RNA, tumor microenvironment and metastasis

Tumor-metastatic niche crosstalk

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 pre-metastatic niche. However, due to complicated detection and modeling of the (pre-)metastatic niche in mouse models, numerous events, particularly early in the metastatic cascade, remain yet to be elucidated.

Human pluripotent stem cell-derived organoids have recently emerged as powerful ex vivo systems to model human development and disease. Their cell type complexity, defined and scalable culture conditions, and genetic tractability offer substantial complementarity to available in vivo models. In our lab we use the established human lung organoid differentiation protocols to model lung (pre-)metastatic niche conditioning by breast cancer cells ex vivo. Our data, acquired using the state-of-the-art stem cell biology and genomics techniques, including at a single cell resolution, suggests that we can recapitulate multiple molecular events associated with breast cancer progression and metastasis to lungs, previously observed in mouse models and patient biopsies.

Les organoïdes pulmonaires dérivés des cellules souches humaines, au 50e jour de la culture.

Albertas Navickas

We are currently focusing on multiple mechanistic aspects of the systemic crosstalk between the metastatic niche and tumor cells, specifically from the perspective of the niche:

• identifying RNA regulatory networks as metastatic strategies in the niche. We have collected a large amount of multi-omics data and continue its integrative exploration aiming to better understand the dysfunctional gene regulation in the distant tissue before and upon the metastatic colonization.
• understanding the dynamics of lineage plasticity in the metastatic niche. We have observed that breast cancer cells impact the cell type composition of the growing lung organoids ex vivo. We are applying lineage tracing tools coupled to single cell RNA sequencing readout aiming to uncover the key plasticity events both in epithelial and mesenchymal lineages of the niche.
• dissecting the cell-extracellular matrix interactions in the metastatic niche. We used the niche labeling technique (described in Ombrato et al., 2019) to identify a population of cancer cell-adjacent fibroblasts ex vivo, activating an extracellular matrix (ECM) remodeling program. We are currently applying functional genomics techniques with a single cell readout aiming to identify the ECM sensors activated within this cancer associated fibroblast (CAF)-like population.