82 results on '"Pannequin J"'
Search Results
2. Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy
- Author
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Bansard, L, Bouvet, O, Moutin, E, Le Gall, G, Giammona, A, Pothin, E, Bacou, M, Hassen-Khodja, C, Bordignon, B, Bourgaux, JF, Prudhomme, M, Hollande, F, Pannequin, J, Pascussi, JM, Planque, C, Bansard, L, Bouvet, O, Moutin, E, Le Gall, G, Giammona, A, Pothin, E, Bacou, M, Hassen-Khodja, C, Bordignon, B, Bourgaux, JF, Prudhomme, M, Hollande, F, Pannequin, J, Pascussi, JM, and Planque, C
- Abstract
Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer.
- Published
- 2022
3. TRM6/61 connects PKCα with translational control through stabilization: impact on tumorigenesis
- Author
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Macari, F, El-houfi, Y, Boldina, G, Xu, H, Khoury-Hanna, S, Ollier, J, Yazdani, L, Zheng, G, Bièche, I, Legrand, N, Paulet, D, Durrieu, S, Byström, A, Delbecq, S, Lapeyre, B, Bauchet, L, Pannequin, J, Hollande, F, Pan, T, Teichmann, M, Vagner, S, David, A, Choquet, A, and Joubert, D
- Published
- 2016
- Full Text
- View/download PDF
4. CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM
- Author
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Belthier, G, Homayed, Z, Grillet, F, Duperray, C, Vendrell, J, Krol, I, Bravo, S, Boyer, J-C, Villeronce, O, Vitre-Boubaker, J, Heaug-Wane, D, Macari-Fine, F, Smith, J, Merlot, M, Lossaint, G, Mazard, T, Portales, F, Solassol, J, Ychou, M, Aceto, N, Mamessier, E, Bertucci, F, Pascussi, JM, Samalin, E, Hollande, F, Pannequin, J, Belthier, G, Homayed, Z, Grillet, F, Duperray, C, Vendrell, J, Krol, I, Bravo, S, Boyer, J-C, Villeronce, O, Vitre-Boubaker, J, Heaug-Wane, D, Macari-Fine, F, Smith, J, Merlot, M, Lossaint, G, Mazard, T, Portales, F, Solassol, J, Ychou, M, Aceto, N, Mamessier, E, Bertucci, F, Pascussi, JM, Samalin, E, Hollande, F, and Pannequin, J
- Abstract
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.
- Published
- 2021
5. Progastrin production transitions from Bmi1(+)/Prox1(+) to Lgr5(high) cells during early intestinal tumorigenesis
- Author
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Giraud, J, Foroutan, M, Boubaker-Vitre, J, Grillet, F, Homayed, Z, Jadhav, U, Crespy, P, Breuker, C, Bourgaux, J-F, Hazerbroucq, J, Pignodel, C, Brulin, B, Shivdasani, RA, Jay, P, Hollande, F, Pannequin, J, Giraud, J, Foroutan, M, Boubaker-Vitre, J, Grillet, F, Homayed, Z, Jadhav, U, Crespy, P, Breuker, C, Bourgaux, J-F, Hazerbroucq, J, Pignodel, C, Brulin, B, Shivdasani, RA, Jay, P, Hollande, F, and Pannequin, J
- Abstract
Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.
- Published
- 2021
6. Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization
- Author
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Sirvent, A, Bénistant, C, Pannequin, J, Veracini, L, Simon, V, Bourgaux, J-F, Hollande, F, Cruzalegui, F, and Roche, S
- Published
- 2010
- Full Text
- View/download PDF
7. Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis
- Author
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Giraud, J., primary, Foroutan, M., additional, Boubaker-Vitre, J., additional, Grillet, F., additional, Homayed, Z., additional, Jadhav, U., additional, Crespy, P., additional, Breuker, C., additional, Bourgaux, J-F., additional, Hazerbroucq, J., additional, Pignodel, C., additional, Brulin, B., additional, Shivdasani, R.A., additional, Jay, P., additional, Hollande, F., additional, and Pannequin, J., additional
- Published
- 2021
- Full Text
- View/download PDF
8. PETH AND INTESTINAL HYPERPLASIA: P195
- Author
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Hollande, F. and Pannequin, J.
- Published
- 2010
9. Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells
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Paquet-Fifield, S, Koh, SL, Cheng, L, Beyit, LM, Shembrey, C, Molck, C, Behrenbruch, C, Papin, M, Gironella, M, Guelfi, S, Nasr, R, Grillet, F, Prudhomme, M, Bourgaux, J-F, Castells, A, Pascussi, J-M, Heriot, AG, Puisieux, A, Davis, MJ, Pannequin, J, Hill, AF, Sloan, EK, Hollande, F, Paquet-Fifield, S, Koh, SL, Cheng, L, Beyit, LM, Shembrey, C, Molck, C, Behrenbruch, C, Papin, M, Gironella, M, Guelfi, S, Nasr, R, Grillet, F, Prudhomme, M, Bourgaux, J-F, Castells, A, Pascussi, J-M, Heriot, AG, Puisieux, A, Davis, MJ, Pannequin, J, Hill, AF, Sloan, EK, and Hollande, F
- Abstract
Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-fluorouracil–based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer.
- Published
- 2018
10. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture
- Author
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Grillet, F, Bayet, E, Villeronce, O, Zappia, L, Lagerqvist, EL, Lunke, S, Charafe-Jauffret, E, Pham, K, Molck, C, Rolland, N, Bourgaux, JF, Prudhomme, M, Philippe, C, Bravo, S, Boyer, JC, Canterel-Thouennon, L, Taylor, GR, Hsu, A, Pascussi, JM, Hollande, F, Pannequin, J, Grillet, F, Bayet, E, Villeronce, O, Zappia, L, Lagerqvist, EL, Lunke, S, Charafe-Jauffret, E, Pham, K, Molck, C, Rolland, N, Bourgaux, JF, Prudhomme, M, Philippe, C, Bravo, S, Boyer, JC, Canterel-Thouennon, L, Taylor, GR, Hsu, A, Pascussi, JM, Hollande, F, and Pannequin, J
- Abstract
OBJECTIVE: Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full. DESIGN: Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells. RESULTS: Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds. CONCLUSIONS: Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT01577511.
