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The Department of Biomedicine

CCBIO seminar: Kalle Sipilä

Integrative genomic and functional analysis of human primary oral SCC cells

Kalle Sipilä
Centre for Stem Cells and Regenerative Medicine, King's College London, UK

Oral squamous cell carcinoma (OSCC) is heterogeneous both at the cellular and genetic levels. A panel of HPV-negative OSCC cell lines was created by the Rheinwald-Green method in order to produce an in vitro model to study the questions arising from this heterogeneity. The mutational landscapes of the lines were generated by whole exome sequencing and the results demonstrated that the spectrum of genetic lesions in cell lines is representative of primary OSCC in The Cancer Genome Atlas. Among the findings, there was loss of function and truncation mutations in FAT1 (an atypical cadherin) and CASP8 (Caspase 8) that are incompletely characterized in OSCC. Decreased function of FAT1 and CASP8 in our OSCC cells led to increased cell migration and clonal growth as well as resistance to apoptosis.

High-throughput drug screening of OSCC cell lines revealed sensitivity of some cell lines to an HSP90 inhibitor that has been shown to elicit an effect by modulating the Hippo pathway. In another study performed in our lab, the hippo effector YAP was one of the most important growth regulators in squamous cell carcinoma cells. Inhibition of HSP90 reduced both growth and tumour metastasis in OSCC xenograft models.

The OSCC lines represent a useful resource for studying the impact of different mutations on cancer cell behavior. The future aim is to use this resource for linking drug sensitivity to genetic markers.


Selected references:

Hayes TF, Benaich N, Goldie SJ, Sipilä K, Ames-Draycott A, Cai W, Yin G, Watt FM (2016). Integrative genomic and functional analysis of human oral squamous cell carcinoma cell lines reveals synergistic effects of FAT1 and CASP8 inactivation. Cancer Lett. 383:106-14

Kilpinen H, Goncalves A, Leha A, Afzal V, Alasoo K, ... Watt FM, Durbin R, Stegle O, Gaffney DJ (2017). Common genetic variation drives molecular heterogeneity in human iPSCs. Nature. May 10. doi: 10.1038/nature22403

Walko G, Woodhouse S, Pisco AO, Rognoni E, Liakath-Ali K, Lichtenberger BM, Mishra A, Telerman SB, Viswanathan P, Logtenberg M, Renz LM, Donati G, Quist SR, Watt FM (2017). A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells. Nat Commun. 8:14744

Sipilä KH, Ranga V, Rappu P, Torittu A, Pirilä L, Käpylä J, Johnson MS, Larjava H, Heino J (2016). Extracellular citrullination inhibits the function of matrix associated TGF-beta. Matrix Biol. 55:77-79

Silberstein L, Goncalves KA, Kharchenko PV, Turcotte R, Kfoury Y, Mercier F, Baryawno N, Severe N, Bachand J, Spencer JA, Papazian A, Lee D, Chitteti BR, Srour EF, Hoggatt J, Tate T, Lo Celso C, Ono N, Nutt S, Heino J, Sipilä K, Shioda T, Osawa M, Lin CP, Hu GF, Scadden DT (2016). Proximity-Based differential single-cell analysis of the niche to identify stem/progenitor cell regulators. Cell Stem Cell. 19:530-43
 

Chairperson: Donald Gullberg <donald.gullberg@uib.no>, CCBIO