# Core1:  Computational

> **NIH NIH U54** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $308,862

## Abstract

Computational Core (Core A): SUMMARY
To guide and interpret the in vitro (Project 1) and in vivo experiments (Project 2) and to provide a physical basis
for changes in transcriptional patterns in response to mechanical stresses (Core B), this core will employ an
array of computational tools spanning a wide range of length and time scales. These include models for cell
adhesion, cytoskeletal function, cell-matrix interactions and 3D multiscale models for nuclear mechano-
transduction and chromatin organization. This suite of modeling tools will reveal non-linear interactions between
cell and nuclear deformation during of extravasation and migration, mechano-adaptation in response to fluid and
solid stresses, intravascular and extravascular niche properties and cell death for individual compared to
clustered CTCs. Significantly, modelling of 3D genome organization will allow us to elucidate the relationship
between the mechanics of the cell, chromatin organization, and transcription, thus providing new insights on how
mechanical stresses regulate gene expression during metastasis, and identification of reversible and persisting
chromatin deformation associates with cell survival or death.
Cancer cells invade individually or collectively, but the factors that govern their strategies to colonize the tissue
and their ability to survive intravascular stress and extravasation are poorly understood. While the coupling
between cell contractility, nuclear mechanotransduction, and adhesive interactions with the ECM and vessel wall
is known to affect cell adhesion and motility, the effects of this interplay on cell survival has yet to be rigorously
investigated. To elucidate the physical mechanisms involved in such regulation, we developed 3D chemo-
mechanical models to describe the three-way feedback between the adhesions, the cytoskeleton, and the
nucleus. The model shows local tensile stresses generated at the interface of the cell and the extracellular
environment regulate the properties of the nucleus, including nuclear morphology, levels of lamin A/C, histone
deacetylation and nucleo-cytoplasmic shuttling of YAP/TAZ, which in turn govern spatial chromatin organization,
gene expression and the ability of the cells to survive and cope with the mechanical stresses. Building on these
tools, the specific aims of this project are:
· Aim 1. Predict the role of vascular flow on tumor cell arrest and survival in the intravascular niche.
· Aim 2. Model the mechanochemical/molecular mechanisms of individual/collective extravasation
 of CTCs.
· Aim 3. Predict the influence of alterations in chromatin organization and transcriptional patterns
 induced by intravascular stress and extravasation on the survival and growth of migrating tumor
cells

## Key facts

- **NIH application ID:** 10271569
- **Project number:** 1U54CA261694-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Vivek Shenoy
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $308,862
- **Award type:** 1
- **Project period:** 2021-09-17 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271569

## Citation

> US National Institutes of Health, RePORTER application 10271569, Core1:  Computational (1U54CA261694-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271569. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*