Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma

Among the numerous changes associated with the transformation to cancer, cellular metabolism is one of the first discovered and most prominent[[1][1], [2][2]]. However, despite the knowledge that nearly every cancer is associated with the strong upregulation of various metabolic pathways, there has yet to be much clinical progress on the treatment of cancer by targeting a single metabolic enzyme directly[[3][3]–[6][4]]. We previously showed that inhibition of glycolysis through lactate dehydrogenase (LDHA) deletion in cancer cells of origin had no effect on the initiation or progression of cutaneous squamous cell carcinoma[[7][5]], suggesting that these cancers are metabolically flexible enough to produce the necessary metabolites required for sustained growth in the absence of glycolysis. Here we focused on glutaminolysis, another metabolic pathway frequently implicated as important for tumorigenesis in correlative studies. We genetically blocked glutaminolysis through glutaminase (GLS) deletion in cancer cells of origin, and found that this had little effect on tumorigenesis, similar to what we previously showed for blocking glycolysis. Tumors with genetic deletion of glutaminolysis instead upregulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We also found that the metabolic flexibility observed upon inhibition of glycolysis or glutaminolysis is due to post-transcriptional changes in the levels of plasma membrane lactate and glutamine transporters. To define the limits of metabolic flexibility in cancer initiating hair follicle stem cells, we genetically blocked both glycolysis and glutaminolysis simultaneously and found that frank carcinoma was not compatible with abrogation of both of these carbon utilization pathways. These data point towards metabolic flexibility mediated by regulation of nutrient consumption, and suggest that treatment of cancer through metabolic manipulation will require multiple interventions on distinct pathways. ### Competing Interest Statement WEL and HC are founders, shareholders, and consultants for Pelage Pharmaceuticals, which develops drugs to promote hair growth. WEL is a founder and shareholder of Sardona Therapeutics, which creates therapies for the treatment of cancer. WEL is a founder and shareholder of Cellio Biotechnology, which specializes in cell-based therapeutics. None of the work described in this manuscript was supported by these companies. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-6 [5]: #ref-7