- Published
- 2017
11. TRM6/61 connects PKCα with translational control through tRNAiMet stabilization : impact on tumorigenesis
- Author
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Macari, F., El-houfi, Y., Boldina, G., Xu, Hao, Khoury-Hanna, S., Ollier, J., Yazdani, L., Zheng, G., Bieche, I., Legrand, N., Paulet, D., Durrieu, S., Byström, Anders S., Delbecq, S., Lapeyre, B., Bauchet, L., Pannequin, J., Hollande, F., Pan, T., Teichmann, M., Vagner, S., David, A., Choquet, A., Joubert, D., Macari, F., El-houfi, Y., Boldina, G., Xu, Hao, Khoury-Hanna, S., Ollier, J., Yazdani, L., Zheng, G., Bieche, I., Legrand, N., Paulet, D., Durrieu, S., Byström, Anders S., Delbecq, S., Lapeyre, B., Bauchet, L., Pannequin, J., Hollande, F., Pan, T., Teichmann, M., Vagner, S., David, A., Choquet, A., and Joubert, D.
- Abstract
Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C [alpha] (PKC[alpha]) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAiMet), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAiMet. In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAiMet-overexpressing cells, PKC[alpha] overexpression decreased tRNAiMet expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAiMet expression with decreased expression of PKC[alpha] mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKC[alpha] tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development., Supplementary information available for this article at http://www.nature.com/onc/journal/vaop/ncurrent/suppinfo/onc2015244s1.html
- Published
- 2016
- Full Text
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12. Pregnane X-receptor promotes stem cell-mediated colon cancer relapse
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Planque, C, Rajabi, F, Grillet, F, Finetti, P, Bertucci, F, Gironella, M, Lozano, JJ, Beucher, B, Giraud, J, Garambois, V, Vincent, C, Brown, D, Caillo, L, Kantar, J, Pelegrin, A, Prudhomme, M, Ripoche, J, Bourgaux, JF, Ginestier, C, Castells, A, Hollande, F, Pannequin, J, Pascussi, JM, Planque, C, Rajabi, F, Grillet, F, Finetti, P, Bertucci, F, Gironella, M, Lozano, JJ, Beucher, B, Giraud, J, Garambois, V, Vincent, C, Brown, D, Caillo, L, Kantar, J, Pelegrin, A, Prudhomme, M, Ripoche, J, Bourgaux, JF, Ginestier, C, Castells, A, Hollande, F, Pannequin, J, and Pascussi, JM
- Abstract
Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.
- Published
- 2016
13. TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis
- Author
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Macari, F, primary, El-houfi, Y, additional, Boldina, G, additional, Xu, H, additional, Khoury-Hanna, S, additional, Ollier, J, additional, Yazdani, L, additional, Zheng, G, additional, Bièche, I, additional, Legrand, N, additional, Paulet, D, additional, Durrieu, S, additional, Byström, A, additional, Delbecq, S, additional, Lapeyre, B, additional, Bauchet, L, additional, Pannequin, J, additional, Hollande, F, additional, Pan, T, additional, Teichmann, M, additional, Vagner, S, additional, David, A, additional, Choquet, A, additional, and Joubert, D, additional
- Published
- 2015
- Full Text
- View/download PDF
14. Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization
- Author
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Sirvent, A, primary, Bénistant, C, additional, Pannequin, J, additional, Veracini, L, additional, Simon, V, additional, Bourgaux, J-F, additional, Hollande, F, additional, Cruzalegui, F, additional, and Roche, S, additional
- Published
- 2009
- Full Text
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15. 68 Methylation-induced regulation of claudin-4 expression
- Author
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Boireau, S., primary, Buchert, M., additional, Pannequin, J., additional, Ryan, J., additional, Choquet, A., additional, Rebillard, X., additional, Avances, C., additional, Mottet, N., additional, and Hollande, F., additional
- Published
- 2005
- Full Text
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16. Divergent roles for ferric ions in the biological activity of amidated and non-amidated gastrins
- Author
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Pannequin, J, primary, Tantiongco, JP, additional, Kovac, S, additional, Shulkes, A, additional, and Baldwin, GS, additional
- Published
- 2004
- Full Text
- View/download PDF
17. TRM6/61 connects PKCa with translational control through tRNAiMetstabilization: impact on tumorigenesis
- Author
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Macari, F, El-houfi, Y, Boldina, G, Xu, H, Khoury-Hanna, S, Ollier, J, Yazdani, L, Zheng, G, Bièche, I, Legrand, N, Paulet, D, Durrieu, S, Byström, A, Delbecq, S, Lapeyre, B, Bauchet, L, Pannequin, J, Hollande, F, Pan, T, Teichmann, M, Vagner, S, David, A, Choquet, A, and Joubert, D
- Abstract
Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C a (PKCa) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAiMet), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAiMet. In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAiMet-overexpressing cells, PKCa overexpression decreased tRNAiMetexpression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAiMetexpression with decreased expression of PKCa mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKCa tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.
- Published
- 2016
- Full Text
- View/download PDF
18. L-365,260 inhibits in vitro acid secretion by interacting with a PKA pathway.
- Author
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Oiry, Catherine, Pannequin, Julie, Cormier, Anne, Galleyrand, Jean-Claude, Martinez, Jean, Oiry, C, Pannequin, J, Cormier, A, Galleyrand, J C, and Martinez, J
- Published
- 1999
- Full Text
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19. A synthetic glycine-extended bombesin analogue interacts with the GRP/bombesin receptor
- Author
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Oiry, C., Pannequin, J., Bernad, N., Artis, A. M., Galleyrand, J. C., Devin, C., Cristau, M., Fehrentz, J. A., and Martinez, J.
- Published
- 2000
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20. Progastrin production transitions from Bmi1+/Prox1+to Lgr5highcells during early intestinal tumorigenesis
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Giraud, J., Foroutan, M., Boubaker-Vitre, J., Grillet, F., Homayed, Z., Jadhav, U., Crespy, P., Breuker, C., Bourgaux, J-F., Hazerbroucq, J., Pignodel, C., Brulin, B., Shivdasani, R.A., Jay, P., Hollande, F., and Pannequin, J.
