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Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients
Rationale: Renal cell carcinoma (RCC) accounts for about 2% of all adult cancers, and clear cell RCC (ccRCC) is the most common RCC histologic subtype. A hallmark of ccRCC is the loss of the primary cilium, a cellular antenna that senses a wide variety of signals. Loss of this key organelle in ccRCC...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052902/ https://www.ncbi.nlm.nih.gov/pubmed/32194829 http://dx.doi.org/10.7150/thno.41001 |
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author | Fabbri, Lucilla Dufies, Maeva Lacas-Gervais, Sandra Gardie, Betty Gad-Lapiteau, Sophie Parola, Julien Nottet, Nicolas Meyenberg Cunha de Padua, Monique Contenti, Julie Borchiellini, Delphine Ferrero, Jean-Marc Leclercq, Nathalie Rioux Ambrosetti, Damien Mograbi, Baharia Richard, Stéphane Viotti, Julien Chamorey, Emmanuel Sadaghianloo, Nirvana Rouleau, Matthieu Craigen, William J. Mari, Bernard Clavel, Stéphan Pagès, Gilles Pouysségur, Jacques Bost, Frédéric Mazure, Nathalie M. |
author_facet | Fabbri, Lucilla Dufies, Maeva Lacas-Gervais, Sandra Gardie, Betty Gad-Lapiteau, Sophie Parola, Julien Nottet, Nicolas Meyenberg Cunha de Padua, Monique Contenti, Julie Borchiellini, Delphine Ferrero, Jean-Marc Leclercq, Nathalie Rioux Ambrosetti, Damien Mograbi, Baharia Richard, Stéphane Viotti, Julien Chamorey, Emmanuel Sadaghianloo, Nirvana Rouleau, Matthieu Craigen, William J. Mari, Bernard Clavel, Stéphan Pagès, Gilles Pouysségur, Jacques Bost, Frédéric Mazure, Nathalie M. |
author_sort | Fabbri, Lucilla |
collection | PubMed |
description | Rationale: Renal cell carcinoma (RCC) accounts for about 2% of all adult cancers, and clear cell RCC (ccRCC) is the most common RCC histologic subtype. A hallmark of ccRCC is the loss of the primary cilium, a cellular antenna that senses a wide variety of signals. Loss of this key organelle in ccRCC is associated with the loss of the von Hippel-Lindau protein (VHL). However, not all mechanisms of ciliopathy have been clearly elucidated. Methods: By using RCC4 renal cancer cells and patient samples, we examined the regulation of ciliogenesis via the presence or absence of the hypoxic form of the voltage-dependent anion channel (VDAC1-ΔC) and its impact on tumor aggressiveness. Three independent cohorts were analyzed. Cohort A was from PREDIR and included 12 patients with hereditary pVHL mutations and 22 sporadic patients presenting tumors with wild-type pVHL or mutated pVHL; Cohort B included tissue samples from 43 patients with non-metastatic ccRCC who had undergone surgery; and Cohort C was composed of 375 non-metastatic ccRCC tumor samples from The Cancer Genome Atlas (TCGA) and was used for validation. The presence of VDAC1-ΔC and legumain was determined by immunoblot. Transcriptional regulation of IFT20/GLI1 expression was evaluated by qPCR. Ciliogenesis was detected using both mouse anti-acetylated α-tubulin and rabbit polyclonal ARL13B antibodies for immunofluorescence. Results: Our study defines, for the first time, a group of ccRCC patients in which the hypoxia-cleaved form of VDAC1 (VDAC1-ΔC) induces resorption of the primary cilium in a Hypoxia-Inducible Factor-1 (HIF-1)-dependent manner. An additional novel group, in which the primary cilium is re-expressed or maintained, lacked VDAC1-ΔC yet maintained glycolysis, a signature of epithelial-mesenchymal transition (EMT) and more aggressive tumor progression, but was independent to VHL. Moreover, these patients were less sensitive to sunitinib, the first-line treatment for ccRCC, but were potentially suitable for immunotherapy, as indicated by the immunophenoscore and the presence of PDL1 expression. Conclusion: This study provides a new way to classify ccRCC patients and proposes potential therapeutic targets linked to metabolism and immunotherapy. |
format | Online Article Text |
