title: Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs).
abstract: Patients with breast cancer often develop malignant regrowth of residual drug-resistant dormant tumor cells years after primary treatment, a process defined as cancer relapse. Deciphering the causal basis of tumor dormancy therefore has obvious therapeutic significance. Because cancer cell behavior is strongly influenced by stromal cells, particularly the mesenchymal stem/stromal cells (MSCs) that are actively recruited into tumor-associated stroma, we assessed the impact of MSCs on breast cancer cell (BCC) dormancy. Using 3D cocultures to mimic the cellular interactions of an emerging tumor niche, we observed that MSCs sequentially surrounded the BCCs, promoted formation of cancer spheroids, and then were internalized/degraded through a process resembling the well-documented yet ill-defined clinical phenomenon of cancer cell cannibalism. This suspected feeding behavior was less appreciable in the presence of a rho kinase inhibitor and in 2D monolayer cocultures. Notably, cannibalism of MSCs enhanced survival of BCCs deprived of nutrients but suppressed their tumorigenicity, together suggesting the cancer cells entered dormancy. Transcriptome profiles revealed that the resulting BCCs acquired a unique molecular signature enriched in prosurvival factors and tumor suppressors, as well as inflammatory mediators that demarcate the secretome of senescent cells, also referred to as the senescence-associated secretory phenotype. Overall, our results provide intriguing evidence that cancer cells under duress enter dormancy after cannibalizing MSCs. Importantly, our practical 3D coculture model could provide a valuable tool to understand the antitumor activity of MSCs and cell cannibalism further, and therefore open new therapeutic avenues for the prevention of cancer recurrence.
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76502; Medical Physiology, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76504 bartosh@medicine.tamhsc.edu prockop@medicine.tamhsc.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bartosh
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76502.
authors.forename: Mujib
authors.initials: M
authors.lastname: Ullah
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76502.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Zeitouni
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76502; Medical Physiology, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76504.
authors.forename: Joshua
authors.initials: J
authors.lastname: Beaver
authors.affiliation: Institute for Regenerative Medicine, College of Medicine, Texas A&M University System Health Science Center, Temple, TX 76502; bartosh@medicine.tamhsc.edu prockop@medicine.tamhsc.edu.
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
mesh_terms: D000818:Animals; D015415:Biomarkers; D002450:Cell Communication; D045744:Cell Line, Tumor; D002470:Cell Survival; D016207:Cytokines; D057899:Cytophagocytosis; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D064593:Heterografts; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction; D018874:Spheroids, Cellular; D013312:Stress, Physiological; D014407:Tumor Cells, Cultured
chemical_list: D015415:Biomarkers; D016207:Cytokines
keywords: MSC; cancer; cannibalism; dormancy; inflammation