DNA repair is a double-edged sword: it is essential for homeostasis in normal tissues, but limits the effectiveness of anticancer therapies. Research in this laboratory is addressing the major gap in our knowledge from two different angles - the nucleus and the extracellular matrix (ECM) - using 2D and 3D cell culture models, clinical samples, as well as newly developed 'breast-on-chip' devices that mimic tumors in mammary ducts.  Our long-term goal is to identify new avenues to potentiate genome maintenance in normal tissues and disrupt DNA repair in cancer cells.

Research Highlights

Cell-ECM Signaling and Genome Maintenance

a6/b4-integrins and are essential for cell survival. Using 3D cell culture models of breast epithelia, we found that a6/b4-integrin signaling enhances DNA repair. Hence, loss of cell-ECM contacts during malignant transformation may contribute to alter the DNA damage response and drive genomic instability.

In addition, retention of basement membrane signaling in populations of cancer cells may lead to radioresistance. Ongoing research is addressing the mechanisms downstream a6/b4-integrin that promote genome maintenance.

Nuclear Organization and DNA Repair

A second aspect of our research is to understand how signals from the cellular microenvironment are transduced at the level of the cell nucleus.

During cancer progression, loss of tissue architecture leads to dramatic changes in nuclear organization. For instance, the distribution of the structural nuclear protein NuMA is altered in cancer cells or upon blocking cell-ECM communication in pre-malignant cells. Mechanistically, we found that NuMA interacts with the chromatin remodeling factor SNF2h and mediates SNF2h accumulation at DNA breaks, thereby facilitating chromatin opening and DNA repair.

Follow-up studies are indicating that NuMA associates with additional DDR factors and that the protein may play a broader role in DNA repair.

Obesity and Breast Cancer

This line of research examines why obesity increases breast cancer risk. Clinical evidence suggests lower DNA repair activity in obese cancer patients compared to patients with a BMI below 25.

It is also known that the ECM is profoundly altered in obese contexts. We are mimicking lean and obese microenvironments with 3D culture systems to assess the impact of obesity on epithelial architecture and DNA repair efficacy, two major factors contributing to cancer risk.