Beyond Seed and Soil: A Bacterial-Passenger Framework for Organ-Tropic Breast Cancer Metastasis.

Breast cancer metastasis reflects both tumor cell heterogeneity and compatibility with distant organ microenvironments. Tumor-resident bacteria add a potential nongenetic layer to this process, but the strength of evidence varies substantially across proposed mechanisms. Here, we introduce the concept of a "bacterial passenger", which is operationally defined as a viable bacterium localized within, rather than merely adherent to, a tumor cell or circulating tumor cell during dissemination. Passenger status must be distinguished from nonviable microbial DNA, extracellular signals, and environmental or reagent contamination through viability-aware imaging, culture or functional assays, and matched strain-level evidence across primary tumors, circulating tumor cells, and metastases. The term describes physical codissemination and does not itself imply a causal effect. Breast cancer models show that intracellular bacteria can increase survival under fluid shear stress and metastatic colonization, yet direct evidence that they determine organ tropism, brain metastasis, or treatment resistance remains limited. We therefore present the seed-soil-passenger triad as a bacteria-centered, falsifiable extension of the seed-soil framework rather than a replacement. Its value lies in testable predictions about codissemination, organ-dependent effects, and stage-specific bacterial perturbation, coupled to rigorous low-biomass controls. Fungi and viruses are outside the present operational framework because comparable evidence for viable codissemination with breast cancer cells is not available.