Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive bioma ricers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DORT is upregulated during chemotherapy both in vitro and in viva. Moreover, analysis of a cohort of patients with LUAD suggested that high DOR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DORI inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD

The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

BACKGROUND: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. METHODS: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. RESULTS: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. CONCLUSIONS: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes

Etude des rétrotransposons LINE-1 dans la leucémie myéloïde chronique

Le gène hybride BCR-ABL1, responsable de la leucémie myéloïde chronique (LMC), code une protéine à activité tyrosine kinase constitutive. Lors d une étude transcriptomique menée au laboratoire sur des patients résistants secondaires à l imatinib, les deux gènes codant les protéines des rétrotransposons LINE-1 ont été trouvés sous exprimés d environ 20 fois lorsque les patients rechutent. Le rôle des transposons n a jamais été clairement défini, ils assurent certainement une fonction importante puisqu ils sont conservés au cours de l évolution et présents chez tous les organismes. Le but de ce travail a été d étudier l implication de LINE-1 dans la LMC. La sous-expression de LINE-1 est-elle une conséquence de la présence de BCR-ABL1 ou une cause de son apparition ? Différents groupes ont montré que les rétrotransposons LINE-1 possédent la capacité de réparation des cassures double-brin de l ADN. Nous avons fait l hypothèse qu une diminution de l expression des gènes codés par les rétrotransposons LINE-1 entraînerait l instabilité génétique observée dans la LMC. Une étude réalisée chez des patients atteints de LMC et des sujets contrôles a montré une correlation inverse entre l expression de LINE-1 et celle de l oncogène BCR-ABL1. Parallèlement, une étude sur des lignées cellulaires leucémiques humaines BCR-ABL positives et négatives a été réalisée. Nous avons recherché le lien qui existe entre l expression de LINE 1, de BCR-ABL1 et la réparation des cassures double-brin de l ADN. Nous avons montré d une part qu une inhibition de l expression de BCR-ABL1 induit une augmentation de l expression des transposons LINE-1 D autre part, une diminution de l expression de LINE-1 entraîne une apparition du transcrit BCR-ABL1 dans les cellules BCR-ABL negatives.BCR-ABL1 fusion gene, responsible of the chronic myeloid leukemia (CML) encodes a constitutively activated tyrosine kinase protein. Expression of both LINE-1 retrotransposon ORFs were found decreased at the time of imatinib resistance in a comparative transcriptional study focused on secondary resistant patients. The role of retrotransposons is unclear. They are conserved through evolution. This project focuses on the involvement of LINE-1 in CML. Is LINE-1 under expression a result of BCR-ABL1 expression or is it at the origin of BCR ABL1? Different groups have shown that LINE-1 retrotransposons were able to repair DNA double strands breaks. We suggest that LINE-1 under expression could be responsible of genetic instability observed in CML. We show in a study on CML patients and healthy subjects that LINE-1 expression is inverse correlated to BCR-ABL1 expression. Moreover, study on BCR-ABL+ and BCR-ABL- human leukemic cell lines was carried on. First, we show that decrease of BCR-ABL1 expression induces increase of LINE-1 expression. Then that decrease of LINE-1 expression generates BCR-ABL1 transcript in BCR-ABL negatives cell lines.BORDEAUX2-Bib. électronique (335229905) / SudocSudocFranceF

Combined use of foraminifera Mg/Ca and Sr/Ca concentrations to strengthen temperature reconstructions over geological timescales.

International audienceTo overcome the lack of long-term instrumental records, paleo-reconstructions using geochemical signatures preserved in the carbonate shells of foraminifera, provide a unique opportunity to reconstruct changes in seawater environmental parameters over time and evaluate the validity of climate change scenarios. High resolution paleoceanographic studies can provide new insights about Paleoclimatic perturbations allowing better prediction of biotic responses to modern warming and acidification. In this study, we will present calibrations using modern foraminifera sampled from surface seawater of the Atlantic Ocean, where all environmental parameters were recorded. Mg and Sr concentrations were determined using LA-ICP-MS, while the oxygen isotope composition of the same tests as used for the elemental analyses was subsequently measured by IRMS. Our results show that combining Mg and Sr data to compute temperature improve temperature reconstruction most probably by accounting for the impact of salinity and/or carbonate chemistry.To further test this hypothesis a new set of temperature data covering the Paleogene was extracted from δ18O, porosity, and combined Mg/Ca and Sr/Ca data, measured on Subbotina linaperta, from three localities: South and North Atlantic, and North Pacific. This foraminifera multi-proxies approach allowed to determine a continuous Paleogene sub-surface temperature. For the first time, the results of the three proxies are consistent with each other and highlight the existence of a latitudinal gradient over the Paleogene, punctuated by short term variations. Hence, we emphasize here: 1) the combined use of Mg/Ca and Sr/Ca concentrations within temperature equation reconstruction to strengthen paleoenvironmental reconstructions on geological timescales, and 2) the utility of porosity as a complementary ecological proxy, to either discard or complement geochemical data