- Abstract
•Secretion of progastrin is a signature event of early malignant transformation in the colon.•In the healthy epithelium, progastrin is produced by a subset of enteroendocrine cells expressing both Bmi1 and Prox1.•LGR5-high intestinal stem cells are a primary source of progastrin production in early mouse and human intestinal adenomas.
- Published
- 2021
- Full Text
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21. Comparison of methods for cancer stem cell detection in prognosis of early stages NSCLC.
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Chandouri B, Naves T, Yassine M, Ikhlef L, Tricard J, Chaunavel A, Homayed Z, Pannequin J, Girard N, Durand S, Carré V, and Lalloué F
- Abstract
Background: Despite advances in diagnosis and treatment in lung cancer, therapies still fail to improve patient management due to resistance mechanisms and relapses. As Cancer stem cells (CSCs) directly contribute to tumor growth and therapeutic resistance, their clinical detection represents a major challenge. However specific and additional CSC markers lack. Thus, our aim was to achieve selective detection of CSCs with specific glycan patterns and assess the CSCs burden to predict the risk of relapse in NSCLC tumors., Methods: The lung CSCs detection and sorting with a lectin MIX were assessed and compared to CD133 in vitro. Then, its putative role as CSC biomarker was evaluated in vivo and its clinical significance on 221 NSCLC patients., Results: We showed a significant CSCs enrichment in the MIX+ sorted fraction compared to CD133+ cells and confirmed its high tumorigenic capacity. The MIX prognostic value on the overall survival from early stages patients was validated suggesting its potential for detecting CSCs directly linked to tumor aggressiveness., Conclusion: The MIX could be more relevant for detecting and sorting CSCs than CD133. Moreover, its prognosis value could enable clinicians to better classify early-stage patients at high risk of relapse in order to tailor therapeutic decisions., (© 2024. The Author(s).)
- Published
- 2024
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22. Tuft cell acetylcholine is released into the gut lumen to promote anti-helminth immunity.
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Ndjim M, Gasmi I, Herbert F, Joséphine C, Bas J, Lamrani A, Coutry N, Henry S, Zimmermann VS, Dardalhon V, Campillo Poveda M, Turtoi E, Thirard S, Forichon L, Giordano A, Ciancia C, Homayed Z, Pannequin J, Britton C, Devaney E, McNeilly TN, Berrard S, Turtoi A, Maizels RM, Gerbe F, and Jay P
- Subjects
- Animals, Mice, Choline O-Acetyltransferase metabolism, Interleukin-13 metabolism, Interleukin-13 immunology, Mice, Knockout, Mice, Inbred C57BL, Helminthiasis immunology, Helminthiasis parasitology, Epithelial Cells immunology, Epithelial Cells metabolism, Immunity, Innate, Nematospiroides dubius immunology, Tuft Cells, Acetylcholine metabolism, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa parasitology
- Abstract
Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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23. [Presurgical immunotherapy: A promising therapy to prevent tumor relapse in colorectal cancer].
- Author
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Homayed Z, Belthier G, and Pannequin J
- Subjects
- Humans, Recurrence, Immunotherapy, Colorectal Neoplasms therapy
- Published
- 2023
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24. CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma.
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Giraud J, Seeneevassen L, Rousseau B, Bouriez D, Sifré E, Giese A, Nguyen TL, Tiffon C, Lippi Y, Azzi-Martin L, Pannequin J, Ménard A, Bessède E, Staedel C, Mégraud F, Belleannée G, Lehours P, Gronnier C, Dubus P, and Varon C
- Subjects
- Humans, Neoplastic Stem Cells metabolism, Hyaluronan Receptors, Epithelial-Mesenchymal Transition, Stomach Neoplasms pathology, Carcinoma pathology
- Abstract
Background: Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+ cells and their clinical significance in GC patients., Methods: Using GC cell lines and patient-derived xenografts, we evaluated CD44+ and CD44v3+ GC cells molecular signature and their tumorigenic, chemoresistance, invasive and metastatic properties, and expression in patients-derived tissues., Results: CD44v3+ cells, which represented a subpopulation of CD44+ cells, were detected in advanced preneoplastic lesions and presented CSCs chemoresistance and tumorigenic properties in vitro and in vivo. Molecular and functional analyses revealed two subpopulations of gastric CSCs: CD44v3+ CSCs with an epithelial-mesenchymal transition (EMT)-like signature, and CD44+/v3- CSCs with an epithelial-like signature; both were tumorigenic but CD44v3+ cells showed higher invasive and metastatic properties in vivo. CD44v3+ cells detected in the primary tumours of GC patients were associated with a worse prognosis., Conclusion: CD44v3 is a marker of a subpopulation of CSCs with metastatic properties in GC. The identification of metastasis-initiating cells in GC represents a major advance for further development of anti-metastatic therapeutic strategies., (© 2022. The Author(s).)
- Published
- 2023
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25. A Label-Free Cell Sorting Approach to Highlight the Impact of Intratumoral Cellular Heterogeneity and Cancer Stem Cells on Response to Therapies.
- Author
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Hervieu C, Verdier M, Barthout E, Bégaud G, Christou N, Sage M, Pannequin J, Battu S, and Mathonnet M
- Subjects
- Cell Line, Tumor, Cell Movement, Cell Separation, Humans, Cell Transformation, Neoplastic metabolism, Neoplastic Stem Cells pathology
- Abstract
Cancer stem cells play a crucial role in tumor initiation, metastasis, and resistance to treatment. Cellular heterogeneity and plasticity complicate the isolation of cancer stem cells. The impact of intra-tumor cellular heterogeneity using a label-free approach remains understudied in the context of treatment resistance. Here, we use the sedimentation field-flow fractionation technique to separate, without labeling, cell subpopulations of colorectal cancer cell lines and primary cultures according to their biophysical properties. One of the three sorted cell subpopulations exhibits characteristics of cancer stem cells, including high tumorigenicity in vivo and a higher frequency of tumor-initiating cells compared to the other subpopulations. Due to its chemoresistance, two- and three-dimensional in vitro chemosensitivity assays highlight the therapeutic relevance of this cancer stem cell subpopulation. Thus, our results reveal the major implication of intra-tumor cellular heterogeneity, including cancer stem cells in treatment resistance, thanks to our label-free cell sorting approach. This approach enables-by breaking down the tumor-the study the individualized response of each sorted tumor cell subpopulation and to identify chemoresistance, thus offering new perspectives for personalized therapy.
