Human head and neck cancer is a devastating disease with poor survival rates.
The molecular heterogeneity of the disease and the lack of laboratory models have hindered the development of improved treatment modalities for heterogeneous head and neck cancer patients.
We have recently discovered the genetic defects that trigger head and neck cancer development. These defects are also evident in subsets of human cancers. We are currently exploring novel treatment strategies aimed at targeting the genetic defects, and we expect that our findings will lead to new personalised therapies for head and neck cancer patients that are likely to improve their outcomes.
Squamous cell carcinoma (SCC)
SCC is the most common form of cancer in the world. It most frequently originates in sun-exposed skin, with two-thirds of Australians being diagnosed with skin cancer before the age of 70. However, SCC can also arise in many other tissues, including the head and neck, oesophagus, cervix, rectum and lung, where treatments are often ineffectual. Like most cancers, SCC results from a series of discrete, irreversible and sequential alterations in genes that control cell growth and squamous differentiation, together with genetic aberrations promoting invasion and metastasis. However, despite its prevalence, the molecular basis of SCC has remained poorly understood. This knowledge gap has been a major roadblock for the development of targeted therapeutic approaches.
Grainyhead-like 3 (GRHL3)
We have recently identified the GRHL3 gene as a critical tumour suppressor that is lost in more than 90 per cent of skin SCC and head and neck SCC (HNSCC). We have also identified two novel microRNA-21 (miR-21)-dependent proto-oncogenic networks that target GRHL3, underpinning SCC in both mice and humans. As a result, we now understand the signalling pathways activated by loss of GRHL3 in these cancers. Interestingly, the pathways differ, with skin SCC dependent on PI3K/AKT/mTOR signalling and HNSCC on GSK3B/c-MYC signalling, paving the way for targeted therapies in SCC of diverse tissue origins.
Stratification of therapies in HNSCC through discovery of molecular signatures
Our goal is scientific excellence in addressing how SCC cells suppress tumour suppressor genes to gain a potent proliferative advantage. In our research program, we are also working towards identifying the cell of origin of these cancers, characterising its molecular identity, and finding ways to prevent and treat the cancer. Our projects are inducing paradigm shifts in our understanding of the molecular basis for the prevention and treatment of SCC, and are particularly germane in the context of HNSCC resistant to standard treatment regimens.
The vast majority of HNSCC involves neoplastic lesions in the oral cavity, lip, pharynx and larynx. Our recent advances aim to increase the amounts of GRHL3 in these tissues to prevent SCC in high-risk patients, including smokers and heavy alcohol drinkers. In addition, the identification of distinct molecular signatures is serving as the forerunner to elucidate genetic changes that contribute to the evolution of neoplastic oral cells. We are also using this knowledge to pinpoint the cell of origin and its malignant progression, to ultimately develop innovative personalised therapeutic approaches for head and neck cancer patients.
Current research projects
- Development of genetically-defined and chemically-induced oral-specific in vivo models to study subsets of HNSCC.
- Genomic and proteomic approaches to decrypting human HNSCC.
- Analysis of the molecular mechanisms involved in the malignant reprogramming of oral epithelial cells into cancer-initiating cells.
- Pre-clinical evaluation of novel mechanism-based targeting for HSNCC prevention and treatment, with emphasis on miR-21 and the PI3K/AKT/mTOR and GSK3B/c-MYC pathways.
Darido C, Georgy SR, Jane SM (2016). The role of Barrier Genes in Epidermal Malignancy. Oncogene.35(44):5705-5712.
Mlacki M, Darido C, Jane SM, Wilanowski T (2014). Loss of Grainy head-like 1 is associated with disruption of the epidermal barrier and squamous cell carcinoma of the skin. PLoS One. 9(2):e89247.
Georgy SR, Cangkrama M, Srivastava S, Partridge D, Auden A, Dworkin S, McLean CA, Jane SM, Darido C (2015). Identification of a Novel Proto-oncogenic Network in Head and Neck Squamous Cell Carcinoma. J Natl Cancer Inst.107(9).
Darido C, Georgy SR, Wilanowski T, Dworkin S, Auden A, Zhao Q, Rank G, Srivastava S, Finlay MJ, Papenfuss AT, Pandolfi PP, Pearson RB, Jane SM (2011). Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis. Cancer Cell.20(5):635-48.
Caddy J, Wilanowski T, Darido C, Dworkin S, Ting SB, Zhao Q, Rank G, Auden A, Srivastava S, Papenfuss TA, Murdoch JN, Humbert PO, Parekh V, Boulos N, Weber T, Zuo J, Cunningham JM, Jane SM (2010). Epidermal wound repair is regulated by the planar cell polarity signaling pathway. Dev Cell.19(1):138-47.
Darido C, Buchert M, Pannequin J, Bastide P, Zalzali H, Mantamadiotis T, Bourgaux JF, Garambois V, Jay P, Blache P, Joubert D, Hollande F (2008). Defective claudin-7 regulation by Tcf-4 and Sox-9 disrupts the polarity and increases the tumorigenicity of colorectal cancer cells. Cancer Res.68(11):4258-68.