id | pubmed-7052902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-70529022020-03-19 Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients Fabbri, Lucilla Dufies, Maeva Lacas-Gervais, Sandra Gardie, Betty Gad-Lapiteau, Sophie Parola, Julien Nottet, Nicolas Meyenberg Cunha de Padua, Monique Contenti, Julie Borchiellini, Delphine Ferrero, Jean-Marc Leclercq, Nathalie Rioux Ambrosetti, Damien Mograbi, Baharia Richard, Stéphane Viotti, Julien Chamorey, Emmanuel Sadaghianloo, Nirvana Rouleau, Matthieu Craigen, William J. Mari, Bernard Clavel, Stéphan Pagès, Gilles Pouysségur, Jacques Bost, Frédéric Mazure, Nathalie M. Theranostics Research Paper Rationale: Renal cell carcinoma (RCC) accounts for about 2% of all adult cancers, and clear cell RCC (ccRCC) is the most common RCC histologic subtype. A hallmark of ccRCC is the loss of the primary cilium, a cellular antenna that senses a wide variety of signals. Loss of this key organelle in ccRCC is associated with the loss of the von Hippel-Lindau protein (VHL). However, not all mechanisms of ciliopathy have been clearly elucidated. Methods: By using RCC4 renal cancer cells and patient samples, we examined the regulation of ciliogenesis via the presence or absence of the hypoxic form of the voltage-dependent anion channel (VDAC1-ΔC) and its impact on tumor aggressiveness. Three independent cohorts were analyzed. Cohort A was from PREDIR and included 12 patients with hereditary pVHL mutations and 22 sporadic patients presenting tumors with wild-type pVHL or mutated pVHL; Cohort B included tissue samples from 43 patients with non-metastatic ccRCC who had undergone surgery; and Cohort C was composed of 375 non-metastatic ccRCC tumor samples from The Cancer Genome Atlas (TCGA) and was used for validation. The presence of VDAC1-ΔC and legumain was determined by immunoblot. Transcriptional regulation of IFT20/GLI1 expression was evaluated by qPCR. Ciliogenesis was detected using both mouse anti-acetylated α-tubulin and rabbit polyclonal ARL13B antibodies for immunofluorescence. Results: Our study defines, for the first time, a group of ccRCC patients in which the hypoxia-cleaved form of VDAC1 (VDAC1-ΔC) induces resorption of the primary cilium in a Hypoxia-Inducible Factor-1 (HIF-1)-dependent manner. An additional novel group, in which the primary cilium is re-expressed or maintained, lacked VDAC1-ΔC yet maintained glycolysis, a signature of epithelial-mesenchymal transition (EMT) and more aggressive tumor progression, but was independent to VHL. Moreover, these patients were less sensitive to sunitinib, the first-line treatment for ccRCC, but were potentially suitable for immunotherapy, as indicated by the immunophenoscore and the presence of PDL1 expression. Conclusion: This study provides a new way to classify ccRCC patients and proposes potential therapeutic targets linked to metabolism and immunotherapy. Ivyspring International Publisher 2020-02-03 /pmc/articles/PMC7052902/ /pubmed/32194829 http://dx.doi.org/10.7150/thno.41001 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Fabbri, Lucilla Dufies, Maeva Lacas-Gervais, Sandra Gardie, Betty Gad-Lapiteau, Sophie Parola, Julien Nottet, Nicolas Meyenberg Cunha de Padua, Monique Contenti, Julie Borchiellini, Delphine Ferrero, Jean-Marc Leclercq, Nathalie Rioux Ambrosetti, Damien Mograbi, Baharia Richard, Stéphane Viotti, Julien Chamorey, Emmanuel Sadaghianloo, Nirvana Rouleau, Matthieu Craigen, William J. Mari, Bernard Clavel, Stéphan Pagès, Gilles Pouysségur, Jacques Bost, Frédéric Mazure, Nathalie M. Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients |
title | Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients |
title_full | Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients |
title_fullStr | Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients |
title_full_unstemmed | Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients |
title_short | Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients |
title_sort | identification of a new aggressive axis driven by ciliogenesis and absence of vdac1-δc in clear cell renal cell carcinoma patients |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052902/ https://www.ncbi.nlm.nih.gov/pubmed/32194829 http://dx.doi.org/10.7150/thno.41001 |
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