- Published
- 2022
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26. Paracrine signalling between intestinal epithelial and tumour cells induces a regenerative programme.
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Jacquemin G, Wurmser A, Huyghe M, Sun W, Homayed Z, Merle C, Perkins M, Qasrawi F, Richon S, Dingli F, Arras G, Loew D, Vignjevic D, Pannequin J, and Fre S
- Subjects
- Animals, Ecosystem, Epithelial Cells metabolism, Mice, Signal Transduction, Transcription Factors metabolism, Adaptor Proteins, Signal Transducing metabolism, Neoplasms
- Abstract
Tumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the critical role of stromal cells in affecting tumour growth is well established, the impact of mutant cancer cells on healthy surrounding tissues remains poorly defined. Here, using mouse intestinal organoids, we uncover a paracrine mechanism by which intestinal cancer cells reactivate foetal and regenerative YAP-associated transcriptional programmes in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identify the glycoprotein thrombospondin-1 (THBS1) as the essential factor that mediates non-cell-autonomous morphological and transcriptional responses. Importantly, Thbs1 is associated with bad prognosis in several human cancers. This study reveals the THBS1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells in intestinal tumours., Competing Interests: GJ, AW, MH, WS, ZH, CM, MP, FQ, SR, FD, GA, DL, DV, JP, SF No competing interests declared, (© 2022, Jacquemin et al.)
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- 2022
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27. Correction to: Regulation of Src tumor activity by its N-terminal intrinsically disordered region.
- Author
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Aponte E, Lafitte M, Sirvent A, Simon V, Barbery M, Fourgous E, Boublik Y, Maffei M, Armand F, Hamelin R, Pannequin J, Fort P, Pons M, and Roche S
- Published
- 2022
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28. Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy.
- Author
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Bansard L, Bouvet O, Moutin E, Le Gall G, Giammona A, Pothin E, Bacou M, Hassen-Khodja C, Bordignon B, Bourgaux JF, Prudhomme M, Hollande F, Pannequin J, Pascussi JM, and Planque C
- Subjects
- Animals, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells metabolism, Niclosamide metabolism, Niclosamide pharmacology, Niclosamide therapeutic use, Pregnane X Receptor genetics, Pregnane X Receptor metabolism, Colonic Neoplasms drug therapy, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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29. Regulation of Src tumor activity by its N-terminal intrinsically disordered region.
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Aponte E, Lafitte M, Sirvent A, Simon V, Barbery M, Fourgous E, Boublik Y, Maffei M, Armand F, Hamelin R, Pannequin J, Fort P, Pons M, and Roche S
- Subjects
- Humans, Animals, Mice, NIH 3T3 Cells, Intrinsically Disordered Proteins metabolism, Intrinsically Disordered Proteins genetics, Intrinsically Disordered Proteins chemistry, Mice, Nude, Phosphorylation, Cell Line, Tumor, Colonic Neoplasms pathology, Colonic Neoplasms metabolism, Colonic Neoplasms genetics, Protein Domains, src-Family Kinases metabolism, src-Family Kinases genetics
- Abstract
The membrane-anchored Src tyrosine kinase is involved in numerous pathways and its deregulation is involved in human cancer. Our knowledge on Src regulation relies on crystallography, which revealed intramolecular interactions to control active Src conformations. However, Src contains a N-terminal intrinsically disordered unique domain (UD) whose function remains unclear. Using NMR, we reported that UD forms an intramolecular fuzzy complex involving a conserved region with lipid-binding capacity named Unique Lipid-Binding Region (ULBR), which could modulate Src membrane anchoring. Here we show that the ULBR is essential for Src's oncogenic capacity. ULBR inactive mutations inhibited Src transforming activity in NIH3T3 cells and in human colon cancer cells. It also reduced Src-induced tumor development in nude mice. An intact ULBR was required for MAPK signaling without affecting Src kinase activity nor sub-cellular localization. Phospho-proteomic analyses revealed that, while not impacting on the global tyrosine phospho-proteome in colon cancer cells, this region modulates phosphorylation of specific membrane-localized tyrosine kinases needed for Src oncogenic signaling, including EPHA2 and Fyn. Collectively, this study reveals an important role of this intrinsically disordered region in malignant cell transformation and suggests a novel layer of Src regulation by this unique region via membrane substrate phosphorylation., (© 2021. The Author(s).)
- Published
- 2022
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30. Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance.
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Therizols G, Bash-Imam Z, Panthu B, Machon C, Vincent A, Ripoll J, Nait-Slimane S, Chalabi-Dchar M, Gaucherot A, Garcia M, Laforêts F, Marcel V, Boubaker-Vitre J, Monet MA, Bouclier C, Vanbelle C, Souahlia G, Berthel E, Albaret MA, Mertani HC, Prudhomme M, Bertrand M, David A, Saurin JC, Bouvet P, Rivals E, Ohlmann T, Guitton J, Dalla Venezia N, Pannequin J, Catez F, and Diaz JJ
- Subjects
- Cell Line, Tumor, Cell Survival drug effects, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, DNA Replication, DNA, Neoplasm metabolism, Drug Resistance, Neoplasm genetics, HCT116 Cells, Halogenation, Humans, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Ribosomal genetics, RNA, Ribosomal metabolism, Receptor, IGF Type 1 agonists, Receptor, IGF Type 1 metabolism, Ribosomes drug effects, Ribosomes genetics, Ribosomes metabolism, Xenograft Model Antitumor Assays, Antimetabolites, Antineoplastic pharmacology, Colorectal Neoplasms drug therapy, DNA, Neoplasm genetics, Drug Tolerance genetics, Fluorouracil pharmacology, Protein Biosynthesis drug effects, Receptor, IGF Type 1 genetics
- Abstract
Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes., (© 2022. The Author(s).)
