Description of Research Expertise

Research Interests: Our research program focuses on elucidating how the cell nucleus affects cell function and fate as a consequence of different degrees of nuclear deformation observed during cell migration in complex microenvironments and tissue crowding.

Keywords: nuclear mechanosensing, DNA damage, cell migration, nuclear deformation, microfabrication.

Available Projects:

1-Testing for a link between nuclear rupture and the regulation of migratory strategies
 
As a postdoc, I identified TREX1 as the nuclease responsible for nuclear DNA damage following nuclear envelope (NE) rupture due to mechanical stress in dense tissues. TREX1 activity promoted invasiveness in cancer cells or senescence in healthy cells in vitro and in vivo. Nuclear stress and DNA damage are likely common consequences of cell growth in pathological scenarios such as a solid tumor or cell migration within dense tissues to execute physiological functions, such as interstitial leukocyte migration. We are interested in investigating the mechanisms orchestrating cell motility and invasion following events of NE stretch or in more extreme scenarios, NE rupture and chronic DNA damage. We would like to explore a potential link between changes in NE tension and the activation of signaling pathways that orchestrate different migratory strategies of cell collectives experiencing environmental physical constraints.

2-Defining the transcriptional program of confined cancer cells

Fragile mutant nuclei are associated with many degenerative diseases and often rupture spontaneously or in response to cytoskeletal forces such as in skeletal muscle. NE rupture also occurs in vivo in otherwise healthy cells that experience high mechanical stress, such as in the beating heart of embryos. We recently documented confinement-dependent NE ruptures both in vitro, using microfabricated and organ-on-a-chip devices that mimic in vivo environments, and in vivo in overcrowded solid tumors. These NE ruptures events led to TREX1 (a nuclease)-dependent DNA damage. We will perform bulk RNAseq analysis to evaluate the transcriptomic profiles and activated pathways of cancer cells that are subjected to sustained TREX1-dependent DNA damage. To exclude mRNAs that are upregulated by DNA damage independently of TREX1, we will compare transcriptional programs activated by NE rupture and by DNA damaging agents alone.

3-Mechanical regulation of cancer dissemination
 
Many factors promote the development of a stiff microenvironment in tumors by inducing changes in ECM architecture and composition. Excessive synthesis and deposition of matrix proteins, a hallmark of the carcinoma-associated stroma, is primarily mediated by cancer-associated fibroblasts (CAFs). CAFs are major components of the stroma surrounding carcinomas and are critical for tumor cell invasion by modifying the organization, stiffness and molecular composition of the ECM that surrounds cancer cells. Importantly, ECM stiffening increases tumor pressure. During tumor progression, CAFs form highly contractile intra-tumoral capsules that compress cancer cells and their nuclei. In our recent study, densely packed ductal carcinomas displayed nuclear deformation, rupture, and DNA damage. We are interested in studying whether the composition/architecture of the tumor microenvironment and the associated CAFs promote extreme nuclear deformations in crowded carcinomas, shaping cell behavior and tumor progression.

For more details: www.naderlab.org