Chimie et Biologie du Cancer

SONY DSC

Raphaël Rodriguez Chef d'équipe, DR2 CNRS Tél :

« Nature is dominated by chemically favoured processes. While biology is prone to evolution, universal principles of physical chemistry are not (at least not on the same time scale). It is my opinion that life has evolved mechanisms to circumvent undesired chemistry’’ -Raphaël Rodriguez-

Our laboratory has adopted ‘the small molecule approach’ to biology. We study cell biology at the molecular level using an integrated approach combining synthetic organic chemistry and molecular biology techniques. We custom design new probes and protocols to delineate mechanisms of action of small molecules. These includes cutting-edge small molecule imaging in cells by means of click chemistry, next generation sequencing and quantitative proteomics. During the course of our studies, these unbiased methods have led to the identification of novel therapeutic targets such as the lysine acetyl transferase NAT10 as a master regulator of ageing, iron homeostasis has a druggable network in cancer stem cells and new anti-cancer strategies that consist of altering the chromatin landscape to control genome targeting with cisplatin drugs. The lab is currently focused on developing methods for personalised cancer treatments and elucidating roles of iron in the maintenance of cancer stem cells. The group seeks to employ universal principles of physical chemistry and knowledge of biology to impact human medicine.

Research overview

Key words: small molecules, chromatin biology, epigenetics, traffic, signaling, cancer, EMT, iron metabolism, cell imaging, next generation sequencing, proteomics

Role of chromatin in genotoxic drug responses: Genotoxic agents represent a major class of drugs used in the clinical management of cancer. We seek to establish unbiased protocols based on DNA target pull down coupled to next generation sequencing (e.g. ChIP-Seq, Click-Seq) and quantitative proteomics (e.g. SILAC) to identify genomic targets of these drugs and further delineate and control drug responses. We aim to pharmacologically alter the structure of chromatin to orchestrate the genomic responses of genotoxic agents. We have previously employed small molecule imaging in cells to screen for potential regulators of genome targeting and identified DNMT and HDAC inhibitors that altered genome targeting with cisplatin, activating translesion synthesis and apoptosis. Ultimately, we aim to exploit these technologies to predict and modulate drug responses, a step forward towards personalised medicine.

A) Detection of labeled DNA-Pt in U2OS cells. B) Schematic representation of a strategy for enhancing the detection of DNA-Pt in cells. C) Detection of labeled DNA-Pt in U2OS cells subjected to pre-extraction. Cells were treated with APPA (250 mm for 3 h). Zoomed images are 3x . Scale bar, 20 μm. Unt., untreated.
A) Detection of labeled DNA-Pt in U2OS cells. B) Schematic representation of a strategy for enhancing the detection of DNA-Pt in cells. C) Detection of labeled DNA-Pt in U2OS cells subjected to pre-extraction.

Iron metabolism in EMT and cancer stem cell maintenance: During embryogenesis, epithelial cells undergo extensive epigenetic reprogramming, allowing them to transdifferentiate and to acquire physical properties of mesenchymal cells, a process called epithelial-to-mesenchymal transition (EMT). In this manner, cells can detach from primary tissues and migrate to distant locations. The paradigm of cancer stem cells (CSC) defines the existence of subpopulations of cells able to harness similar mechanisms to disseminate, initiate and sustain tumour growth. We have recently identified iron homeostasis as a druggable network in CSCs, raising a putative role of iron in these cells. Thus, we seek to characterise features of iron homeostasis in CSCs and elucidate its role in the maintenance of these cells.

Salinomycin targets Cancer Stem Cells by sequestering iron in lysosomes, leading to ROS production and ferroptosis.