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- 2022
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31. Circulating Tumor Cell Lines: an Innovative Tool for Fundamental and Translational Research.
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Belthier G, Homayed Z, Bouclier C, Asari M, and Pannequin J
- Subjects
- Animals, Biomarkers, Tumor, Cell Count, Cell Line, Tumor, Humans, Liquid Biopsy, Mice, Neoplasm Metastasis, Translational Research, Biomedical, Neoplastic Cells, Circulating pathology
- Abstract
Metastasis is a leading cause of cancer death. Despite improvements in treatment strategies, metastatic cancer has a poor prognosis. We thus face an urgent need to understand the mechanisms behind metastasis development, and thus to propose efficient treatments for advanced cancer. Metastatic cancers are hard to treat, as biopsies are invasive and inaccessible. Recently, there has been considerable interest in liquid biopsies including both cell-free circulating deoxyribonucleic acid (DNA) and circulating tumor cells from peripheral blood and we have established several circulating tumor cell lines from metastatic colorectal cancer patients to participate in their characterization. Indeed, to functionally characterize these rare and poorly described cells, the crucial step is to expand them. Once established, circulating tumor cell (CTC) lines can then be cultured in suspension or adherent conditions. At the molecular level, CTC lines can be further used to assess the expression of specific markers of interest (such as differentiation, epithelial or cancer stem cells) by immunofluorescence or cytometry analysis. In addition, CTC lines can be used to assess drug sensitivity to gold-standard chemotherapies as well as to targeted therapies. The ability of CTC lines to initiate tumors can also be tested by subcutaneous injection of CTCs in immunodeficient mice. Finally, it is possible to test the role of specific genes of interest that might be involved in cancer dissemination by editing CTC genes, by short hairpin ribonucleic acid (shRNA) or Crispr/Cas9. Modified CTCs can thus be injected into immunodeficient mouse spleens, to experimentally mimic part of the metastatic development process in vivo. In conclusion, CTC lines are a precious tool for future research and for personalized medicine, where they will allow prediction of treatment efficiency using the very cells that are originally responsible for metastasis.
- Published
- 2021
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32. CD44v6 Defines a New Population of Circulating Tumor Cells Not Expressing EpCAM.
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Belthier G, Homayed Z, Grillet F, Duperray C, Vendrell J, Krol I, Bravo S, Boyer JC, Villeronce O, Vitre-Boubaker J, Heaug-Wane D, Macari-Fine F, Smith J, Merlot M, Lossaint G, Mazard T, Portales F, Solassol J, Ychou M, Aceto N, Mamessier E, Bertucci F, Pascussi JM, Samalin E, Hollande F, and Pannequin J
- Abstract
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.
- Published
- 2021
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33. GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer.
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Brun S, Pascussi JM, Gifu EP, Bestion E, Macek-Jilkova Z, Wang G, Bassissi F, Mezouar S, Courcambeck J, Merle P, Decaens T, Pannequin J, Halfon P, and Caron de Fromentel C
- Abstract
Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and can regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmed in vivo in HCC from a DEN-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90
+ CD45- ). Thus, GNS561 offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC sub-population. Accordingly, a global phase 1b clinical trial in liver cancers was recently completed., Competing Interests: Competing Interests: SB, EB, FB, SM, JC and PH are employees of Genoscience Pharma. SB, FB and PH are shareholders of Genoscience Pharma. SB, FB, JC and PH are co-inventors of a pending patent. The other authors declare that they have no conflicts of interest to report., (© The author(s).)- Published
- 2021
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34. G protein-coupled receptors can control the Hippo/YAP pathway through Gq signaling.
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Zindel D, Mensat P, Vol C, Homayed Z, Charrier-Savournin F, Trinquet E, Banères JL, Pin JP, Pannequin J, Roux T, Dupuis E, and Prézeau L
- Subjects
- Activating Transcription Factor 6 genetics, Cell Cycle Proteins genetics, GTP-Binding Protein alpha Subunits, G12-G13 genetics, GTP-Binding Protein alpha Subunits, Gq-G11 genetics, HEK293 Cells, Hippo Signaling Pathway, Humans, Phosphorylation, Protein Serine-Threonine Kinases genetics, Receptors, G-Protein-Coupled genetics, Transcription Factors genetics, Activating Transcription Factor 6 metabolism, Cell Cycle Proteins metabolism, GTP-Binding Protein alpha Subunits, G12-G13 metabolism, GTP-Binding Protein alpha Subunits, Gq-G11 metabolism, Gene Expression Regulation, Protein Serine-Threonine Kinases metabolism, Receptors, G-Protein-Coupled metabolism, Transcription Factors metabolism
- Abstract
The Hippo pathway is an evolutionarily conserved kinase cascade involved in the control of tissue homeostasis, cellular differentiation, proliferation, and organ size, and is regulated by cell-cell contact, apical cell polarity, and mechanical signals. Miss-regulation of this pathway can lead to cancer. The Hippo pathway acts through the inhibition of the transcriptional coactivators YAP and TAZ through phosphorylation. Among the various signaling mechanisms controlling the hippo pathway, activation of G12/13 by G protein-coupled receptors (GPCR) recently emerged. Here we show that a GPCR, the ghrelin receptor, that activates several types of G proteins, including G12/13, Gi/o, and Gq, can activate YAP through Gq/11 exclusively, independently of G12/13. We revealed that a strong basal YAP activation results from the high constitutive activity of this receptor, which can be further increased upon agonist activation. Thus, acting on ghrelin receptor allowed to modulate up-and-down YAP activity, as activating the receptor increased YAP activity and blocking constitutive activity reduced YAP activity. Our results demonstrate that GPCRs can be used as molecular switches to finely up- or down-regulate YAP activity through a pure Gq pathway., (© 2021 Federation of American Societies for Experimental Biology.)
- Published
- 2021
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35. A stem cell population at the anorectal junction maintains homeostasis and participates in tissue regeneration.