Combined use of foraminifera Mg/Ca and Sr/Ca concentrations to strengthen temperature reconstructions over geological timescales.

International audienceTo overcome the lack of long-term instrumental records, paleo-reconstructions using geochemical signatures preserved in the carbonate shells of foraminifera, provide a unique opportunity to reconstruct changes in seawater environmental parameters over time and evaluate the validity of climate change scenarios. High resolution paleoceanographic studies can provide new insights about Paleoclimatic perturbations allowing better prediction of biotic responses to modern warming and acidification. In this study, we will present calibrations using modern foraminifera sampled from surface seawater of the Atlantic Ocean, where all environmental parameters were recorded. Mg and Sr concentrations were determined using LA-ICP-MS, while the oxygen isotope composition of the same tests as used for the elemental analyses was subsequently measured by IRMS. Our results show that combining Mg and Sr data to compute temperature improve temperature reconstruction most probably by accounting for the impact of salinity and/or carbonate chemistry.To further test this hypothesis a new set of temperature data covering the Paleogene was extracted from δ18O, porosity, and combined Mg/Ca and Sr/Ca data, measured on Subbotina linaperta, from three localities: South and North Atlantic, and North Pacific. This foraminifera multi-proxies approach allowed to determine a continuous Paleogene sub-surface temperature. For the first time, the results of the three proxies are consistent with each other and highlight the existence of a latitudinal gradient over the Paleogene, punctuated by short term variations. Hence, we emphasize here: 1) the combined use of Mg/Ca and Sr/Ca concentrations within temperature equation reconstruction to strengthen paleoenvironmental reconstructions on geological timescales, and 2) the utility of porosity as a complementary ecological proxy, to either discard or complement geochemical data

Combined use of foraminifera Mg/Ca and Sr/Ca concentrations to strengthen temperature reconstructions over geological timescales.

International audienc

Combined use of foraminifera Mg/Ca and Sr/Ca concentrations to strengthen temperature reconstructions over geological timescales.

International audienceTo overcome the lack of long-term instrumental records, paleo-reconstructions using geochemical signatures preserved in the carbonate shells of foraminifera, provide a unique opportunity to reconstruct changes in seawater environmental parameters over time and evaluate the validity of climate change scenarios. High resolution paleoceanographic studies can provide new insights about Paleoclimatic perturbations allowing better prediction of biotic responses to modern warming and acidification. In this study, we will present calibrations using modern foraminifera sampled from surface seawater of the Atlantic Ocean, where all environmental parameters were recorded. Mg and Sr concentrations were determined using LA-ICP-MS, while the oxygen isotope composition of the same tests as used for the elemental analyses was subsequently measured by IRMS. Our results show that combining Mg and Sr data to compute temperature improve temperature reconstruction most probably by accounting for the impact of salinity and/or carbonate chemistry.To further test this hypothesis a new set of temperature data covering the Paleogene was extracted from δ18O, porosity, and combined Mg/Ca and Sr/Ca data, measured on Subbotina linaperta, from three localities: South and North Atlantic, and North Pacific. This foraminifera multi-proxies approach allowed to determine a continuous Paleogene sub-surface temperature. For the first time, the results of the three proxies are consistent with each other and highlight the existence of a latitudinal gradient over the Paleogene, punctuated by short term variations. Hence, we emphasize here: 1) the combined use of Mg/Ca and Sr/Ca concentrations within temperature equation reconstruction to strengthen paleoenvironmental reconstructions on geological timescales, and 2) the utility of porosity as a complementary ecological proxy, to either discard or complement geochemical data

La porosité des tests de Subbotina linaperta (foraminifère planctonique) comme marqueur des températures de subsurface au Paléogène

International audienc