# How Circulating Melanoma Cells Usurp the Leukocyte Transmigration Mechanism for Successful Metastasis

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $417,398

## Abstract

Most deaths from solid tumors are due to metastases—cancer cells breaking off the primary tumor,
traveling to distant parts of the body and establishing new growths there. Patients with cancer shed millions of
circulating tumor cells (CTCs) into their bloodstream every day. There is a good deal known about how malignant
cells break away from the primary tumor and move through connective tissue into lymphatics and blood vessels.
Almost all CTCs die in the vasculature or are eliminated by the body’s inflammatory response. However, those
tumor cells that manage to extravasate out of the bloodstream and into tissues have the potential to grow as
metastatic colonies that spread the cancer far beyond the primary site. Unfortunately, there is almost nothing
known about this step. We have evidence that a substantial fraction of melanoma cells can cross blood vessels
using the same molecular machinery that white blood cells do.
 Leukocytes migrate across endothelial cells (EC) without increasing vascular permeability or inducing
tissue damage. They do this through a series of molecular interactions with molecules on the endothelial cells
that recruit membrane from a perijunctional organelle called the lateral border recycling compartment (LBRC).
Membrane from the LBRC increases the surface area of the junction allowing leukocytes to pass across without
harming the EC; the junction barriers remain tight and there is no exposure of the basement membrane. Our
preliminary data show that a major fraction (1/3 to ½ ) of melanoma cells can migrate across endothelial cells.
Moreover, we can selectively block their transmigration in vitro and in vivo using a novel cell-permeable inhibitor
of LBRC movement. Strikingly, the number of metastatic colonies that develop in mice treated with the inhibitor
is disproportionately lower than the degree to which extravasation is blocked. This suggests that those melanoma
cells that transmigrate using the LBRC have a survival advantage. We hypothesize that blocking recruitment of
the LBRC by melanoma cells would be an efficient way to block successful metastases. We will test our
hypothesis in mechanistic studies that determine the extent to which different driver mutations affect the ability
of melanoma cell lines and malignant melanoma cells derived from patients recruit the LBRC to transmigrate
(Aim I). We will use our novel selective inhibitor of LBRC movement to block metastases of murine melanomas
in syngeneic wild-type mice as well metastases from human patient-derived melanoma xenografts (PDX) in NSG
mice (Aim II). Melanomas do not express the molecules used by leukocytes to recruit the LBRC; Aim III will
determine the mechanisms used by tumor cells to recruit the LBRC. This will reveal therapeutic targets for
selectively blocking metastasis without inhibiting the immune response. Preliminary data show that inhibitors of
reactive oxygen species as well as endothelial EP4 receptors block melanoma transmigration in vitro...

## Key facts

- **NIH application ID:** 10380853
- **Project number:** 5R01CA236904-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** William A Muller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $417,398
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380853

## Citation

> US National Institutes of Health, RePORTER application 10380853, How Circulating Melanoma Cells Usurp the Leukocyte Transmigration Mechanism for Successful Metastasis (5R01CA236904-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380853. Licensed CC0.

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