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Mitoyan L, Chevrier V, Hernandez-Vargas H, Ollivier A, Homayed Z, Pannequin J, Poizat F, De Biasi-Cador C, Charafe-Jauffret E, Ginestier C, and Guasch G
- Subjects
- Animals, Cell Differentiation, Cell Lineage, Cell Plasticity, Humans, Intestinal Mucosa cytology, Keratin-17 genetics, Keratin-17 metabolism, Mice, Organoids cytology, Stem Cells cytology, Stem Cells metabolism, Transcription Factors genetics, Transcription Factors metabolism, Wound Healing, Anal Canal cytology, Homeostasis, Rectum cytology, Regeneration, Stem Cells physiology
- Abstract
At numerous locations of the body, transition zones are localized at the crossroad between two types of epithelium and are frequently associated with neoplasia involving both type of tissues. These transition zones contain cells expressing markers of adult stem cells that can be the target of early transformation. The mere fact that transition zone cells can merge different architecture with separate functions implies for a unique plasticity that these cells must display in steady state. However, their roles during tissue regeneration in normal and injured state remain unknown. Here, by using in vivo lineage tracing, single-cell transcriptomics, computational modeling and a three-dimensional organoid culture system of transition zone cells, we identify a population of Krt17+ basal cells with multipotent properties at the squamo-columnar anorectal junction that maintain a squamous epithelium during normal homeostasis and can participate in the repair of a glandular epithelium following tissue injury.
- Published
- 2021
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36. FTO-mediated cytoplasmic m 6 A m demethylation adjusts stem-like properties in colorectal cancer cell.
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Relier S, Ripoll J, Guillorit H, Amalric A, Achour C, Boissière F, Vialaret J, Attina A, Debart F, Choquet A, Macari F, Marchand V, Motorin Y, Samalin E, Vasseur JJ, Pannequin J, Aguilo F, Lopez-Crapez E, Hirtz C, Rivals E, Bastide A, and David A
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Adenosine metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Cell Line, Tumor, Cell Nucleus metabolism, Colorectal Neoplasms genetics, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Methyltransferases metabolism, Nuclear Proteins metabolism, RNA, Messenger metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO metabolism, Colorectal Neoplasms metabolism, Cytoplasm metabolism, Demethylation
- Abstract
Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N
6 ,2'-O-dimethyladenosine (m6 Am ) demethylase activity. While m6 Am is strategically located next to the m7 G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6 Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6 Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6 Am modification in stem-like properties acquisition. FTO-mediated regulation of m6 Am marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6 Am modification and its potential adverse consequences for colorectal cancer management.- Published
- 2021
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37. Progastrin production transitions from Bmi1 + /Prox1 + to Lgr5 high cells during early intestinal tumorigenesis.
- Author
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Giraud J, Foroutan M, Boubaker-Vitre J, Grillet F, Homayed Z, Jadhav U, Crespy P, Breuker C, Bourgaux JF, Hazerbroucq J, Pignodel C, Brulin B, Shivdasani RA, Jay P, Hollande F, and Pannequin J
- Abstract
Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1
+ /Prox1+ /LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas., Competing Interests: Declaration of Competing Interest None of the authors has a conflict of interest, (Copyright © 2020. Published by Elsevier Inc.)- Published
- 2021
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38. Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis.
- Author
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Chiavarina B, Costanza B, Ronca R, Blomme A, Rezzola S, Chiodelli P, Giguelay A, Belthier G, Doumont G, Van Simaeys G, Lacroix S, Yokobori T, Erkhem-Ochir B, Balaguer P, Cavailles V, Fabbrizio E, Di Valentin E, Gofflot S, Detry O, Jerusalem G, Goldman S, Delvenne P, Bellahcène A, Pannequin J, Castronovo V, and Turtoi A
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor genetics, Cell Movement, Cell Proliferation, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Extracellular Matrix Proteins genetics, Humans, Liver Neoplasms metabolism, Liver Neoplasms secondary, Mice, Neovascularization, Pathologic metabolism, Prognosis, Signal Transduction, Transforming Growth Factor beta genetics, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Colorectal Neoplasms blood supply, Extracellular Matrix Proteins metabolism, Gene Expression Regulation, Neoplastic, Liver Neoplasms blood supply, Neovascularization, Pathologic pathology, Transforming Growth Factor beta metabolism
- Abstract
Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo . Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo , underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
- Published
- 2021
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39. Overexpression of sortilin is associated with 5-FU resistance and poor prognosis in colorectal cancer.
- Author
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Blondy S, Talbot H, Saada S, Christou N, Battu S, Pannequin J, Jauberteau MO, Lalloué F, Verdier M, Mathonnet M, and Perraud A
- Subjects
- Adaptor Proteins, Vesicular Transport genetics, Aged, Aged, 80 and over, Animals, Cell Line, Tumor, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Nude, Neoplasm Grading, Prognosis, Protein Transport drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, Treatment Outcome, Xenograft Model Antitumor Assays, Mice, Adaptor Proteins, Vesicular Transport metabolism, Colorectal Neoplasms drug therapy, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Fluorouracil therapeutic use
- Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. Even if 5-fluorouracil (5-FU) is used as the first-line chemotherapeutic drug, responsiveness is only 20-30%. Acquired resistance to 5-FU contributes to both poor patient prognosis and relapse, emphasizing the need to identify biomarkers. Sortilin, a vacuolar protein sorting 10 protein (Vps10p), implicated in protein trafficking, is over expressed in CRC cell lines cultured 72 hours in presence of 5-FU. This overexpression was also observed in 5-FU-resistant cells derived from these cell lines as well as in CRC primary cultures (or patients derived cell lines). A significantly higher expression of sortilin was observed in vivo, in 5-FU-treated tumours engrafted in Nude mice, as compared with non-treated tumour. A study of transcriptional regulation allowed identifying a decrease in ATF3 expression, as an explanation of sortilin overexpression following 5-FU treatment. In silico analysis revealed SORT1 expression correlation with poor prognosis. Moreover, sortilin expression was found to be positively correlated with CRC tumour grades. Collectively, our findings identify sortilin as a potential biomarker of 5-FU resistance associated with poor clinical outcomes and aggressiveness in CRC. As a new prognostic factor, sortilin expression could be used to fight against CRC., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2021
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40. HTRF ® Total and Phospho-YAP (Ser127) Cellular Assays.
