Pierre-Alexandre Vidi Laboratory
DNA repair is a double-edged sword: it is
essential for homeostasis in normal tissues, but limits the effectiveness of
the cellular microenvironment influence DNA repair? Research
in my laboratory is addressing this 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.
A Breast glandular unit (left)
and invasive ductal carcinoma (IDC, right) recapitulated in 3D cell culture.
B Normal breast tissue (left)
and IDC (right) stained with H&E.
C 'Breast-on-chip' device
recapitulating a cancer nodule (red) in the context of a mammary duct. The SEM
image shows a cross section of a hemichannel.
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.
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.
3) Obesity and
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.