Vahey, J. | Search bioRxiv

bioRxiv2026

Mapping breast cancer lineage in radiation and immunotherapy using the REMAP mouse

We present REMAP (Recording Evolution in Mammary tumors via Active PyMT), a lineage-tracing mouse model that integrates inducible CRISPR recording with the MMTV-PyMT model of hormone receptor-positive (HR+) breast cancer. Inducible Cas9 drives editing of MARC1 homing guide RNAs (hgRNAs), generating heritable lineage marks, and enables reconstruction of clonal relationships. Using REMAP, we profiled tumor evolution and response to radiation combined with anti-PD1 immunotherapy. Treatment reduced tumor burden locally and systemically, and single-cell RNA sequencing revealed remodeling of the tumor microenvironment (TME). We identified metastatic clones present across primary tumors and distant sites, which exhibited elevated epithelial-mesenchymal transition (EMT) programs as a heritable clonal state. Treatment reduced EMT-associated transcriptional programs and reshaped immune composition, with radiation driving clonal expansion of T cells and reduced repertoire diversity. In contrast, cancer-associated fibroblast clones spanned multiple transcriptional states, indicating substantial stromal plasticity. Together, REMAP enables high-resolution coupling of clonal history and cellular state in vivo, revealing that tumor progression, metastasis, and therapeutic response are governed by heritable lineage programs.

cancer biology↗

bioRxiv2022

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program

The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic change over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). The MVP was divided into five birth cohorts (N-range=123,888 [born from 1943-1947] to 136,699 [born from 1948-1953]). Groups of participants were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP+HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010<Cohens d<0.259, p<7.80x10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept=1.08{+/-}0.042). The 1kGP+HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction=0.045{+/-}0.007, p<0.05) confounding in the GWAS statistics. This study provides a comprehensive characterization of ancestry diversity of the MVP cohort over time and highlights that more refined modeling of genetic diversity (e.g., the 1kGP+HGDP-based ancestry assignment) can more accurately capture the polygenic architecture of traits and diseases that could be affected by population stratification.

genomics↗