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Holding hands: cell-cell junctions in breast cancer metastasis and resistance to therapy

Periodic Reporting for period 3 - HOLDING-HANDS (Holding hands: cell-cell junctions in breast cancer metastasis and resistance to therapy)

Reporting period: 2019-03-01 to 2020-08-31

(1) What is the problem/issue being addressed?

This project is focused on the issue of cancer metastasis development and maintenance. Specifically, we recently found that clusters of circulating tumor cells (CTC-clusters) are highly efficient metastatic effectors in breast cancer. Our project aims at finding methods to disrupt CTC-clusters and as a consequence, suppress the development of metastasis.

(2) Why is it important for society?

The development of cancer metastasis from various cancer types is responsible for more than 7 million deaths per year worldwide. Targeting CTC-clusters might reduce or suppress metastasis formation and be benefitial to patients with metastatic cancers.

(3) What are the overall objectives?

We aim to identify and target cell-cell junction components that are required for the formation and maintenance of CTC-clusters. We also aim at identifying FDA-approved compounds whose net effect is to disrupt CTC-clusters. Overall, our objectives are focused on the identification of a CTC-cluster-suppressing therapy.
The project is well underway and neither problems nor major deviations occurred in this first reporting period. Among the major achievements, we have generated and validated a shRNA library to knockdown a panel of cell-cell junction components as well as we have tested a collection of FDA-approved drugs to attempt CTC-clusters disruption in vitro and in vivo. In terms of specific cell-cell junction genes, we identified CLDN3 and CLDN4 as contributors to CTC-clustering. We also identified a number of FDA-approved drugs whose net effect is to disrupt CTC-clusters in culture without affecting proliferation or viability of CTCs, and their efficacy has also been confirmed in animal models of breast cancer. Cancer cells that were depleted in key cell-cell junction components or treated with clusters-targeting compounds were also processed for RNA-sequencing and bisulfite sequencing to assess their transcriptome and DNA-methylation status. This approach has already allowed us to demonstrate that CTC-cluster disruption alters the DNA methylation and RNA expression profile of CTCs, mostly suppressing their tumor seeding potential.
By the end of the project, we expect to identify key vulnerabilities of CTC-clusters and, more broadly, to identify new clusters-targeted therapies to implement in the clinical setting. We also aim to identify signaling pathways that contribute to CTC-clustering and metastasis.