Cell Competition Shapes Metastatic Latency and Relapse

Abstract

Cell competition, a fitness sensing process is essential for tissue homeostasis. Employing cancer metastatic latency models, we show that cell competition results in displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. Remodelled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting SPARC reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC post-extravasation in lung resident Lat-M cells increased metastatic outgrowth. Furthermore, multi-regional transcriptomic analyses of matched primary tumors and metachronous metastases from kidney cancer patients identified tumor subclones with latent metastatic traits. Kidney cancer enriched for these latent metastatic traits had rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is displacement of cells with latent metastatic potential, thereby shaping metastatic latency and relapse.

ENO2 promotes anoikis resistance in anaplastic thyroid cancer by maintaining redox homeostasis

“…Once detached from the ECM, some cancer cells acquire resistance to anoikis, enabling their survival in blood and lymphatics vessels, thereby facilitating migration to new sites and subsequent metastasis ( 33 , 34 ). In the prevention of tumor metastasis, anoikis resistance represents a key factor contributing to treatment failure ( 35 ).…”

Development and validation of a novel anoikis-related gene signature for predicting prognosis in ovarian cancer

“…Inhibition of anoikis in TME may contributed to tumor migration and metastasis [38,39]. Anoikis resistance was found to be caused by multiple complex pathways [9,[40][41][42].…”

Metastatic cells exploit their stoichiometric niche in the network of cancer ecosystems

“…These modules were observed when primary tumors occur in organs with high cellular turnover (e.g., skin, stomach, small intestine, and lung), forming clusters with acceptor organs having lower cellular turnover but among the most metabolically active, such as the brain, thyroids, or adrenal glands (37). This pattern indicates potential drivers associated with cell proliferation, competition, and resource exploitation (29).…”

“…A network approach coupled with an ecological framework provides new insights into metastatic phenomena (74) by studying macroscopic attributes (nestedness, degree distribution, and modularity), which are common in other complex systems (75)(76)(77). Harnessing niche and stoichiometric ecological theories (19,29,32) show that the emerging macroscopic patterns of metastatic incidence result from local ecologies orchestrating the habitat suitability for metastatic spread. Thus, ecological analysis of individuals as ecosystems could be essential to understanding tumor biology, evolution, and clinical progression, providing a framework for potential therapeutic targets.…”

“…Cell proliferation is enhanced by redirecting P molecules to the synthesis of phosphatases and the overexpression of enzymes such as the reduced form of nicotinamide adenine dinucleotide phosphate oxidase (encoded by the NOX gene family), increasing the number of transporters and promoting angiogenesis ( 20 , 28 ). As the primary tumor grows, access to resources by tumor cells becomes increasingly nonuniform, exacerbating chemical gradients and competition between cells and potentially leading to dispersal ( 20 , 29 ). We hypothesize that competitive stresses lead to both a dispersive phenotype and the up-regulation of P metabolism for proliferation in the otherwise unfamiliar habitat at the acceptor organ site ( 30 ).…”