# Project 3: The Evolving Role of Regional Lymph Nodes in Melanoma Progression

> **NIH NIH U54** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $357,230

## Abstract

PROJECT 3 SUMMARY
Cancers commonly spread from their primary site and colonize regional lymph nodes (LNs), representing a
hallmark of progression and a key parameter for staging. The prognostic impact of LN metastasis and utility of
complete LN dissection in patients with micrometastatic LN disease, however, varies between solid tumor types
and patient subsets. The clinical observation that removal of micrometastatic LN disease does not by definition
improve survival has highlighted a gap in our understanding of regional LN metastasis and calls into question
the simple model of sequential metastasis. Given that LNs are both an early site of metastasis and immunological
organs, the interplay between dissemination and immunity may be critical to understanding how LNs impact
outcome. Here we will investigate the biology of tumor-draining LNs to ask whether regional draining LNs act as
an educational site that ultimately shifts the systemic macroenvironment to favor distant tumor outgrowth.
In this proposal we test the hypothesis that sentinel LNs undergo a cascade of cellular and molecular events
that prime the host to be receptive to tumor progression. To test this hypothesis, we will build an unbiased,
temporally, and spatially resolved map of regional draining LNs. This will enable us to identify clinically relevant
mechanisms that determine outcome by integrating a deep, mechanistic understanding of lymphatic and LN
biology together with high-dimensional imaging and novel, computational tools in mice and humans. To build
this map, we will leverage fresh frozen LNs from surgical cases, archived, FFPE matched primary and metastasis
pairs, and a clinically relevant mouse model, and determine the early changes that support tumor cell seeding
and the melanoma cell states that first arrive in LNs (Aim 1). We will further test causal programs, including type
I interferon signaling, that may functionally initiate this tumor permissive state and install local mechanisms of
adaptive immune suppression that limit systemic immune surveillance and thereby distant metastasis (Aim 2).
Finally, we will leverage the extensive resource and expertise of Core B to investigate the utility of immune
markers to stratify patient risk from archived sentinel LN tissue and thereby predict recurrence in Stage II and III
melanoma patients (Aim 3). The work we propose here promises to significantly reimagine the role of the sentinel
LN in systemic melanoma progression. This conceptual shift may inform personalized strategies to manage local
disease and thereby mobilize anti-tumor immunity and systemic tumor control across solid tumor types and
identify immune-based LN features to stratify risk for recurrence in melanoma and guide clinical care.
The resources and knowledge generated through this proposal will be made publicly accessible through NYULH
MetNet Center Cores B and C, which will enable extension of these observations to other solid tumor types (e.g.
breast cancer) ...

## Key facts

- **NIH application ID:** 10900749
- **Project number:** 5U54CA263001-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Amanda W. Lund
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,230
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900749

## Citation

> US National Institutes of Health, RePORTER application 10900749, Project 3: The Evolving Role of Regional Lymph Nodes in Melanoma Progression (5U54CA263001-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10900749. Licensed CC0.

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