# Project 1: Tumor Cell Intrinsic Determinants of Early Dissemination in Melanoma

> **NIH NIH U54** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $314,862

## Abstract

PROJECT 1 SUMMARY
Increasing data suggest that phenotypic and transcriptional plasticity are important features that contribute to
metastatic progression, tropism, and response to therapy of cancer cells. We and others have provided
compelling evidence that intratumoral heterogeneity exists in primary melanomas, suggesting it is an early
feature important for tumorigenesis. Further, recent reports demonstrate that melanoma cells can switch
between phenotypic states, some of which are associated with more aggressive biology, implicating
transcriptional plasticity in this phenotypic variation. However, the evolution of tumor cell intrinsic features
associated with melanoma progression remains largely uncharacterized. The studies that have evaluated
transcriptomic and epigenetic features involved in melanoma metastasis have typically focused on individual
molecular features restricted to a specific cell population, and have fallen short of integrating the metastatic
process as a whole. We hypothesize that emergence of transcriptional heterogeneity that gives rise to distinct
cell states in primary cutaneous melanoma is a critical step driving early metastatic dissemination, and that cells
with a specific transcriptional program harbor the bulk of metastatic potential. The goal of Project 1 is to
investigate the timing and function of molecular drivers of metastasis, the emergence and evolution of
transcriptional heterogeneity and metastatic trajectories of cell states. We will do this in novel genetically
engineered mouse models that reflect human disease as well as in clinically annotated patient samples. Using
an innovative approach that integrates genetic bar coding, single cell RNA sequencing, spatial transcriptomics,
and highly-multiplexed immunohistochemistry, we will assess the presence of specific transcriptional cell states
within murine and human primary melanomas, and assess their influence on metastatic potential using animal
models and statistical correlates to known patient outcomes (Aim 1). We will then study the mechanisms driving
these transcriptional cell states by testing the contribution of individual candidate genes to their emergence and
maintenance and their impact on metastatic potential (Aim 2).
This research project will leverage the pathological, technological, and analytical resources of Cores B and C.
Integration with Projects 2 and 3 will dissect the evolving, bidirectional crosstalk between melanoma cells and
their microenvironment that culminates in a metastasizing tumor. Understanding the contribution of specific cell
states and the molecular programs underlying early dissemination can improve our ability to subclassify patients
diagnosed with primary melanoma by their risk of metastasis and identify those patients who could benefit most
from increased surveillance or adjuvant therapies. Our studies might also provide a rationale for novel
therapeutic approaches to prevent or target metastasis. Finally, findings from...

## Key facts

- **NIH application ID:** 10900744
- **Project number:** 5U54CA263001-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Eva Hernando
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $314,862
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900744

## Citation

> US National Institutes of Health, RePORTER application 10900744, Project 1: Tumor Cell Intrinsic Determinants of Early Dissemination in Melanoma (5U54CA263001-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10900744. Licensed CC0.

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