Cell Competition Shapes Metastatic Latency and Relapse

Cell competition, a fi tness-sensing process, is essential for tissue homeostasis. Using cancer metastatic latency models, we show that cell competition results in the displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. A memodeled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by deplet-ing secreted protein and rich in cysteine (SPARC) reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC after extravasation in lung-resident Lat-M cells increased metastatic outgrowth. Furthermore, multiregional transcriptomic analyses of matched primary tumors and metachronous metastases from patients with kidney cancer identifi ed tumor subclones with Lat-M traits. Kidney cancer enriched for these Lat-M traits had a rapid onset of metachronous metastases and signifi cantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is the displacement of cells with Lat-M potential, thereby shaping metastatic latency and relapse.SIGNIFICANCE: We demonstrate that cell competition within the primary tumor results in the displace-ment of Lat-M cells. We further show the impact of altering cell competition dynamics on metastatic incidence that may guide strategies to limit metastatic recurrences.