**2.4 Cancer LCs have stem cell-like phenotype**

Cancer LCs play a critical role in early-stage invasion and tumour micrometastatic seeding [34, 35, 42, 66, 67]. Multiple studies investigating cancer micrometastasis in patient-derived-xenograft (PDX) models further characterised cancer LCs at a single cell level. A study by Lawson et al. analysing breast cancer PDX micrometastases by single cell sequencing demonstrated a distinct basal/stem-cell signature in early-stage metastatic cells [68]. This study demonstrated a distinctive molecular signature for low and high- burden metastatic tumours with elevated stem cell signatures and dormancy in low burden tumours and high proliferation and differentiation signatures in high-burden tumours [68]. Another study with the same approach for the analysis of breast cancer micrometastasis identified 330 differentially expressed genes. Among the genes significantly upregulated in the micrometastatic lesions were those encoding heat shock proteins HSPB1, HSPA8 and HSPE1 as well as cytokeratins KRT14, KRT16, KRT7 and KRT17 [69]. HSPB1 is involved in protein folding, apoptosis evasion and actin remodelling [70, 71], whereas KRT14 is a marker of invasion driving LCs in breast and ovarian cancer [34, 37]. This study also showed that mitochondrial oxidative phosphorylation (OXPHOS) was significantly up-regulated in metastatic cell seedings, suggesting a potential alternative metabolic pathway is utilised by the LCs to fuel the metastatic process [72–74].