Selective targeting of the lysosomal compartment with small molecules: Our laboratory has recently established the first synthetic scheme towards the production of the complex natural products Marmycin A and B in 18 steps. Contrary to belief, we have discovered that these natural products do not target genomic DNA but quantitatively accumulates in lysosomes and enter cells by means of endocytosis. We have taken advantage of this finding to physically drive other small molecules (the effector) inside this organelle by chemically linking these structures to the scaffold of Marmycin (the driver), a strategy we have termed ‘molecular driver’. This strategy enables to virtually deliver any effector in the lysosomal compartment given that hybrid structures also target the plasma membrane in a similar manner thanks to the driver. Proof-of-concept was established through the conception of the hybrid structure we named Artesumycin, a dimer of the natural products Artemisinin and Marmycin A. While Artemisinin does not in itself quantitatively target the lysosomal compartments, we found that Artesumycin, effectively target lysosomes and chemically react with lysosomal iron to produce toxic free radicals. We seek to elaborate on this strategy to target iron homeostasis in the context of cancer.

Artesumycin, a hybrid between Artemisinin and Marmycin that targets the lysosomal compartement.
Artesumycin, a hybrid of Artemisinin and Marmycin that targets the lysosomal compartement.

Vacancies

We are recruiting a Post-Doc to work on the roles of iron homeostasis in Cancer Stem Cells. We always seek talented young scientists from around the world. If our research is of interest to you, be in touch! You are most welcome to send us a short CV, cover letter and names of two academic references. Original research proposals are most welcome and will be considered.

The Group Leader

Raphaël Rodriguez was born in 1978 in Avignon. He performed his PhD studies under the supervision of Prof Sir Jack E. Baldwin and Prof Maurice Santelli at the University of Oxford and in Marseille, where he completed the synthesis of structurally complex natural products by means of pericyclic processes. He joined The University of Cambridge in November 2005 as a postdoctoral fellow, working under the mentorship of Prof. Sir Shankar Balasubramanian, where his work led to the invention of the potent G-quadruplex targeting small molecule pyridostatin. Together with Prof. Steve Jackson (Gurdon Institute, UK), they firmly established a link between G-quadruplex DNA structures and genomic instability. Raphaël joined the CNRS as a group leader in 2012 and was promoted Director of Research at Institut Curie in 2017. His recent achievements include the development of the anti-aging small molecule remodelin, the first chemical synthesis of the complex natural product marmycin and the iron metabolism targeting drug ironomycin. His group has recently elucidated the mechanism of action of salinomycin against cancer stem cells and identified a role of iron in the maintenance of these cells. The group has also provided evidence for a role of chromatin in regulating genome targeting with cisplatin.

Awards and Nominations

  • Franco-British Young Leaders
  • K2 Trophy in oncology
  • Pierre Fabre Award for Therapeutic Innovation
  • ERC Consolidator Award
  • Emergence Ville de Paris Award
  • Junior Scientists Participation Program 48th Bürgenstock Conference
  • Fournier-SFC Prize

Selected publications

(* Corresponding author)

An iron hand over cancer stem cells. A. Hamaï, T. Cañeque, S. Müller, T. T. Mai,A. Hienzsch, C. Ginestier, E. Charafe-Jauffret, P. Codogno, M. Mehrpour, R. Rodriguez. Autophagy, 2017, DOI:10.1080/15548627.2017.1327104

Click chemistry enables preclinical evaluation of targeted epigenetic therapies. Dean S. Tyler, Johanna Vappiani, Tatiana Cañeque, Enid Y. N. Lam, Aoife Ward, Omer Gilan, Yih-Chih Chan, Antje Hienzsch, Anna Rutkowska, Thilo Werner, Anne J. Wagner, Dave Lugo, Richard Gregory, Cesar Ramirez Molina, Neil Garton, Christopher R. Wellaway, Susan Jackson, Laura MacPherson, Margarida Figueiredo, Sabine Stolzenburg, Charles C. Bell, Colin House, Sarah-Jane Dawson, Edwin D. Hawkins, Gerard Drewes, Rab K. Prinjha, Raphaël Rodriguez, Paola Grandi, Mark A. Dawson Science DOI: 10.1126/science.aal2066

Chromatin regulates genome targeting with cisplatin. Emmanouil Zacharioudakis, Poonam Agarwal, Alexandra Bartoli, Nathan Abell, Lavaniya Kunalingam, Valérie Bergoglio, Blerta Xhemalce, Kyle M. Miller*, Raphaël Rodriguez* Angew. Chem. Int. Ed. DOI: 10.1002/anie.201701144R1

Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Trang Thi Mai, Ahmed Hamaï, Antje Hienzsch, Tatiana Cañeque, Sebastian Müller, Julien Wicinski, Olivier Cabaud, Christine Leroy, Amandine David, Verónica Acevedo, Akihide Ryo, Christophe Ginestier, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Patrice Codogno, Maryam Mehrpour*, Raphaël Rodriguez* Nature Chem. DOI: 10.1038/NCHEM.2778, Highlighted in chemical & engineering news

Click quantitative mass spectrometry identifies PIWIL3 as a mechanistic target of RNA interference activator enoxacin in cancer cells. Nathan S. Abell, Marvin Mercado, Tatiana Cañeque, Raphaël Rodriguez*, Blerta Xhemalce* J. Am. Chem. Soc. 139, 1400-1403 (2017)

Targeting cancer stem cells with small molecules. Sebastian Müller, Tatiana Cañeque, Verónica Acevedo, Raphaël Rodriguez* Isr. J. Chem. DOI: 10.1002/ijch.201600109. Special Stuart L. Schreiber & Kyriacos C. Nicolaou Wolf Prize special issue

Synthesis of marmycin A and investigation into its cellular activity. Tatiana Cañeque, Filipe Gomes, Trang Thi Mai, Giovanni Maestri, Max Malacria, Raphaël Rodriguez* Nature Chem. 7, 744-751 (2015)

Unravelling the genomic targets of small molecules using high-throughput sequencing. Raphaël Rodriguez*, Kyle M. Miller* Nature Rev. Genet. 15, 783-796 (2014)

Chemical inhibition of NAT10 corrects defects of laminopathic cells. Delphine Larrieu, Sébastien Britton, Mukerrem Demir, Raphaël Rodriguez*, Stephen P. Jackson* Science 344, 527-532 (2014), Highlight in CEN

Modular construction of dynamic nucleodendrimers. Valentina Abet, Robert Evans, Florian Guibbal, Stefano Caldarelli, Raphaël Rodriguez* Angew. Chem. Int. Ed. 53, 4862-4866 (2014)

Selective RNA versus DNA G-quadruplex targeting by in situ click chemistry. Marco Di Antonio, Giulia Biffi, Angelica Mariani, Eun-Ang Raiber, Raphaël Rodriguez*, Shankar Balasubramanian* Angew. Chem. Int. Ed. 51, 11073-11078 (2012)

Small molecule-induced DNA damage identifies alternative DNA structures in human genes. Raphaël Rodriguez, Kyle M. Miller, Josep V. Forment, Charles R. Bradshaw, Sébastien Britton, Tobias Oelschlaegel, Mehran Nikan, Blerta Xhemalce, Shankar Balasubramanian, Stephen P. Jackson Nature Chem. Biol. 8, 301-310 (2012), Highlights in Nature Chem. Biol. and F1000; Most Accessed Article

A single-molecule platform for investigation of interactions between G-quadruplexes and small-molecule ligands. Deepak Koirala, Soma Dhakal, Beth Ashbridge, Yuta Sannohe, Raphaël Rodriguez, Hiroshi Sugiyama, Shankar Balasubramanian, Hanbin Mao Nature Chem. 3, 782-787 (2011)

The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nagaratna S. Hegde, Deborah A. Sanders, Raphaël Rodriguez, Shankar Balasubramanian Nature Chem. 3, 725-731 (2011)

G-quadruplex-binding benzo[a]phenoxazines down-regulate c-KIT expression in human gastric carcinoma cells. Keith I. E. McLuckie, Zoë A. E. Waller, Deborah A. Sanders, David Alves, Raphaël Rodriguez, Jyotirmayee Dash, Grahame J. McKenzie, Ashok R. Venkitaraman, Shankar Balasubramanian J. Am. Chem. Soc. 133, 2658-2663 (2011)

