissemination of the colorectal cancer.Le processus de dissémination du cancer colorectal (CCR) est un processus extrêmement peu efficace mais qui de par sa fréquence, parvient à initier des métastases. Elle débute par le départ de quelques cellules depuis la tumeur primaire selon différents modes de migration et des stratégies individuelles ou collectives. Parvenues à entrer dans un vaisseau sanguin, les cellules cancéreuses deviennent des cellules tumorales circulantes (CTCs). Ces CTCs profitent de la circulation sanguine pour se propager dans l’organisme. Cependant chacune de ces étapes les confronte à un micro-environnement qui peut être un avantage ou un désavantage. Certaines cellules tumorales disséminées (CTDs) parviennent cependant à éduquer le micro-environnement en un micro-environnement pro-tumoral. Si ce n’est pas le cas, elles peuvent entrer en dormance et attendre que ce dernier change et devienne pro-tumoral. Chacune des étapes de ce processus peuvent faire l’objet d’une stratégie thérapeutique visant à empêcher la dissémination colorectale. Il est donc nécessaire de mieux comprendre l’hétérogénéité tumorale et les interactions quelles ont avec le micro-environnement. De plus, le processus de dissémination est un phénomène dynamique et qui doit être pris en compte dorénavant très tôt afin d’intégrer la notion de dissémination précoce du cancer colorectal

Deciphering the colorectal cancer dissemination

Le processus de dissémination du cancer colorectal (CCR) est un processus extrêmement peu efficace mais qui de par sa fréquence, parvient à initier des métastases. Elle débute par le départ de quelques cellules depuis la tumeur primaire selon différents modes de migration et des stratégies individuelles ou collectives. Parvenues à entrer dans un vaisseau sanguin, les cellules cancéreuses deviennent des cellules tumorales circulantes (CTCs). Ces CTCs profitent de la circulation sanguine pour se propager dans l’organisme. Cependant chacune de ces étapes les confronte à un micro-environnement qui peut être un avantage ou un désavantage. Certaines cellules tumorales disséminées (CTDs) parviennent cependant à éduquer le micro-environnement en un micro-environnement pro-tumoral. Si ce n’est pas le cas, elles peuvent entrer en dormance et attendre que ce dernier change et devienne pro-tumoral. Chacune des étapes de ce processus peuvent faire l’objet d’une stratégie thérapeutique visant à empêcher la dissémination colorectale. Il est donc nécessaire de mieux comprendre l’hétérogénéité tumorale et les interactions quelles ont avec le micro-environnement. De plus, le processus de dissémination est un phénomène dynamique et qui doit être pris en compte dorénavant très tôt afin d’intégrer la notion de dissémination précoce du cancer colorectal.The colorectal cancer (CRC) dissemination is an extremely inefficient multistep, but despite this, metastasis can be successfully formed. Dissemination starts by few cells that leave the primary tumor and use different type of migration individually or collectively. Once they enter into blood vessels, cancer cells become circulating tumors cells (CTCs). CTCs use the blood stream circulation to disseminate to distant organs. However, in each of the dissemination step, CTCs can face a new microenvironment that can give them advantages or disadvantages. Some of these disseminated tumor cells (DTCs) transform the microenvironment to a pro-tumoral microenvironment. If not, they can enter in dormancy and wait until that the microenvironment changes and became permissive. Each of these steps could be used to develop a targeted therapeutic strategy in order to impede the colorectal cancer dissemination. We face thus an urgent need to better understand the tumoral heterogeneity and their microenvironmental interactions. Furthermore, the dissemination process is a dynamic phenomenon and it must be considered earlier in order to integrate the early dissemination of the colorectal cancer

Immunothérapie pré-chirurgicale : un nouvel espoir pour prévenir la récidive métastatique dans le cancer du côlon

International audienceNo abstract availabl

CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM

Circulating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches—immune detection coupled with magnetic beads and fluorescence-activated cell sorting—were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity

Epithelial-to-Mesenchymal Transition in the Light of Plasticity and Hybrid E/M States

