Cell competition, a fitness-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 depleting 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 identified tumor subclones with Lat-M traits. Kidney cancer enriched for these Lat-M traits had a rapid onset of metachronous metastases and significantly 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 displacement 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. This article is highlighted in the In This Issue feature, p. 1

中文翻译：

---

细胞竞争影响转移潜伏期和复发

细胞竞争是一种适应度感知过程，对于组织稳态至关重要。使用癌症转移潜伏期模型，我们发现细胞竞争导致潜在转移（Lat-M）细胞从原发肿瘤中转移。Lat-M 细胞抵抗失巢凋亡并作为残留转移性疾病存活。模型化的细胞外基质促进 Lat-M 细胞在循环中的移位和存活。通过消耗富含半胱氨酸的分泌蛋白 (SPARC) 来破坏细胞竞争动态，减少原位肿瘤的移位并减弱转移。相比之下，肺驻留 Lat-M 细胞外渗后 SPARC 的耗尽会增加转移性生长。此外，对肾癌患者的匹配原发肿瘤和异时转移瘤进行多区域转录组分析，鉴定出具有 Lat-M 特征的肿瘤亚克隆。富含这些 Lat-M 特征的肾癌会迅速发生异时转移，并显着降低无病生存率。因此，细胞竞争的一个意想不到的结果是具有 Lat-M 电位的细胞被取代，从而形成转移潜伏期和复发。意义：我们证明原发肿瘤内的细胞竞争导致 Lat-M 细胞的移位。我们进一步展示了改变细胞竞争动态对转移发生率的影响，这可能指导限制转移复发的策略。这篇文章在本期特稿中重点介绍，第 17 页。1