**2.5 KRT14 is a reliable dynamic cancer LC marker**

KRT14 is a member of the intermediate filaments (IFs) and is generally expressed within the basal layer of epithelium to provide structural support [75]. In cancer cells, the direction of collective migration cell cluster movement and formation of protrusive structures are mediated via the interplay between the keratin IFs and cadherin [76]. Elevated expression of KRT14 has been identified in invasive LCs of breast [34], ovarian [37], bladder [49], and salivary adenoid cystic carcinoma (SACC) [77]. *In vitro* studies on KRT14 expressing LCs in OC demonstrated that spheroids generated from KRT14 depleted cells failed to maintain stable attachment with the mesothelial layer and to generate invasive protrusions [37]. RNA-sequencing revealed that the KRT14<sup>+</sup> breast cancer LCs show a significantly higher level of DSG3, encoding a major desmosomal protein, as well as gene

**143**

**Table 1.**

*Targeting Leader Cells in Ovarian Cancer as an Effective Therapeutic Option*

expression signatures associated with cell and matrix adhesion [34]. Desmosomes play a critical role in maintaining cell–cell adhesion throughout the collective movement via intracellular connection of keratin filaments in neighbouring cells [78, 79]. However, the exact mechanisms of KRT14 involvement in driving collective invasion remains unknown. It was hypothesised that keratin IFs may regulate focal adhesions via intertwined interactions with the AKT and integrin/focal adhesion kinase (FAK) pathways [80–83]. More specifically, KRT14 has been shown to stabilise hemidesmosomes by regulating the levels of integrin β4 on the surface of keratinocytes [80]. Furthermore, KRT14 can mediate the phosphorylation of desmosomal cell junctions via PKCα, which is important in regulating epithelial cell adhesion [81, 82]. These results suggest that the KRT14 expression in LCs can be a determining factor to maintain the integrity of the collective movement via cell–cell

**Study Model LC-specific** 

LCs

strands of a spheroid embedded in collagen matrix using a micromanipulator

metastatic cells followed by Fluidigm dynamic array experiments identified signatures of micrometastases.

DEGs comparing KRT14+

FCs

DEGs in the LCs isolated from a collectively invading spheroid

and transcriptomic signatures for LCs via parallel mutation and

micrometastases compared to the primary tumour.

LCs and

**signatures**

Differentiation Proliferation Dormancy exit

ECM proteins Immune system regulators Cell–cell and cellmatrix adhesion Regulators of the metastatic niche

Focal adhesion molecules RNA polymerase II transcription

Lung cancer VEGF signalling

Breast cancer Pro-metastatic

NSCLC collective

Breast cancer / PDX model

genes Matrix adhesion

movement Actin filament proteins Mitochondrial enzymes

Heat shock proteins Cytokeratins OXPHOS Mitochondrial electron transport Mitochondrial ribosomal genes

Rac Integrin β1 PI3K

Kidney epithelial

Breast cancer PDX model

Breast cancer cells/ PDX model

cells

*DOI: http://dx.doi.org/10.5772/intechopen.98689*

and cell-matrix adhesion [54, 83].

Yamaguchi et al. [43] LCs isolated from invasive

Lawson et al. [66] FACS-based isolation of single

Cheung et al. [33] RNA-sequencing identified 239

Konen et al. [62] SAGA identification of 788

model

Sonzogni et al. [50] RNA sequencing and secretome

Zoeller et al. [52] SAGA identification of genomic

Davis et al. [67] Single-cell RNA sequencing of

*Summary of studies investigating LCs profile.*

KRT14− FCs

analysis of KRT14+

RNA-seq analysis

and KRT14−

### *Targeting Leader Cells in Ovarian Cancer as an Effective Therapeutic Option DOI: http://dx.doi.org/10.5772/intechopen.98689*

expression signatures associated with cell and matrix adhesion [34]. Desmosomes play a critical role in maintaining cell–cell adhesion throughout the collective movement via intracellular connection of keratin filaments in neighbouring cells [78, 79]. However, the exact mechanisms of KRT14 involvement in driving collective invasion remains unknown. It was hypothesised that keratin IFs may regulate focal adhesions via intertwined interactions with the AKT and integrin/focal adhesion kinase (FAK) pathways [80–83]. More specifically, KRT14 has been shown to stabilise hemidesmosomes by regulating the levels of integrin β4 on the surface of keratinocytes [80]. Furthermore, KRT14 can mediate the phosphorylation of desmosomal cell junctions via PKCα, which is important in regulating epithelial cell adhesion [81, 82]. These results suggest that the KRT14 expression in LCs can be a determining factor to maintain the integrity of the collective movement via cell–cell and cell-matrix adhesion [54, 83].


### **Table 1.** *Summary of studies investigating LCs profile.*
