Abstract:
Most cancer-related deaths are caused by metastases, yet the mechanisms that promote metastatic dissemination are not fully defined. To identify mutational drivers of metastasis in skin cancer, we analyzed 41 metastatic cutaneous squamous cell carcinomas (cSCC) and patient-matched controls. 29% (12 of 41) of cSCC metastases but only 6% (4 of 61) of primary cSCC contained a recurrent somatic mutation in the 5’ untranslated region (UTR) of OXA1L, a nuclear gene encoding a mitochondrial protein. Examination of the originating primary tumor in the 29% of patients with metastatic cSCC identified the same OXA1L mutation, consistent with an early event in carcinogenesis. This 5’UTR mutation reduced OXA1L expression by decreasing mRNA stability and led to accelerated neoplastic invasion in organoids, as well as enhanced tumor growth and increased metastasis of OXA1L-mutant cells in vivo. Compared to wild type (WT) keratinocytes, isogenic OXA1L-mutant cells had decreased differentiation markers, increased stemness markers, and greater proliferative capacity. Targeted metabolomic profiling showed accumulation of fructose-1,6-bisphosphate (FBP) in OXA1L-mutant cells at ~50-fold higher levels than WT and this was confirmed using a fluorescent FBP biosensor. OXA1L mutagenesis also led to reduced aldolase activity, suggesting glucose flux constrained at this step may stimulate the pentose phosphate pathway. In line with this possibility, increased levels of reduced glutathione and a higher ratio over total glutathione were identified in OXA1L-mutant cells, suggesting greater capacity to buffer differentiation-promoting oxidative stress. Taken together, these findings indicate that mutation of OXA1L leads to metabolic reprogramming via aldolase suppression, which may underlie dedifferentiation and tumor metastasis in cSCC.
Audience Take Away Notes:
- Tumor metastasis has many potential mutational drivers, including the OXA1L UTR in cSCC.
- The regenerated human skin model, in vivo models, and cell-based assays are all methods that can be utilized to demonstrate cancer cell invasion, increased proliferation, and metabolic flux.
- The focus on cell energetics and metabolomic reprogramming as a phenotype of cSCC metastasis is applicable to different cancer types.
