Melanoma evolution in the lymph node shapes systemic outcomes
- 1NYU Grossman School of Medicine
Abstract
Lymph node (LN) metastasis predicts poor patient outcomes, but the mechanistic drivers that shape metastatic fitness, immune evasion, and clinical impact remain elusive. While preclinical models indicate that active tumor adaptation is necessary for LN metastasis, observations of clonal heterogeneity in human tumors has supported a stochastic model of passive and continuous seeding. Reconciling LN metastasis as a passive or active process is essential to understanding if LN metastasis is simply a marker of disease progression or a clinically informative therapeutic target. Here, we report evidence that LNs are active niches that facilitate ongoing melanoma evolution to progressively subvert immune surveillance and enable progression. To construct a spatial trajectory of LN metastasis, we examined paired primary melanomas and metastatic sentinel LNs through integrated genomic, phenotypic, and immunologic analyses. In contrast to a model of continuous seeding, we observe that early dissemination from the primary tumor is followed by extensive intra-nodal diversification, indicating that metastatic outgrowth requires ongoing adaptation within the LN. As clones evolve in the LN, they re-differentiate towards a melanocytic state and reprogram the microenvironment for immune exclusion. In further evolved clones, loss of inflammatory interferon signaling and induction of p53 and mitochondrial stress are associated with decreased overall survival. Collectively, these results implicate the LN as a critical battleground for melanoma progression, where tumor evolution drives adaptation and immune escape to biologically link regional metastasis to patient survival.
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BibTeX
@misc{ventre2026melanoma,
title = {{Melanoma evolution in the lymph node shapes systemic outcomes}},
author = {K. S. Ventre and T. Muijlwijk and R. Stagnitta and S. Qiu and Z. Chen and I. Illa Bochaca and A. S. Moshiri and T. Davoli and I. Osman and I. Yanai and M. Schober and A. W. Lund},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751777},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751777v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Melanoma evolution in the lymph node shapes systemic outcomes
AU - K. S. Ventre
AU - T. Muijlwijk
AU - R. Stagnitta
AU - S. Qiu
AU - Z. Chen
AU - I. Illa Bochaca
AU - A. S. Moshiri
AU - T. Davoli
AU - I. Osman
AU - I. Yanai
AU - M. Schober
AU - A. W. Lund
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751777
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751777v1
AB - Lymph node (LN) metastasis predicts poor patient outcomes, but the mechanistic drivers that shape metastatic fitness, immune evasion, and clinical impact remain elusive. While preclinical models indicate that active tumor adaptation is necessary for LN metastasis, observations of clonal heterogeneity in human tumors has supported a stochastic model of passive and continuous seeding. Reconciling LN metastasis as a passive or active process is essential to understanding if LN metastasis is simply a marker of disease progression or a clinically informative therapeutic target. Here, we report evidence that LNs are active niches that facilitate ongoing melanoma evolution to progressively subvert immune surveillance and enable progression. To construct a spatial trajectory of LN metastasis, we examined paired primary melanomas and metastatic sentinel LNs through integrated genomic, phenotypic, and immunologic analyses. In contrast to a model of continuous seeding, we observe that early dissemination from the primary tumor is followed by extensive intra-nodal diversification, indicating that metastatic outgrowth requires ongoing adaptation within the LN. As clones evolve in the LN, they re-differentiate towards a melanocytic state and reprogram the microenvironment for immune exclusion. In further evolved clones, loss of inflammatory interferon signaling and induction of p53 and mitochondrial stress are associated with decreased overall survival. Collectively, these results implicate the LN as a critical battleground for melanoma progression, where tumor evolution drives adaptation and immune escape to biologically link regional metastasis to patient survival.
ER -