# Project 2: Mechanochemical Mechanisms and Vulnerabilities of Individual and Collective Organ-Preferential Metastasis In Vivo

> **NIH NIH U54** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $376,488

## Abstract

Project 2: SUMMARY
Organ colonization and survival of circulating tumor cells (CTCs) depends on a response program in tumor
cells (TCs), termed mechano-adaptation, to cope with mechanical and molecular stresses on the cytoplasm
and nucleus experienced during intravascular arrest and extravasation. The strength and duration of
mechanical stress differs in vascular beds among organs, such as liver and skin, and further differs between
individual-cell and collective organ colonization. Molecular systems implicated in the mechano-adaptation of
CTCs include coordinated cell-cell adhesions, cytoskeletal contractility, protease systems and deformation
or the nucleus, which cooperate to secure multistep movement into the secondary site and TC survival. We
hypothesize that successful metastasis in vivo depends on an adaptive interplay between the mechanical
and molecular intra- and perivascular stresses present at distant site and the coping ability of CTCs to
overcome these stresses. By coordinated cell-cell adhesion, cytoskeletal contractility, deformation of the
nucleus, and protease systems we predict that mechano-adaptation secures individual-cell and collective TC
survival and further mediates lasting reprogramming towards growth or dormancy. Consequently, we
anticipate that interfering with cell mechanical adaptation strategies will increase cell stress, support CTC
death and diminish metastatic organ colonization. By combining intravital microscopy in mouse models,
computational modeling (Core A) and transcriptomic and chromatin structure analyses (Core B), we will
address the rate-limiting steps of single-cell and collective organ colonization of triple-negative breast cancer
and melanoma cells to skin and liver. In Aim 1 we will examine the mechanisms of collective and single-cell
organ colonization and metastatic outcomes, by interfering with adherens junctions (p120-catenin) and
intravascular coagulation. In Aim 2, we will identify the rate-limiting steps of cytoskeletal and nuclear
mechanics and the ability to remodel the vascular wall during single-cell and collective organ colonization.
Targeted interference with CD44-mediated adhesion to perivascular substrate, actomyosin contractility,
nuclear deformability by lamin A/C expression variation and the ability to reorganize the basement membrane
will be performed. In Aim 3, we will identify the molecular responses underlying stress-induced mechano-
adaptation and associated effects on nuclear chromatin conformation, using transcriptomic and ultrastructural
analyses combined with computational modeling. Identified key pathways implicated in mediating mechano-
adaptation and TC survival, cell cycle arrest (dormancy) and outgrowth will be inhibited by combined
molecular interference to limit TC survival and both single-cell and collective metastasis. This project will
deliver an integrated view on cell migration, molecular reprogramming, fate decisions, and reveal potential
intervention points t...

## Key facts

- **NIH application ID:** 10271568
- **Project number:** 1U54CA261694-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Peter Friedl
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,488
- **Award type:** 1
- **Project period:** 2021-09-17 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271568

## Citation

> US National Institutes of Health, RePORTER application 10271568, Project 2: Mechanochemical Mechanisms and Vulnerabilities of Individual and Collective Organ-Preferential Metastasis In Vivo (1U54CA261694-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10271568. Licensed CC0.

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