Metastasis is the main reason behind cancer-related mortality, with limited therapeutic opportunities currently available. This is mostly due to an early dissemination of cancer cells to distant organs, long before the apparent metastases can be detected. Various cancer types differ in their ability to metastasize to different organs which has led to a “seed and soil” hypothesis, and established the concepts of tumor microenvironment and metastatic niche. However, due to complicated detection and modeling of the metastatic niche in mouse models, our understanding of the tumor-metastatic niche crosstalk remains incomplete.
In our lab, we combine human pluripotent stem cell-derived organoids and functional genomics techniques, including at a single cell resolution, to study RNA regulatory networks underlying the establishment of the pro-metastatic tumor microenvironment and the metastatic niche.
Merits of the lab:
The Navickas lab has been recently established at Institut Curie, with a track record in studying RNA translation, stability and alternative splicing in cancer progression (Navickas, Asgharian, et al., bioRxiv, 2021; Fish, Khoroshkin, Navickas, et al., Science, 2021; Yu, Navickas, Asgharian, et al., Cancer Discov, 2020; Fish, Navickas, et al., Mol Cell, 2019) and using hPSC-derived organoids for disease modeling (Samuel et al., Cell Stem Cell, 2020).
Why do we want medical doctors?
We believe in the necessity of a close collaboration between specialists working in the clinics and the lab, especially in the field of cancer progression that is moving towards precision oncology. We have had a great experience mentoring medical students during their extended research internships, and are looking forward to continuing it.
In the lab, we use hPSC-derived lung organoids to model lung metastatic niche establishment by breast cancer cells ex vivo. Our data shows that lung metastatic breast cancer cells, in contrast to normal mammary epithelial cells, cause the downregulation of RNASE1 expression when co-cultured with lung organoids. RNASE1 is expressed in a subset of lung epithelium, both in lung organoids and in human lung specimens, however its role in lung biology as well as tumor microenvironment is unknown. By its enzymatic function, RNASE1 has been linked to the degradation of extracellular RNA (eRNA). Importantly, cancer cells, including breast cancer, are the known producers of eRNA, that act as pro-inflammatory molecules. It is thus tempting to think that downregulating RNASE1 could be a metastatic strategy employed by cancer cells to prevent the eRNA decay and sustain the inflammatory environment in the metastatic niche. In line with this hypothesis, the lower RNASE1 expression is associated with worse prognostic metrics in breast cancer patient cohorts.
How we will do it?
To address the role of RNASE1 in the establishment of lung metastatic niche, we will first take advantage of the ex vivo model. Using scRNAseq, we will compare the transcriptomic signatures in control and RNASE1 knockdown lung organoids, both in mono- and co-cultures with lung metastatic breast cancer cells. In parallel, we will evaluate the contribution of eRNA to the observed phenotypes by including the recombinant RNase in the culture media. Our secretome data will help us to identify which extracellular signals from the cancer cells mediate the downregulation of RNASE1 in lung organoids at a distance. Furthermore, via the collaboration with Ronald Raines (MIT, USA), we obtained the Rnase1fl/fl mice and thus will compare the lung colonization capacity by breast cancer cells in wild type and Rnase1 KO animals. This will allow us to confirm the role of RNASE1 in breast cancer progression at an organism level, using widely accepted in vivo models, and complement our ex vivo findings. The transcriptomic analysis of the wild-type and Rnase1 KO mouse lungs bearing metastatic foci will further inform us on the inflammatory gene expression programs counteracted by RNASE1. Recombinant RNases are currently studied as anticancer therapies, and we will address the potential to counteract the breast cancer progression in vivo by systemic RNase treatment. Finally, we will collaborate with oncologists at Institut Curie and evaluate the association of RNASE1 expression in the tumor microenvironment with breast cancer progression in clinical samples.
Why is this important?
This project aims to bridge ex vivo, in vivo disease modeling and clinical studies, to better understand, and eventually prevent, breast cancer metastasis. As the current data suggests the crucial role for the tumor microenvironment and metastatic niche in the disease progression, it is necessary to draw our full attention to all modes of crosstalk between the primary tumor and the distant tissue.
Who is a good fit for the project?
We expect the candidate to be interested in cancer, stem cell and molecular biology, with a particular attention to the molecular mechanisms behind cancer metastasis. Any experience in breast cancer research, hPSC and/or organoid biology, or sequencing-based experimental and computational techniques will be highly valuable.
IDIBAPS#1 – Developing and investigating computing, machine learning and physiological modelling for understanding each individual heart towards personalised medicineDavid Brena2022-05-17T10:37:53+00:00