- Author
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Zindel D, Vol C, Lecha O, Bequignon I, Bilgic M, Vereecke M, Charrier-Savournin F, Romier M, Trinquet E, Pin JP, Pannequin J, Roux T, Dupuis E, and Prézeau L
- Subjects
- Cell Cycle Proteins, Humans, Phosphoproteins metabolism, Phosphorylation, Protein Binding, Protein Transport, Sensitivity and Specificity, Signal Transduction, Biological Assay methods, Biological Assay standards, Nuclear Proteins metabolism, Serine metabolism, Transcription Factors metabolism
- Abstract
The YAP protein is a co-transcription factor increasing the expression of genes involved in cell proliferation and repressing the expression of genes important for cell differentiation and apoptosis. It is regulated by several inputs, like the Hippo pathway, through the action of kinases that phosphorylate YAP on several residues. The level of phosphorylation of the residues serine 127 (S127) of YAP is generally assessed in cellular models, native tissues, and organs, as a marker of YAP activity and location, and is regulated by numerous partners. This phosphorylation event is classically detected using a western blot technical approach. Here, we describe a novel approach to detect both the relative amount of total YAP (T-YAP assay) and the phosphorylation of the residue S127 of YAP (S127-P-YAP assay) using a HTRF
® -based method. This easy-to-run method can easily be miniaturized and allows for a high-throughput analysis in 96/384-well plate format, requiring less cellular material and being more rapid than other approaches.- Published
- 2019
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41. Correction: Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells.
- Author
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Müller S, Versini A, Sindikubwabo F, Belthier G, Niyomchon S, Pannequin J, Grimaud L, Cañeque T, and Rodriguez R
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0206764.].
- Published
- 2018
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42. Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells.
- Author
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Müller S, Versini A, Sindikubwabo F, Belthier G, Niyomchon S, Pannequin J, Grimaud L, Cañeque T, and Rodriguez R
- Subjects
- Antineoplastic Agents chemistry, Cell Death drug effects, Cell Death physiology, Cell Line, Cell Survival drug effects, Cell Survival physiology, Click Chemistry, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition physiology, Humans, Membrane Potential, Mitochondrial drug effects, Membrane Potential, Mitochondrial physiology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells pathology, Metformin chemistry, Mitochondria metabolism, Mitochondria pathology, Neoplasms metabolism, Neoplasms pathology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Reactive Oxygen Species metabolism, Antineoplastic Agents pharmacology, Copper metabolism, Metformin pharmacology, Mitochondria drug effects, Neoplasms drug therapy
- Abstract
The 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 metformin 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 dysfunction 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., Competing Interests: RR, SM and TC have filed provisional patent applications related to metformin derivatives, used as therapeutics and diagnostic tools. All other authors declare no competing interests.
- Published
- 2018
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43. Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells.
- Author
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Paquet-Fifield S, Koh SL, Cheng L, Beyit LM, Shembrey C, Mølck C, Behrenbruch C, Papin M, Gironella M, Guelfi S, Nasr R, Grillet F, Prudhomme M, Bourgaux JF, Castells A, Pascussi JM, Heriot AG, Puisieux A, Davis MJ, Pannequin J, Hill AF, Sloan EK, and Hollande F
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation physiology, Gene Expression Regulation, Neoplastic physiology, Humans, Mice, Mice, Inbred NOD, Mice, SCID, MicroRNAs, Signal Transduction physiology, Cell Self Renewal physiology, Claudin-2 metabolism, Colorectal Neoplasms metabolism, Colorectal Neoplasms physiopathology, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells physiology, Zonula Occludens-2 Protein metabolism
- Abstract
Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-fluorouracil-based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDH
High CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer. Significance: Claudin-2-mediated regulation of YAP activity and miR-222-3p expression drives CSC renewal in colorectal cancer, making it a potential target for therapy. Cancer Res; 78(11); 2925-38. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
- Full Text
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44. Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer.
- Author
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Jeitany M, Leroy C, Tosti P, Lafitte M, Le Guet J, Simon V, Bonenfant D, Robert B, Grillet F, Mollevi C, El Messaoudi S, Otandault A, Canterel-Thouennon L, Busson M, Thierry AR, Martineau P, Pannequin J, Roche S, and Sirvent A
- Subjects
- Animals, Discoidin Domain Receptor 1 genetics, HCT116 Cells, HEK293 Cells, Humans, Mice, Phosphoproteins metabolism, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins c-bcr genetics, Pyrimidines pharmacology, Receptors, Collagen genetics, Signal Transduction drug effects, Signal Transduction genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Discoidin Domain Receptor 1 metabolism, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins c-bcr metabolism, Receptors, Collagen metabolism
- Abstract
The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining β-catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines. Collectively, our results indicate that the targeting DDR1 kinase activity with nilotinib may be beneficial for patients with mCRC., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2018
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- View/download PDF
45. [Cancer stem cells and metastatic dissemination].
- Author
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Pannequin J
- Subjects
- Animals, Biomarkers, Tumor metabolism, Cell Physiological Phenomena, Disease Models, Animal, Epithelial-Mesenchymal Transition physiology, Humans, Mice, Neoplastic Cells, Circulating, Neoplastic Stem Cells metabolism, Neoplasm Metastasis, Neoplastic Stem Cells physiology
- Published
- 2017
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- View/download PDF
46. [Cancer stem cells in colon cancer].
- Author
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Pannequin J
- Subjects
- AC133 Antigen analysis, Aldehyde Dehydrogenase analysis, Animals, CD24 Antigen analysis, Colonic Neoplasms pathology, Colorectal Neoplasms chemistry, Colorectal Neoplasms pathology, Dipeptidyl Peptidase 4 analysis, Humans, Hyaluronan Receptors analysis, Neoplastic Stem Cells cytology, Neoplastic Stem Cells immunology, Prognosis, Biomarkers, Tumor analysis, Colonic Neoplasms chemistry, Neoplastic Stem Cells chemistry
- Published
- 2017
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47. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture.
