# A Mechanoimmunological Basis for Metastatic Site Preference

> **NIH NIH F31** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $48,974

## Abstract

This proposal outlines a three-year training plan in cellular immunology and mechanobiology, offering the
applicant diverse expertise in these fields. The sponsor's laboratory excels in modeling immune responses in
relation to biophysical features of target cells, and the institutional strengths in immunology, mechanobiology,
and cell biology create an exceptional training environment conducive to success.
Metastasis occurs in a variety of organs with varying mechanical states. In recent years, the biophysical
properties of these microenvironments have emerged as an influencer of metastatic site preference (MSP) via
mutual biomechanical crosstalk where cancer cells mimic the stiffness of their environments’, otherwise known
as mechanoreciprocity. Our preliminary data has shown that cytotoxic lymphocytes, comprising of cytotoxic T
cells and natural killer cells, selectively destroy stiffer cancer cells during metastatic dissemination, a process
that we call mechanosurveillance. Our study combines biophysical measurements with in vivo models,
demonstrating that microenvironmental stiffness influences immune vulnerability, impacting the organ
distribution of metastatic outgrowth. In-depth analyses of metastatic cells from different organ sites, utilizing
atomic force microscopy and single-cell RNA sequencing, indicate that microenvironmental stiffness shapes
immune discrimination. Specifically, bone metastases exhibit increased stiffness, with the gene Spp1 playing a
role in maintaining this stiffness. Further studies using CRISPR-based knockout systems show that loss of
Spp1 softens cancer cells. This suggests mechanosurveillance targets stiff organ metastases, forming a
biophysical basis for metastatic site preference. Building on these preliminary observations we propose that
microenvironmental stiffness dictates the efficacy of mechanosurveillance and that this relationship shapes
both metastatic site preference and the power of anti-tumor immunotherapy. We will investigate this hypothesis
in two specific aims. Aim 1 employs in vivo mouse models to examine how distinct microenvironments affect
cancer cell mechanics, transcriptomics, and immune vulnerability. Specific genes, including Spp1, will be
manipulated to explore their role in mechanosurveillance. Aim 2 utilizes synthetic cancer cell niches to
investigate if environmental stiffness independently controls mechanosurveillance efficiency. The successful
completion of these aims could identify biomarkers guiding antitumor immunotherapy and inform novel
strategies for treating metastatic growth, advancing knowledge to enhance human health.

## Key facts

- **NIH application ID:** 10998481
- **Project number:** 1F31CA294974-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Yassmin Elbanna
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-06 → 2027-07-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998481

## Citation

> US National Institutes of Health, RePORTER application 10998481, A Mechanoimmunological Basis for Metastatic Site Preference (1F31CA294974-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10998481. Licensed CC0.

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