Mentor Areas
- Cell migration/invasion
- Cytoskeleton
- Nucleus/Nucleoskeleton
- Mechanobiology
- Microfabrication/Microfluidics
Description:
General description of our research topics
The nucleus has been viewed as a passenger during cell migration that functions merely to protect the genome. However, increasing evidence shows that the nucleus is an active organelle, constantly sensing the surrounding environment and translating extracellular mechanical inputs into intracellular signaling.
My lab seeks to reconstitute the complex interface between mechanical and chemical signaling during cell migration in dense microenvironments and tissue crowding. We employ microfluidics, microfabrication and organ-on-a-chip devices to apply controlled and precise confinement to cells and mechanical stress to the nuclei. We combine these tools with diverse fluorescence microscopy techniques and live cell imaging to investigate how the tissue microenvironment regulates cell function through its impact on nuclear deformation and integrity.
Ultimately, our goal is to identify a signature of signaling pathways associated with nuclear mechanosensing in cells that experience confinement/mechanical stress. This signature will allow us to establish a link between different degrees of nuclear deformation and different cellular behaviors, from orchestrated signaling cascades to cellular perturbations and damage.
Ongoing Projects in the lab:
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.
Defining how nuclear confinement affects immune cell function
Nuclear mechanosensing tailors immune cell function. In particular, macrophages (MØs) represent a large population of immune cells within the tumor microenvironment (TME), and paracrine signaling by cancer cells can modulate MØ differentiation and function. While TME compressive forces trigger known nuclear mechanosensing pathways that affect cancer cell behavior, neither the indirect (via paracrine signaling by cancer cells) nor the direct impact of these forces on MØ function or on MØ crosstalk with cancer cells are known. We hypothesize that mechanical stress within the TME influences MØ transcriptional programs, function, and crosstalk with cancer cells by both direct nuclear mechanosensing imposed by the dense TME and by responding to signals from mechanically stressed cancer cells.
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 TME and the associated CAFs promote extreme nuclear deformations in crowded carcinomas, shaping cell behavior and tumor progression.
Preferred Qualifications
Students willing to do long (> 3 months) as opposed to short internships (10 weeks).
Project Website
Learn more about the researcher and/or the project here. https://www.naderlab.org/
Details:
Preferred Student Year
Junior, Senior
Academic Term
Summer, Fall, Spring
I prefer to have students start during the above term(s).Volunteer
Yes
Yes indicates that faculty are open to volunteers.Paid
No
Yes indicates that faculty are open to paying students they engage in their research, regardless of their work-study eligibility.Work Study
Yes
Yes indicates that faculty are open to hiring work-study-eligible students.