Leader Cells: Invade and Evade-The Frontline of Cancer Progression

Abstract

Metastasis is the leading cause of cancer-related mortality; however, a complete understanding of the molecular programs driving the metastatic cascade is lacking. Metastasis is dependent on collective invasion-a developmental process exploited by many epithelial cancers to establish secondary tumours and promote widespread disease. The key drivers of collective invasion are "Leader Cells", a functionally distinct subpopulation of cells that direct migration, cellular contractility, and lead trailing or follower cells. While a significant body of research has focused on leader cell biology in the traditional context of collective invasion, the influence of metastasis-promoting leader cells is an emerging area of study. This review provides insights into the expanded role of leader cells, detailing emerging evidence on the hybrid epithelial-mesenchymal transition (EMT) state and the phenotypical plasticity exhibited by leader cells. Additionally, we explore the role of leader cells in chemotherapeutic resistance and immune evasion, highlighting their potential as effective and diverse targets for novel cancer therapies.

Keywords: cancer; chemoresistance; collective invasion; keratin 14; leader cell; metastasis.

Figure 1

Leader cells drive collective cancer invasion. Leader cells (LC) at the front of multicellular cancer clusters drive collective invasion. LCs, characterised by front-rear polarity and protrusions such as invadopodia and filopodia, use αβ integrins to attach to the ECM and propel the cluster forward. Due to high energy demands, LCs exchange roles with adjacent FCs which in turn adopt the LC phenotype. Mitochondrial trafficking to invadopodia supports energy requirements. LCs enhance invasion by secreting LOXL3 for ECM stiffening, fibronectin for FAK phosphorylation, and proteases for ECM degradation. LCs also release VEGF-A to maintain cluster integrity and respond to chemokine gradients like SDF-1 through CXCR4. Figure components adapted from Servier Medical Art. MT1-MMP: Membrane type 1-matrix metalloproteinase, CXCR4: CXC-motif chemokine receptor 4, SDF-1: Stromal-derived factor-1, VEGF-A: Vascular endothelial growth factor A, FAK: Focal adhesion kinase, LOXL3: Lysyl oxidase-like 3, ECM: Extracellular matrix, KRT14: Keratin 14. Up arrow represents increased and down arrow represents decreased.

Figure 2

Influences of leader cells on immune subsets. Leader cells interact with immune subsets to promote tumour survival and metastasis. LCs secrete cytokines that can recruit immunosuppressive immune subsets such as TAMs, PMN-MDSCs, neutrophils, and monocytes into tumours coinciding with M2-polarisation of TAMs and impaired T cell proliferation and infiltration. LC-driven collective invasion is enhanced via cell surface CD200-CD200R engagement on TAMs or MDSCs which promotes secretion of cathepsin K to enhance ECM degradation, or, via TNFα-dependent inhibition of PD-L1 degradation in LCs which increases metastatic abilities. LC-directed accumulation of PMN-MDSCs in tumours increases cancer cell stemness and enhances metastasis. Cytotoxic immune subsets, such as NK cells, are also reprogrammed by LCs into a metastasis-supportive phenotype with reduced cytotoxicity. Figure components adapted from Servier Medical Art. BM: Bone marrow, IL-6: Interleukin-6, NO: Nitric oxide, PGE₂: Prostaglandin E2, G-CSF: Granulocyte colony-stimulating factor, LIF: Leukaemia inhibitory factor, TAM: Tumour-associated macrophage, TNFα: Tumour necrosis factor-alpha, PD-L1: Programmed death-ligand 1, PMN-MDSC: Polymorphonuclear myeloid-derived suppressor cells, CHI3L1: Chitinase-3-like protein 1, MMP-9: Matrix metalloproteinase-9, MDSC: Myeloid-derived suppressor cell, NK: Natural killer. Up arrow represents increased and down arrow represents decreased.