La protéine HSP110 : rôle dans le développement tumoral et sur l'immunogénicité du cancer colorectal

Our team studies HSPs, including HSP110. HSPs are chaperones involved in the folding of newly synthesized and denatured proteins. HSPs are overexpressed under stress conditions and are involved in cell survival thanks to their anti-apoptotic and anti-aggregation functions. HSP110 is overexpressed in colorectal cancer and is associated with a poor prognosis. The expression of a mutant HSP110, named HSP110DE9, has been shown in MSI colorectal cancer. This one was shown to act there as a dominant negative, by binding HSP110 and inhibiting its functions. Its expression sensitizes cancer cells to chemotherapy and is associated with a better prognosis for patients.I was first interested in HSP110 role in regulating the oncogenic STAT3 pathway. Its activation is associated with a poor prognosis, as it induces the transcription of genes involved in proliferation and survival. HSP110 favors colorectal cancer cell proliferation through this pathway. Conversely, HSP110DE9 inhibited it.I then focused on the role of HSP110 on macrophage polarization in colorectal cancer. HSP110 can be secreted by cancer cells and induces a pro-tumoral macrophage polarization. In contrast, HSP110DE9, by inhibiting HSP110 release, leads to a pro-inflammatory polarization. HSP110 effect on macrophage polarization involve the TLR4 receptor.All these results show HSP110 role in tumor progression. HSP110 appear as a therapeutic target in the treatment of colorectal cancer.Notre équipe étudie les HSP, et notamment HSP110. Les HSP sont des chaperons impliqués dans le repliement des protéines nouvellement synthétisées et dénaturées. Les HSP sont surexprimées lors des stress et participent à la survie des cellules par leurs propriétés anti-apoptotiques et anti-agrégations. HSP110 est surexprimée dans le cancer colorectal et est associée à un mauvais pronostic. L’expression d’un mutant d’HSP110, nommé HSP110DE9, a été mise en évidence dans les cancers colorectaux de type MSI. Celui-ci y agit comme un dominant négatif, en se liant à HSP110 et en inhibant ses fonctions. Son expression sensibilise les cellules cancéreuses à la chimiothérapie et est associée à un bon pronostic chez les patients.Je me suis tout d’abord intéressé au rôle d’HSP110 dans la régulation de la voie oncogénique STAT3. Son activation est en effet associée à un mauvais pronostic, par l’induction de gènes impliqués dans la prolifération et la survie. La protéine HSP110 favorise la prolifération des cellules colorectales cancéreuses à travers cette voie. HSP110DE9 en revanche l’inhibe. Je me suis ensuite intéressé au rôle d’HSP110 sur la polarisation des macrophages dans le cancer colorectal. Celle-ci peut être sécrétée par les cellules cancéreuses et induit une polarisation pro-tumorale des macrophages. HSP110DE9, en bloquant la sécrétion d’HSP110, conduit en revanche à une polarisation pro-inflammatoire. L’effet d’HSP110 sur la polarisation implique le récepteur TLR4.L’ensemble de ces résultats montrent le rôle d’HSP110 dans la progression tumorale. HSP110 apparaît comme une cible thérapeutique dans le traitement du cancer colorectal

HSP110 : role in colorectal cancer development and immunogenicity

Notre équipe étudie les HSP, et notamment HSP110. Les HSP sont des chaperons impliqués dans le repliement des protéines nouvellement synthétisées et dénaturées. Les HSP sont surexprimées lors des stress et participent à la survie des cellules par leurs propriétés anti-apoptotiques et anti-agrégations. HSP110 est surexprimée dans le cancer colorectal et est associée à un mauvais pronostic. L’expression d’un mutant d’HSP110, nommé HSP110DE9, a été mise en évidence dans les cancers colorectaux de type MSI. Celui-ci y agit comme un dominant négatif, en se liant à HSP110 et en inhibant ses fonctions. Son expression sensibilise les cellules cancéreuses à la chimiothérapie et est associée à un bon pronostic chez les patients.Je me suis tout d’abord intéressé au rôle d’HSP110 dans la régulation de la voie oncogénique STAT3. Son activation est en effet associée à un mauvais pronostic, par l’induction de gènes impliqués dans la prolifération et la survie. La protéine HSP110 favorise la prolifération des cellules colorectales cancéreuses à travers cette voie. HSP110DE9 en revanche l’inhibe. Je me suis ensuite intéressé au rôle d’HSP110 sur la polarisation des macrophages dans le cancer colorectal. Celle-ci peut être sécrétée par les cellules cancéreuses et induit une polarisation pro-tumorale des macrophages. HSP110DE9, en bloquant la sécrétion d’HSP110, conduit en revanche à une polarisation pro-inflammatoire. L’effet d’HSP110 sur la polarisation implique le récepteur TLR4.L’ensemble de ces résultats montrent le rôle d’HSP110 dans la progression tumorale. HSP110 apparaît comme une cible thérapeutique dans le traitement du cancer colorectal.Our team studies HSPs, including HSP110. HSPs are chaperones involved in the folding of newly synthesized and denatured proteins. HSPs are overexpressed under stress conditions and are involved in cell survival thanks to their anti-apoptotic and anti-aggregation functions. HSP110 is overexpressed in colorectal cancer and is associated with a poor prognosis. The expression of a mutant HSP110, named HSP110DE9, has been shown in MSI colorectal cancer. This one was shown to act there as a dominant negative, by binding HSP110 and inhibiting its functions. Its expression sensitizes cancer cells to chemotherapy and is associated with a better prognosis for patients.I was first interested in HSP110 role in regulating the oncogenic STAT3 pathway. Its activation is associated with a poor prognosis, as it induces the transcription of genes involved in proliferation and survival. HSP110 favors colorectal cancer cell proliferation through this pathway. Conversely, HSP110DE9 inhibited it.I then focused on the role of HSP110 on macrophage polarization in colorectal cancer. HSP110 can be secreted by cancer cells and induces a pro-tumoral macrophage polarization. In contrast, HSP110DE9, by inhibiting HSP110 release, leads to a pro-inflammatory polarization. HSP110 effect on macrophage polarization involve the TLR4 receptor.All these results show HSP110 role in tumor progression. HSP110 appear as a therapeutic target in the treatment of colorectal cancer

