# Mechanisms associated with organotropic metastasis

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $510,140

## Abstract

ABSTRACT
Most cancer patients with solid tumors die of metastatic disease and organotropic spread is an understudied aspect
of metastasis, for which new insights are urgently required. The prevailing ‘seed and soil’ concept posits that
permissive environment in a distant organ (soil) is necessary to support the survival and growth of lurking tumor
cells (seeds). Induction of permissive soil in a non-metastatic organ is proposed to re-route metastasis; however,
rigorous experimental evidence and mechanistic analyses are lacking. Fibrotic tissue alterations, including
inflammation, provide cues for metastasis, together with the signals from bone marrow-derived cells (BMDCs),
the tumor secretome, and circulating extracellular vesicles. Our preliminary data suggest organotropic metastasis
is not solely dependent on permissive matrix remodeling and BMDCs in the secondary organs, but is also
contingent on the disruption of vascular endothelial barrier function imposed by organ-specific vascular junction
proteins. Our findings lead to a central hypothesis that ‘vascular heterogeneity functionally contributes to
organotropism of metastasis’. We propose studies to unravel the mechanisms, by which distinct fibrotic niches
effect organ-specific changes in the vascular beds, leading to organotropic metastasis. Preliminary studies
identified angiopoetin-2 (Ang-2) as a putative mediator of lung metastasis. We aim to unravel the mechanisms of
Ang-2 dependent tropism to the lung but not the kidney or liver, which also generate high Ang-2 levels in the
fibrotic setting. Using single-cell RNAseq and CyTOF, we will determine the cellular and molecular targets of
Ang-2 in the pre-metastatic milieu. Preliminary studies show Ang-2 induces vascular leakage in the lung
vasculature without impacting kidney or liver vessels, thus directing metastasis to the lung. Exosomes released
by the fibrotic organs also increase vascular permeability and metastatic colonization in the lung, without affecting
kidney or liver vasculature. Single-cell RNAseq of fibrotic organs, as well as genetically engineered mice
(GEMs), will be used to unravel the rate limiting effect of tissue-specific disruption of Ang-2 in breast cancer
metastasis. Using novel GEMs generated in the lab, we will trace lineage-specific production of metastasis-
inducing exosomes and identify the determinants of organotropism via proteomic analysis. Our preliminary
studies show Ang-2 disrupts vascular barriers through repression of claudin-5 that is found exclusively in the lung
vasculature, in contrast with the kidney and liver vessels, which present with multiple, redundant endothelial
claudins. Integrating mouse models with endothelial-specific deletion of claudin-5 and claudin-5 reporter mice,
and with molecular profiling of organ-specific endothelial cells in loss- and gain-of-function experiments, we will
elucidate functions of specific claudins in organotropic metastasis. Molecular studies will be performed t...

## Key facts

- **NIH application ID:** 10295926
- **Project number:** 1R01CA252729-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** RAGHU KALLURI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $510,140
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295926

## Citation

> US National Institutes of Health, RePORTER application 10295926, Mechanisms associated with organotropic metastasis (1R01CA252729-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10295926. Licensed CC0.

---

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