Skip to main content
Centre for Squamous Cancer
  1. Centre for Squamous Cancer
  2. Research themes
  3. Better treatments for advanced disease

Theme 3: Better treatments for advanced disease

Tumour metastasis, which seeds secondary tumours in distant organs, causes the majority of cancer deaths. Squamous cancers are often highly metastatic – for example, 30% of oral squamous cell carcinomas present with metastatic spread and there is a wide variation in survival depending on metastatic status. Five year overall survival has been put at 75% for node-negative patients, 50% for node-positive patients without extracapsular spread, and 30% for node-positive patients with extracapsular spread. Current therapeutic approaches (surgery, radiation, chemotherapy) have a low rate of success in metastatic disease and it is therefore vitally important that we identify better treatments for advanced disease.

  1. Targeting integrin avb6 for the therapy of squamous cancers (Marshall, O’Toole)

    The Marshall Lab and others has established that squamous cancers (especially of skin, mouth, oesophagus) express high levels (60-80%) of the integrin avb6 whereas the normal epithelial tissue expresses little or none. Moreover targeting avb6 suppresses squamous carcinoma invasion in vitro and cancer growth in vivo. In separate studies the Marshall lab have generated avb6-specific peptide-drug conjugates that effectively suppress growth and spread of avb6-positive cancers. These will be developed for therapy of avb6-positive squamous carcinomas. Additionally, the Marshall and O’Toole labs have strong data showing that avb6-promotes invasion and metastasis in part through de-regulation of the stromal matrix. These initial studies will be expanded to skin, oral and oesophageal cancers

  2. Identifying and manipulating molecular mechanisms controlling cancer stem cell metastatic potential (Biddle, Wang)

    Cancer stem cells (CSCs), the sub-population of tumour cells that possess tumour-initiating potential, can adopt phenotypes that drive tumour invasion and metastasis and express heightened resistance to therapy. Epithelial-to-mesenchymal transition (EMT), a developmental process in which epithelial cells acquire a migratory mesenchymal phenotype, is re-activated by CSCs to drive tumour invasion and migration to secondary sites. Mesenchymal-to-epithelial transition (MET), where migratory CSCs revert back to an epithelial phenotype, enables new tumour growth at metastatic sites. This pathological process is specific to cancer, and drives the metastasis of multiple different squamous cancer types. Therefore, it presents a promising target for development of drugs that can stop metastasis without damaging normal tissue. We have identified functional heterogeneity within the population of CSCs that have undergone EMT in OSCC, with only some of these EMT-CSCs retaining the potential to revert to an epithelial phenotype and thus seed new metastatic outgrowths (Biddle et al., 2011, Shigeishi et al., 2013). We have also demonstrated the important role of this EMT-CSC heterogeneity in tumour metastasis and therapeutic resistance (Biddle et al., 2016, Youssef et al., 2020). We now aim to use single cell RNAseq and CRISPR technology to identify and manipulate the molecular mechanisms controlling the functional status of CSCs, in order that we may therapeutically inhibit the phenotypic transitions that drive tumour metastasis. Using the CREATE lab, we are building metastasis-on-a-chip microfluidic devices that we will use to assess the effect of therapeutic interventions on metastasis of human squamous cancers.

  3. Understanding transcriptional addiction in squamous cancers (Walko)

    The path to a cancer cell involves genetic alterations that lead to changes in the cell’s gene expression programme. The dysregulated gene expression programme can create dependencies on transcriptional regulators that make the cancer cells more sensitive to inhibition of these regulators than normal cells. Our approach to understanding squamous cancer development and progression and to identifying therapeutic targets is to discover the key components on which dysregulated gene expression programmes depend in squamous cell carcinoma cells. Such transcriptional dependencies are not typically identified by cancer genome sequencing but arise through focused mechanistic studies of gene control programmes operating in both normal and neoplastic cells. Our current research focuses on the transcriptional regulators YAP and TAZ, which have emerged as essential drivers of tumour initiation and progression in various types of SCC (Howard et al. Exp. Dermatol. 2022). YAP/TAZ are largely dispensable for normal epithelial tissue homeostasis, pinpointing them as interesting candidates for effective treatments. Using state of the art proteomics and transcriptomics approaches and RNA interference and CRISPR/Cas9 technologies in combination with (i) conventional 2D cell culture techniques, (ii) 3D-organotypic SCC equivalents, and (iii) zebrafish xenograft SCC models, we are defining overlapping and non-redundant roles of YAP and TAZ in human SCC initiation and progression and are identifying the different transcriptional binding partners that enable YAP/TAZ to execute their various downstream transcriptional programmes.

Figure: Cells clustering at the interface between two channels in a metastasis-on-a-chip microfluidic device
Figure: Cells clustering at the interface between two channels in a metastasis-on-a-chip microfluidic device

BIDDLE, A., GAMMON, L., LIANG, X., COSTEA, D. E. & MACKENZIE, I. C. 2016. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. EBioMedicine, 4, 138-45.

BIDDLE, A., LIANG, X., GAMMON, L., FAZIL, B., HARPER, L. J., EMICH, H., COSTEA, D. E. & MACKENZIE, I. C. 2011. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res, 71, 5317-26.

Howard A, Bojko J, Flynn B, Bowen S, Jungwirth U, Walko G. Targeting the Hippo/YAP/TAZ signalling pathway: Novel opportunities for therapeutic interventions into skin cancers. Exp Dermatol. 2022 Oct;31(10):1477-1499. doi: 10.1111/exd.14655. Epub 2022 Aug 12. PMID: 35913427; PMCID: PMC9804452.

SHIGEISHI, H., BIDDLE, A., GAMMON, L., EMICH, H., RODINI, C. O., GEMENETZIDIS, E., FAZIL, B., SUGIYAMA, M., KAMATA, N. & MACKENZIE, I. C. 2013. Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3beta influenced by CD44 and RHAMM. Stem Cells, 31, 2073-83.

YOUSSEF, G., GAMMON, L., AMBLER, L., WICKER, B., PATEL, S., COTTOM, H., PIPER, K., MACKENZIE, I. C., PHILPOTT, M. P. & BIDDLE, A. 2020. Disseminating cells in human tumours acquire an EMT stem cell state that is predictive of metastasis. bioRxiv, 2020.04.07.029009.

Back to top