- Author
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Grillet F, Bayet E, Villeronce O, Zappia L, Lagerqvist EL, Lunke S, Charafe-Jauffret E, Pham K, Molck C, Rolland N, Bourgaux JF, Prudhomme M, Philippe C, Bravo S, Boyer JC, Canterel-Thouennon L, Taylor GR, Hsu A, Pascussi JM, Hollande F, and Pannequin J
- Subjects
- Aldehyde Dehydrogenase genetics, Aldehyde Dehydrogenase metabolism, Aldehyde Dehydrogenase 1 Family, Animals, Antineoplastic Agents metabolism, Cell Differentiation, Cell Self Renewal, Colorectal Neoplasms genetics, Dipeptidyl Peptidase 4 genetics, Dipeptidyl Peptidase 4 metabolism, Drug Resistance, Neoplasm genetics, Humans, Hyaluronan Receptors genetics, Hyaluronan Receptors metabolism, Inactivation, Metabolic genetics, Liver Neoplasms secondary, Mice, Neoplasm Transplantation, Neoplastic Stem Cells physiology, Phenotype, Primary Cell Culture, Retinal Dehydrogenase, Sequence Analysis, RNA, Tumor Cells, Cultured, Up-Regulation, Colorectal Neoplasms blood, Colorectal Neoplasms pathology, Liver Neoplasms pathology, Neoplastic Cells, Circulating metabolism, Neoplastic Stem Cells enzymology, RNA, Neoplasm analysis
- Abstract
Objective: Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full., Design: Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells., Results: Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo . Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds., Conclusions: Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine., Clinical Trial Registration: ClinicalTrial.gov NCT01577511., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
- Published
- 2017
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48. Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism.
- Author
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Bash-Imam Z, Thérizols G, Vincent A, Lafôrets F, Polay Espinoza M, Pion N, Macari F, Pannequin J, David A, Saurin JC, Mertani HC, Textoris J, Auboeuf D, Catez F, Dalla Venezia N, Dutertre M, Marcel V, and Diaz JJ
- Subjects
- Cellular Reprogramming, Colonic Neoplasms genetics, Colorectal Neoplasms genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Drug Resistance, Neoplasm, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, Humans, Protein Biosynthesis drug effects, Transcription Factors genetics, Transcription Factors metabolism, Colonic Neoplasms therapy, Colorectal Neoplasms therapy, Fluorouracil therapeutic use, MicroRNAs genetics, RNA, Messenger genetics
- Abstract
5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the translational machinery and that 5-FU affects the amount of some mRNAs associated with ribosomes. However, the impact of 5-FU on translational regulation remains unclear. Using translatome profiling, we report that a clinically relevant dose of 5-FU induces a translational reprogramming in colorectal cancer cell lines. Comparison of mRNA distribution between polysomal and non-polysomal fractions in response to 5-FU treatment using microarray quantification identified 313 genes whose translation was selectively regulated. These regulations were mostly stimulatory (91%). Among these genes, we showed that 5-FU increases the mRNA translation of HIVEP2, which encodes a transcription factor whose translation in normal condition is known to be inhibited by mir-155. In response to 5-FU, the expression of mir-155 decreases thus stimulating the translation of HIVEP2 mRNA. Interestingly, the 5-FU-induced increase in specific mRNA translation was associated with reduction of global protein synthesis. Altogether, these findings indicate that 5-FU promotes a translational reprogramming leading to the increased translation of a subset of mRNAs that involves at least for some of them, miRNA-dependent mechanisms. This study supports a still poorly evaluated role of translational control in drug response.
- Published
- 2017
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49. Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.
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Planque C, Rajabi F, Grillet F, Finetti P, Bertucci F, Gironella M, Lozano JJ, Beucher B, Giraud J, Garambois V, Vincent C, Brown D, Caillo L, Kantar J, Pelegrin A, Prudhomme M, Ripoche J, Bourgaux JF, Ginestier C, Castells A, Hollande F, Pannequin J, and Pascussi JM
- Subjects
- Aged, Aldehyde Dehydrogenase metabolism, Aldehyde Dehydrogenase 1 Family, Animals, Antineoplastic Agents pharmacology, Biomarkers, Tumor, Cohort Studies, Disease-Free Survival, Drug Resistance, Neoplasm, Female, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Pregnane X Receptor, Prognosis, Retinal Dehydrogenase, Spheroids, Cellular metabolism, Colonic Neoplasms metabolism, Neoplasm Recurrence, Local metabolism, Neoplastic Stem Cells cytology, Receptors, Steroid metabolism
- Abstract
Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy., Competing Interests: Authors have nothing to disclose.
- Published
- 2016
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50. Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells.
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Giraud J, Failla LM, Pascussi JM, Lagerqvist EL, Ollier J, Finetti P, Bertucci F, Ya C, Gasmi I, Bourgaux JF, Prudhomme M, Mazard T, Ait-Arsa I, Houhou L, Birnbaum D, Pélegrin A, Vincent C, Ryall JG, Joubert D, Pannequin J, and Hollande F
- Subjects
- Aldehyde Dehydrogenase metabolism, Animals, Cell Line, Tumor, Cell Survival, Humans, Mice, Tumor Microenvironment, Colonic Neoplasms pathology, Gastrins physiology, Neoplastic Stem Cells physiology, Protein Precursors physiology
- Abstract
Subpopulations of cancer stem-like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in regulating CSC phenotype in advanced colorectal cancer. Progastrin expression and secretion were highly enriched in colon CSC isolated from human colorectal cancer cell lines and colon tumor biopsies. Progastrin expression promoted CSC self-renewal and survival, whereas its depletion by RNA interference-mediated or antibody-mediated strategies altered the homeostatic proportions of CSC cells within heterogeneous colorectal cancer tumors. Progastrin downregulation also decreased the frequency of ALDH(high) cells, impairing their tumor-initiating potential, and inhibited the high glycolytic activity of ALDH(high) CSC to limit their self-renewal capability. Taken together, our results show how colorectal CSC maintain their tumor-initiating and self-renewal capabilities by secreting progastrin, thereby contributing to the tumor microenvironment to support malignancy. Cancer Res; 76(12); 3618-28. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
- Full Text
- View/download PDF
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