Abstract Therapy-induced senescence (TIS) occurs following cytotoxic stress and has previously shown to promote tumor metastasis through senescence-associated secretory phenotype (SASP) of stromal cells in the tumor microenvironment, however, whether senescent cancer cells directly participate in metastatic dissemination remains unclear. Here, we report that therapy-induced senescent breast cancer cells actively promote metastatic seeding by physically adhering to parental breast cancer cells and forming circulating senescent-parental cell clusters. Senescence was induced in MDA-MB-231 cells with doxorubicin (39 nM, 7 days) or in 4T1 cells via irradiation (50 Gy, 7 days) and confirmed by X-gal staining, NIR-BG2 senescence probe activity, and increased p16 and SASP expression. RNA-seq revealed upregulation of migration, motility, and adhesion pathways of senescence cells with specific increases in ICAM1, JUP, CLDN1, and CLDN7. Functionally, senescent cells were able to migrate independently, but the presence of both senescent and parental cells in co-culture significantly enhanced migration of both cell types in trans-well and wound healing assays. Hanging-drop aggregation produced large mixed clusters in co-culture, whereas parental cells alone formed scattered microcolonies. Direct adhesion assays showed parental tumor cells preferentially attached to senescent cells versus the substrate, with individual senescent cells binding multiple parental cells. In vivo, orthotopic co-injection of senescent and parental MDA-MB-231 cells in NSG mice resulted in significantly increased lung metastasis. Early tail-vain tracking revealed greater initial lung seeding when co-injected parental cancer cells with senescent MDA-MB-231 in NSG mice and 4T1 cells in NSG and BALB/c mice models, respectively. Interestingly, in immune competent BALB/c mice, metastatic progression sustained over time. These findings reveal a previously unrecognized mechanism in which senescent cancer cells cooperate with parental cancer cells through cell-cell adhesion mediated clustering to facilitate early metastatic colonization. Ongoing studies examine the functional role of ICAM1 and JUP, and the involvement of the immune system as a second phase of metastasis following dissemination, where senescent cells may reshape the microenvironment to promote tumor cells survival. These results suggest that targeting senescent cell adhesion and immune programs may suppress early dissemination and metastatic relapse following cancer therapy. Citation Format: Seyedehalaleh Anvar, Chandra Maharjan, Zixin Chen, Johnathan D Somers, Zeng Jin, Heather R Kates, Servio H. Ramirez, Allison M. Andrews, Breanna M. Runyon, Madison Elizabeth Carelock, Yuzhao Zhang, Jun Liu, Weizhou Zhang, Lina Cui. Senescent cancer cells facilitate metastasis by adhesion-mediated clustering and immune modulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4087.
Anvar et al. (Fri,) studied this question.