ReTuBi Lecture - Christer Betsholtz
On January 22 of 2018, Christer Betsholtz from Karolinska Institutet (Sweden) was the invited speaker as an expert visit with the lecture “A molecular atlas of the brain vasculature revealed by single cell RNA sequencing”.
Summary of the Lecture:
Angiogenesis – the formation of new blood vessels from pre-existing ones – requires interaction between several cell types and involves signaling molecules, secreted as well as membrane-tethered and their cognate receptors, of many different types. My laboratory focuses on mechanisms of angiogenic sprouting, and the involvement of distinct endothelial phenotypes (tip cells and stalk cells) in this process. We are also investigating the mechanisms leading to the recruitment of vascular mural cells (pericytes and vascular smooth muscle cells) to blood vessels and the role of these cells, in particular the pericytes, in vascular development and function. However, pericyte identification remains challenging due to a paucity of defining markers, and there are not yet any good tools available for their specific genetic manipulation. As a consequence, there is not an accepted consensus about how pericytes should be defined, where they reside, how heterogeneous they are, and what they do. To resolve this problem, we use single cell RNA sequencing to define pericytes and other vascular and vessel-associated cell types of the brain, as well as in other organs. In addition to providing cell type and subtype definitions based on genome–wide quantitative transcriptional information, our data also reveal new insights in the arterio-venous zonation and organotypicity of vascular cell, as well as the identification and definition of hitherto unrecognized vascular cell types.
ReTuBi Lecture - Raphaël Rodriguez
On January 15 of 2018, Raphaël Rodriguez from Institut Curie (France) was the invited speaker as an expert visit with the lecture “An iron hand over cancer stem cells”.
Summary of the Lecture:
Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. We provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo, by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells.
Staff exchange between iMM-Curie (2017/11)
From November 29 to December 02, Gonçalo Bernardes (iMM) made a “ReTuBi Staff Exchange” to Raphael Rodriguez’s lab in Institut Curie to acquire knowledge in bioorthogonal labelling methods for target identification. This is an important area of chemical biology that addresses and helps identifying new targets for active molecules. This particular expertise from the Rodriguez’s lab fits well with current programs at the Bernardes lab in target id of natural products in cancer. The overall goal of this staff exchange was for Gonçalo to learn how to implement a bioorthogonal labelling approach for target id, establish a new collaboration, and also potentiate new projects. In addition, Gonçalo had the opportunity to present a seminar at the Institut Curie during this staff exchange also allowing to disseminate his group’s research to a larger community.
ReTuBi Event: “Oncology: Talking with Scientists”
On November 13 of 2017, the ReTuBi project in partnership with Instituto de Medicina Molecular João Lobo Antunes and Fundo iMM-Laço promoted the event “Oncology: Talking with Scientists”, specially dedicated to the Portuguese cancer patients associations.
This event had the participation of Luís Costa that presented “Science and cancer patient: an evolving partnership” and of Bruno Silva-Santos that presented “DOT-cells: Towards a new immunotherapy for cancer”. An exhibition of the work of some iMM labs/facilities was also organized to promote iMM research. The labs that participated in this event were: Edgar Gomes, Cláudio Franco, João Barata, Luís Costa and Sérgio Dias. The ZebraFish Facility and the Biobank were also present.
ReTuBi Lecture - Andreas Fischer
On October 24 of 2017, Andreas Fischer from DKFZ (Germany) was the invited speaker as an expert visit with the lecture “Notch signaling in vasculature: angiogenesis and beyond”.
Summary of the Lecture:
Abnormal blood vessel growth and vessel function is a hallmark of cancer. Notch signaling is a central coordinator of angiogenesis. We have developed novel Notch inhibitory and stimulatory peptides to manipulate sprouting angiogenesis and identified novel Notch ligand-interacting proteins. Their manipulation alters the tumor vasculature and interferes with tumor growth. In addition we could show that endothelial Notch signaling is frequently hyperactive in the tumor vasculature and that this promotes several steps of the metastatic cascade. Mechanistically, sustained Notch1 activity led to endothelial cell senescence, expression of chemokines, adhesion factors and weakening of cellular junctions. This promotes infiltration of primary tumors with granulocytic myeloid-derived suppressor cells, facilitates tumor cell intravasation and survival at distant sites. Lastly, we will give some insight how Notch signaling in the blood vessel wall controls the flux of nutrients from plasma to muscle cells and how this affects systemic metabolism.
ReTuBi Lecture - Guillaume Montagnac
On October 23 of 2017, Guillaume Montagnac from the Gustave Roussy Institute (France) was the invited speaker as an expert visit with the lecture “Frustrated endocytosis in cell migration and mechanotransduction”.
Summary of the Lecture:
Endocytosis is a fundamental process that allows the cell to feed itself, to control the composition of its plasma membrane, but also to regulate signaling pathways, for example by "shutting down" signaling from receptors activated at the cell surface. Endocytosis therefore allows the cell to adjust to its environment and to provide an adapted response to the different signals it encounters. To be effective, we assume that the dialogue between extracellular medium and endocytosis must be bi-directional. In the laboratory, we study how the physical properties of the cell environment affect clathrin-dependent endocytosis. Our work shows, for example, that the topology or the rigidity of the cellular environment have profound consequences on endocytosis, in particular mechanically preventing the proper formation of endocytosis vesicles. We investigate how this frustrated endocytosis, far from trivial, affects the ability of cells to migrate into complex environments and to proliferate.