Didier Jean is a Senior Research Scientist in cell and molecular biology at Inserm (French National Institute of Health and Medical Research). He is leading a research group within the team “Functional Genomic of Solid Tumors (FunGeST)” at the Centre de Recherche des Cordeliers in Paris, France. After receiving his PhD in 1996 at a French University, he carried out postdoctoral studies at the MD Anderson Cancer Center in Houston, Texas. His primary basic research aims to understand the molecular mechanisms underlying human tumor pathogenesis. His first research projects investigated melanoma carcinogenesis but since 2010, his projects have focused on malignant pleural mesothelioma.
The DM-4 human melanoma cell line, which is highly metastatic in nude mice, expresses a C3-cleavi... more The DM-4 human melanoma cell line, which is highly metastatic in nude mice, expresses a C3-cleaving activity that proteolyzes labeled as well as unlabeled human C3. This C3-cleaving activity is a cysteine proteinase characterized by a M(r) 41,000. The p41 proteinase shares antigenic determinants with murine p39 procathepsin-L and human procathepsin-L. Preincubation of DM-4 cells with anti-p39 F(ab')2 induced up to 45% decrease in their complement resistance. Pretreatment of DM-4 cells with anti-p39 Ab strongly inhibited their tumorigenicity and significantly decreased their metastatic potential in nude mice. Thus, the p41 C3-cleaving proteinase contributes to tumorigenicity and metastasis of human melanoma DM-4 cells.
Le complement est une des composantes seriques du systeme immunitaire impliquee dans la lyse cell... more Le complement est une des composantes seriques du systeme immunitaire impliquee dans la lyse cellulaire. L'activation des composants du complement conduit a la generation de signaux moleculaires qui ont des fonctions biologiques. Des proteases presentes a la surface de cellules normales ou tumorales, capables de modifier la structure des composants du complement representent des molecules de regulation de fonctions cellulaires. Notre laboratoire avait precedemment identifie deux proteases membranaires qui degradent le troisieme composant du complement, le c3. Au cours de ce travail, nous avons identifie un troisieme groupe de proteases membranaires qui clivent le c3 humain. A partir de la lignee de melanome murin dsm, nous avons purifie et caracterise la cysteine protease p39 qui presente des homologies de sequence avec la procathepsine l murine. A partir de la lignee de melanome humain dm-4 fortement metastatique, nous avons identifie la cysteine protease p41 qui presente des communautes antigeniques avec la cysteine protease p39 et la procathepsine l humaine. Les cysteine proteases p39 et p41 sont presentes a la surface des cellules et sont aussi secretees. Nous avons analyse les fonctions biologiques de ces deux proteases. Elles contribuent a la resistance des melanomes a la lyse par le complement. La cysteine protease p41 est egalement impliquee dans le pouvoir tumorigene et metastatique de la lignee dm-4. Nous mettons aussi en evidence que les cellules dm-4 synthetisent et secretent le c3
Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresist... more Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking.Significance:Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.
Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In... more Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a panel of 28 MPM cell lines, including 19 patient-derived cell lines, using a variety of approaches including RNA-sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 over-expression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was...
The DM-4 human melanoma cell line, which is highly metastatic in nude mice, expresses a C3-cleavi... more The DM-4 human melanoma cell line, which is highly metastatic in nude mice, expresses a C3-cleaving activity that proteolyzes labeled as well as unlabeled human C3. This C3-cleaving activity is a cysteine proteinase characterized by a M(r) 41,000. The p41 proteinase shares antigenic determinants with murine p39 procathepsin-L and human procathepsin-L. Preincubation of DM-4 cells with anti-p39 F(ab')2 induced up to 45% decrease in their complement resistance. Pretreatment of DM-4 cells with anti-p39 Ab strongly inhibited their tumorigenicity and significantly decreased their metastatic potential in nude mice. Thus, the p41 C3-cleaving proteinase contributes to tumorigenicity and metastasis of human melanoma DM-4 cells.
Le complement est une des composantes seriques du systeme immunitaire impliquee dans la lyse cell... more Le complement est une des composantes seriques du systeme immunitaire impliquee dans la lyse cellulaire. L'activation des composants du complement conduit a la generation de signaux moleculaires qui ont des fonctions biologiques. Des proteases presentes a la surface de cellules normales ou tumorales, capables de modifier la structure des composants du complement representent des molecules de regulation de fonctions cellulaires. Notre laboratoire avait precedemment identifie deux proteases membranaires qui degradent le troisieme composant du complement, le c3. Au cours de ce travail, nous avons identifie un troisieme groupe de proteases membranaires qui clivent le c3 humain. A partir de la lignee de melanome murin dsm, nous avons purifie et caracterise la cysteine protease p39 qui presente des homologies de sequence avec la procathepsine l murine. A partir de la lignee de melanome humain dm-4 fortement metastatique, nous avons identifie la cysteine protease p41 qui presente des communautes antigeniques avec la cysteine protease p39 et la procathepsine l humaine. Les cysteine proteases p39 et p41 sont presentes a la surface des cellules et sont aussi secretees. Nous avons analyse les fonctions biologiques de ces deux proteases. Elles contribuent a la resistance des melanomes a la lyse par le complement. La cysteine protease p41 est egalement impliquee dans le pouvoir tumorigene et metastatique de la lignee dm-4. Nous mettons aussi en evidence que les cellules dm-4 synthetisent et secretent le c3
Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresist... more Among malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking.Significance:Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.
Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In... more Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a panel of 28 MPM cell lines, including 19 patient-derived cell lines, using a variety of approaches including RNA-sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 over-expression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was...
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