Epithelial-to-mesenchymal transition (EMT) is a cellular program which leads to cells losing epithelial features, including cell polarity, cell–cell adhesion and attachment to the basement membrane, while gaining mesenchymal characteristics, such as invasive properties and stemness. This program is involved in embryogenesis, wound healing and cancer progression. Over the years, the role of EMT in cancer progression has been heavily debated, and the requirement of this process in metastasis even has been disputed. In this review, we discuss previous discrepancies in the light of recent findings on EMT, plasticity and hybrid E/M states. Moreover, we highlight various tumor microenvironmental cues and cell intrinsic signaling pathways that induce and sustain EMT programs, plasticity and hybrid E/M states. Lastly, we discuss how recent findings on plasticity, especially on those that enable cells to switch between hybrid E/M states, have changed our understanding on the role of EMT in cancer metastasis, stemness and therapy resistance

Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells

International audienceThe clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than met-formin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunc-tion and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting

Correction: Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells.

[This corrects the article DOI: 10.1371/journal.pone.0206764.]

A heterodimer formed by bone morphogenetic protein 9 (BMP9) and BMP10 provides most BMP biological activity in plasma

International audienceBone morphogenetic protein 9 (BMP9) and BMP10 are thetwo high-affinity ligands for the endothelial receptor activinreceptor-like kinase 1 (ALK1) and are key regulators of vascularremodeling. They are both present in the blood, buttheir respective biological activities are still a matter ofdebate. The aim of the present work was to characterize theircirculating forms to better understand how their activitiesare regulated in vivo. First, by cotransfecting BMP9 andBMP10, we found that both can form a disulfide-bonded heterodimerin vitro and that this heterodimer is functional onendothelial cells via ALK1. Next, we developed an ELISA thatcould specifically recognize the BMP9–BMP10 heterodimerand which indicated its presence in both human and mouseplasma. In addition to using available Bmp9-KO mice,we generated a conditional Bmp10-KO mouse strain. Theplasma from Bmp10-KO mice, similarly to that of Bmp9-KOmice, completely lacked the ability to activate ALK1-transfected3T3 cells or phospho-Smad1–5 on endothelial cells,indicating that the circulating BMP activity is mostly due tothe BMP9–BMP10 heterodimeric form. This result was confirmedin human plasma that had undergone affinity chromatographyto remove BMP9 homodimer. Finally, we provideevidence that hepatic stellate cells in the liver could be thesource of the BMP9–BMP10 heterodimer. Together, ourfindings demonstrate that BMP9 and BMP10 can heterodimerizeand that this heterodimer is responsible for mostof the biological BMP activity found in plasma

CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM

International audienceCirculating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches-immune detection coupled with magnetic beads and fluorescence-activated cell sorting-were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity

CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM

International audienceCirculating tumor cells (CTCs) are promising diagnostic and prognostic tools for clinical use. In several cancers, including colorectal and breast, the CTC load has been associated with a therapeutic response as well as progression-free and overall survival. However, counting and isolating CTCs remains sub-optimal because they are currently largely identified by epithelial markers such as EpCAM. New, complementary CTC surface markers are therefore urgently needed. We previously demonstrated that a splice variant of CD44, CD44 variable alternative exon 6 (CD44v6), is highly and specifically expressed by CTC cell lines derived from blood samples in colorectal cancer (CRC) patients. Two different approaches—immune detection coupled with magnetic beads and fluorescence-activated cell sorting—were optimized to purify CTCs from patient blood samples based on high expressions of CD44v6. We revealed the potential of the CD44v6 as a complementary marker to EpCAM to detect and purify CTCs in colorectal cancer blood samples. Furthermore, this marker is not restricted to colorectal cancer since CD44v6 is also expressed on CTCs from breast cancer patients. Overall, these results strongly suggest that CD44v6 could be useful to enumerate and purify CTCs from cancers of different origins, paving the way to more efficacious combined markers that encompass CTC heterogeneity