Patients diagnosed with advanced metastatic oral cancer have a 5-year survival rate of 30%. Although metastases are the main cause of cancer lethality, efficient treatments are still lacking (Ganesh & Massagué, 2021). Importantly, phenotypic plasticity markedly influences the metastatic progression, as it enables tumour cells to tolerate and adapt to several different stress factors and changing environments. Moreover, clonal heterogeneity accelerates metastasis dissemination by increasing the probability for invasive subclones. By exploiting the intratumoural heterogeneity of oral cancer cells (SAS), we recently identified the lymphocyte cell-specific protein-tyrosine kinase (LCK) as a driver of invasion and migration (Weiße et al., 2021). Importantly, inhibition of LCK induced cell differentiation and reduced the motility of high invasive SAS subclones. In order to further characterize the mechanisms of invasion and to identify the molecular targets of LCK, we analyzed the proteome, lipidome and metabolome of high and low invasive SAS clones. Intriguingly, key enzymes of the cholesterol synthesis pathway are downregulated in highly invasive clones. Additionally, we observed a switch from free fatty acids to carnitines and phospholipids and a loss of lipid storage capacity. Interestingly, PPARG, a key regulator of fatty acid metabolism, is strongly co-regulated with LCK. Inhibition of PPARG increases the lipid storage and reduces the motility of SAS cells, thereby presenting a potential link between LCK and the observed effects. Our work emphasizes fatty acid and membrane lipid reorganization as an important molecular mechanism involved in oral cancer cell plasticity and invasion into the surrounding tissue.