Rodriguez

Chemical Biology of Cancer

Raphaël Rodriguez
Scientific keywords: cancer, cell imaging, chromatin biology, EMT, epigenetics, iron metabolism, next generation sequencing, proteomics, signaling, small molecules, traffic

« 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-

Congratulations to Raphaël for the Tetrahedron Young Investigator Award for Bioorganic and Medicinal Chemistry 2019.

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 mesenchymal cancer 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 mesenchymal cancer cells. The group seeks to employ universal principles of physical chemistry and knowledge of biology to impact human medicine.

Rodriguez Group

Research

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 mesenchymal cancer 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. Theres is a 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 mesenchymal cancer 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.