Sometimes even apoptosis fails: implications for cancer

International audienceApoptosis is vital for the correct morphogenesis of multi-cellular organisms. However, like most physiological programs, the cell’s ability to commit suicide is hijacked by cancer in its own proliferative and invasive interest. We recently showed that inefficient execution of apoptosis (or failed apoptosis) is used by cancer to boost invasiveness

Apoptosis – Fueling the oncogenic fire

International audienceApoptosis, the most extensively studied form of programmed cell death, is essential for organismal homeostasis. Apoptotic cell death has widely been reported as a tumor suppressor mechanism. However, recent studies have shown that apoptosis exerts noncanonical functions and may paradoxically promote tumor growth and metastasis. The hijacking of apoptosis by cancer cells may arise at different levels, either via the interaction of apoptotic cells with their local or distant microenvironment, or through the abnormal pro-oncogenic roles of the main apoptosis effectors, namely caspases and mitochondria, particularly upon failed apoptosis. In this review, we highlight some of the recently described mechanisms by which apoptosis and these effectors may promote cancer aggressiveness. We believe that a better understanding of the noncanonical roles of apoptosis may be crucial for developing more efficient cancer therapies

Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors

International audienceMembrane structural integrity is essential for optimal mitochondrial function. These organelles produce the energy needed for all vital processes, provided their outer and inner membranes are intact. This prevents the release of mitochondrial apoptogenic factors into the cytosol and ensures intact mitochondrial membrane potential (ΔΨ(m)) to sustain ATP production. Cell death by apoptosis is generally triggered by outer mitochondrial membrane permeabilization (MOMP), tightly coupled with loss of ΔΨ (m). As these two processes are essential for both mitochondrial function and cell death, researchers have devised various techniques to assess them. Here, we discuss current methods and biosensors available for detecting MOMP and measuring ΔΨ (m), focusing on their advantages and limitations and discuss what new imaging tools are needed to improve our knowledge of mitochondrial function

Gap junction-mediated transfer of miR-145-5p from microvascular endothelial cells to colon cancer cells inhibits angiogenesis.

IF 5.008International audienceGap junctional communication between cancer cells and blood capillary cells is crucial to tumor growth and invasion. Gap junctions may transfer microRNAs (miRs) among cells. Here, we explore the impact of such a transfer in co-culture assays, using the antitumor miR-145 as an example. The SW480 colon carcinoma cells form functional gap junction composed of connexin-43 (Cx43) with human microvascular endothelial cells (HMEC). When HMEC are loaded with miR-145-5p mimics, the miR-145 level drastically increases in SW480. The functional inhibition of gap junctions, using either a gap channel blocker or siRNA targeting Cx43, prevents this increase. The transfer of miR-145 also occurs from SW480 to HMEC but not in non-contact co-cultures, excluding the involvement of soluble exosomes. The miR-145 transfer to SW480 up-regulates their Cx43 expression and inhibits their ability to promote angiogenesis. Our results indicate that the gap junctional communication can inhibit tumor growth by transferring miRs from one endothelial cell to neighboring tumor cells. This "bystander" effect could find application in cancer therapy

Additional file 2: of Caspase-independent cell death does not elicit a proliferative response in melanoma cancer cells

Figure S2. (related to Fig. 2). A-B. Detection of PGE2 by ELISA in apoptotic (A) or CICD (B) conditioned media obtained in the presence or absence of celecoxib (5 μM). C. Incucyte analysis for the proliferation of WM115 H2B-mCherry cells grown in apoptotic conditioned media obtained in the presence or absence of celecoxib (5 μM). n = 4 independent experiments; mean values +/− s.e.m. (PDF 142 kb