Niche-dependent epistasis within the cancer genome shapes metastatic fitness
- 1Department of Pathology, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Harold C. Simmons Comprehensive Cancer Center, Dallas, TX, 75390, USA
Abstract
Epistasis, the genetic interaction between loci, directs non-additive genotype-to-phenotype outcomes. Within a multicellular organism, how the tissue niche (E) shapes gene-by-gene epistasis (GxG) and its phenotypic consequences remains poorly studied. Using tumor lung metastasis as an experimental model, we mapped GxGxE through combinatorial CRISPR perturbation coupled with depletion of defined host myeloid populations in mice. The metastatic niche first selects disseminated tumor cells on GxG epistatic fitness, then drives transcriptome convergence regardless of genotype. Removing anatomically distinct myeloid populations reshaped the metastatic epistasis landscape despite identical tumor genotypes. Gene-by-gene-by-environment epistasis therefore operates at the organismal level, with interaction magnitude and sign set by niche cells. Beyond metastasis, our data suggest that the tissue niche conditions how genetic interactions translate into divergent phenotypes.
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BibTeX
@misc{liu2026nichedependent,
title = {{Niche-dependent epistasis within the cancer genome shapes metastatic fitness}},
author = {X. Liu and L. He and M. Zhao and S. M. Golomb and W. Ma and X. Yang and E. Aleksandrovic and H. M. Borges and K. M. Dean and L. Wang and G. C. Hon and D. Gan and H. Zhu and J. Li and L. Xu and S. Zhang},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.756296},
url = {https://www.biorxiv.org/content/10.64898/2026.10.02.756296v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Niche-dependent epistasis within the cancer genome shapes metastatic fitness
AU - X. Liu
AU - L. He
AU - M. Zhao
AU - S. M. Golomb
AU - W. Ma
AU - X. Yang
AU - E. Aleksandrovic
AU - H. M. Borges
AU - K. M. Dean
AU - L. Wang
AU - G. C. Hon
AU - D. Gan
AU - H. Zhu
AU - J. Li
AU - L. Xu
AU - S. Zhang
PY - 2026
DA - 2026/10/02
PB - bioRxiv
DO - 10.64898/2026.10.02.756296
UR - https://www.biorxiv.org/content/10.64898/2026.10.02.756296v1
AB - Epistasis, the genetic interaction between loci, directs non-additive genotype-to-phenotype outcomes. Within a multicellular organism, how the tissue niche (E) shapes gene-by-gene epistasis (GxG) and its phenotypic consequences remains poorly studied. Using tumor lung metastasis as an experimental model, we mapped GxGxE through combinatorial CRISPR perturbation coupled with depletion of defined host myeloid populations in mice. The metastatic niche first selects disseminated tumor cells on GxG epistatic fitness, then drives transcriptome convergence regardless of genotype. Removing anatomically distinct myeloid populations reshaped the metastatic epistasis landscape despite identical tumor genotypes. Gene-by-gene-by-environment epistasis therefore operates at the organismal level, with interaction magnitude and sign set by niche cells. Beyond metastasis, our data suggest that the tissue niche conditions how genetic interactions translate into divergent phenotypes.
ER -