# Rewiring Cancer-Induced Abnormalities in the Vascular Barrier

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $502,563

## Abstract

Summary
Tumors are known to induce the formation of unique microenvironments in distant organs that
facilitate seeding, survival, and growth of metastatic nodules. These sites, known as pre-
metastatic niches, emerge as a response to the combined systemic effects of tumor-derived
factors and shed extracellular vesicles. Aside from premetastatic niches, distant alterations in
otherwise normal tissues of cancer-bearing subjects have not been identified. While evaluating
the systemic vasculature of tumor-bearing mice, we serendipitously found that presence of
certain types of carcinomas implanted subcutaneously have a deleterious effect on intestinal
lymphatics and blood vessels. This surprising finding was directly correlated with severe weight
loss and progressive reduction of skeletal muscle mass, a condition known as cachexia.
Importantly, in cancer patients, cachexia has a meaningful negative impact in their ability to
respond and recover from therapy and thus identification of individuals at risk and effective
treatments to reverse this condition are imperative. Blocking cachexia offers not only a
significant improvement in the quality of life for these patients, but it also improves tolerance
and response to cancer treatment, with measurable increase in survival rates. Although the
clinical consequences of cachexia and its positive response to therapy are well known, read-
outs for early diagnosis and effective treatment remain challenging. Our preliminary findings
uncovered that tumors with high circulating levels of specific inflammatory cytokines induced
vascular and lymphatic barrier dysfunction in the intestine. In particular, the capillaries and
central lymphatic lacteal of intestinal villi showed prolonged and exacerbated levels of
VEGFR2/3 signaling, TAK1 phosphorylation and other alterations that yield compromised
junctional complexes. In turn, we documented changes in food absorption despite unaltered
levels of food consumption and associated weight loss. Collectively, the findings indicate that
cancer-induced alterations in the vasculo-lymphatic compartment of intestinal villi contribute
to, and perhaps trigger, the development of cachexia by affecting their ability to absorb lipids.
The goal of this project is to determine whether deficiencies in lymphatic and vascular
endothelium are a significant underlying cause of cancer-induced cachexia that can be targeted
to reverse the condition. Our two progued approach will delve into further understanding of
the underlying molecular mechanisms while pursuing pre-clinical trials in mouse models to test
therapeutic avenues aimed at correcting the vascular deficiencies. The contribution of the
vasculature as an important culprit in cachexia has not been recognized and it could be
transformative as it may offer an unprecedented opportunity for intervention at early stages by
focusing on rewiring endothelial barrier and blocking this devastating condition.

## Key facts

- **NIH application ID:** 10802955
- **Project number:** 1R01CA279689-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** M. LUISA IRUELA-ARISPE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $502,563
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802955

## Citation

> US National Institutes of Health, RePORTER application 10802955, Rewiring Cancer-Induced Abnormalities in the Vascular Barrier (1R01CA279689-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10802955. Licensed CC0.

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