Small-molecule-mediated G-quadruplex isolation from human cells. Sebastian Müller, Sunita Kumari, Raphaël Rodriguez*, Shankar Balasubramanian* Nature Chem. 2, 1095-1098 (2010). Highlight in F1000

A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres. Raphaël Rodriguez, Sebastian Müller, Justin A. Yeoman, Chantal Trentesaux, Jean-François Riou, Shankar Balasubramanian J. Am. Chem. Soc. 130, 15758-15759 (2008)

Exploring the differential recognition of DNA G-quadruplex targets by small molecules using dynamic combinatorial chemistry. Anthony Bugaut, Katja Jantos, Jean-Luc Wietor, Raphaël Rodriguez, Jeremy K. M. Sanders, Shankar Balasubramanian Angew. Chem. Int. Ed. 47, 2677-2680 (2008)

Tri-substituted isoalloxazines as a new class of G-quadruplex binding ligands: small molecule regulation of c-kit oncogene expression. Mallesham Bejugam, Sven Sewitz, Pravin S. Shirude, Raphaël Rodriguez, Ramla Shahid, Shankar Balasubramanian J. Am. Chem. Soc. 129, 12926-12927 (2007)

Ligand-driven G-quadruplex conformational switching by using an unusual mode of interaction. Raphaël Rodriguez, G. Dan Pantoş, Diana P. N. Gonçalves, Jeremy K. M. Sanders, Shankar Balasubramanian Angew. Chem. Int. Ed. 46, 5405-5407 (2007)

Oxazole-based peptide macrocycles: a new class of G-quadruplex binding ligands. Katja Jantos, Raphaël Rodriguez, Sylvain Ladame, Pravin S. Shirude, Shankar Balasubramanian J. Am. Chem. Soc. 128, 13662-13663 (2006)

Publications clés

Année de publication : 2017

Trang Thi Mai, Ahmed Hamaï, Antje Hienzsch, Tatiana Cañeque, Sebastian Müller, Julien Wicinski, Olivier Cabaud, Christine Leroy, Amandine David, Verónica Acevedo, Akihide Ryo, Christophe Genestier, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Patrice Codogno, Maryam Mehrpour, Raphaël Rodriguez (2017 May 15)

Salinomycin kills cancer stem cells by sequestering iron in lysosomes

Nature Chemistry : DOI : 10.1038/nchem.2778
Emmanouil Zacharioudakis, Poonam Agarwal, Alexandra Bartoli, Nathan Abell, Lavaniya Kunalingam, Valérie Bergoglio, Blerta Xhemalce, Kyle M. Miller, Raphaël Rodriguez (2017 May 5)

Chromatin Regulates Genome Targeting with Cisplatin

Angewandte Chemie : DOI : 10.1002/anie.201701144
Nathan S Abell, Marvin Mercado, Tatiana Cañeque, Raphaël Rodriguez, Blerta Xhemalce (2017 Jan 18)

Click Quantitative Mass Spectrometry Identifies PIWIL3 as a Mechanistic Target of RNA Interference Activator Enoxacin in Cancer Cells.

Journal of the American Chemical Society : 1400-1403 : DOI : 10.1021/jacs.6b11751

Année de publication : 2016

Sebastian Müller, Geneviève Almouzni (2016 Dec 1)

Chromatin dynamics during the cell cycle at centromeres.

Nature Reviews Genetics : 192-208 : DOI : 10.1038/nrg.2016.157

Année de publication : 2015

Tatiana Cañeque, Filipe Gomes, Trang Thi Mai, Giovanni Maestri, Max Malacria, Raphaël Rodriguez (2015 Aug 21)

Synthesis of marmycin A and investigation into its cellular activity.

Nature Chemistry : 744-51 : DOI : 10.1038/nchem.2302

Année de publication : 2014

Delphine Larrieu, Raphaël Rodriguez, Sébastien Britton (2014 Nov 2)

Chemical inhibition of NAT10 corrects defects of laminopathic cells

Science : 344 : 527 : DOI : 10.1126/science.1252651
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