The advent of molecular targeted agents dramatically changed the treatment landscape of advanced melanoma. Nevertheless, melanoma cells adapt to the block of BRAF and MEK, becoming able to thrive even under pharmacological pressure. Thus, achieving a deeper understanding of the forces feeding therapeutic resistance to current pathway-focused inhibitors is of utmost importance. In the present study, we investigated how melanospheres react when exposed to routinely used molecularly targeted agents, namely the BRAF inhibitor vemurafenib and MEK inhibitor binimetinib. Overall, our findings indicate that: i) BRAF and MEK inhibitors are unable to eliminate MSCs, which however do not rely on AKT and/or ERK activation to endure vemurafenib- and binimetinib-induced death stimuli, ii) increased activity of SCD1, the rate-limiting enzyme in the formation of monounsaturated fatty acids, enables melanoma CSCs to survive BRAF and MEK inhibition, iii) this process is related to the control SCD1 operates on YAP/TAZ, and iv) pharmacological inhibition of SCD1, achieved with MF-438, selectively killed melanoma CSCs and partly restored sensitivity to the combination of vemurafenib and trametinib. To our knowledge, this is the first report describing the involvement of lipid metabolism in sustaining therapeutic resistance in melanoma CSCs. Moreover, data herein presented open up a novel therapeutic scenario, envisioning the inhibition of specific metabolic routes to erase melanoma-initiating cells. Moreover, SCD1 inhibition was found to selectively target cancer cells, while sparing non-transformed cells. This is of great relevance for therapeutic purposes, as the potential activity of SCD1 inhibition might not be counterbalanced by excessive side effects.
Metabolic reprogramming is considered a hallmark of cancer. Metabolic changes occurring upon malignant transformation are instrumental to cope with genetically deregulated proliferative signalling, and to withstand hostile environmental conditions such as hypoxia and low availability of nutrients. While glucose and glutamine pathway alterations have been recognized as central metabolic changes since the earliest biochemical studies, the contribution of lipids and cholesterol pathways is still underestimated. Nevertheless, as evidence accumulate, lipid reprogramming is gaining popularity given that alterations in lipid composition (e.g. content of saturated versus unsaturated fatty acids) is intimately tied to protein dynamics and membrane fluidity. In particular, monounsaturated fatty acids, derived from saturated fatty acids by the action of SCDs, have been associated with the acquisition of malignant features [
51,
52]. However, how lipid metabolism is concatenated with CSC fate remains un understudied domain of stem cell biology [
53]. Indeed, since the discovery of CSCs two decades ago, characterization efforts have mostly been oriented toward blocking the so-called stem cell pathways (e.g. Notch, Hedgehog, TGF-β), and to interfere with the molecular network deputed to protect their genome in the attempt of reverting chemo-resistance [
54]. Even though the study of lipid metabolism in CSC is still in its infancy, recent studies are beginning to shed light on a novel regulatory force [
55]. Parallel with the appreciation of metabolic avenues that operate in CSCs, the inhibition of specific metabolic functions has been proposed for therapeutic purposes. For instance, activation of the mevalonate pathway, which is responsible for the synthesis of cholesterol, has been found to endow breast cancer cells with stem cell traits [
56]. Consistently, the targeting of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate cascade, achieved with cholesterol-lowering agents (statins), resulted effective against breast cancer stem cells. Regarding SCD1, previous studies pointed to SCD1 activity as a novel player involved in maintaining stemness in ovarian and lung cancer cells [
26‐
31]. Our study adds a further piece to the puzzle, providing a nexus between lipid alterations, stem cell pathway (YAP/TAZ) and targeted therapy resistance at the CSC level. We envision that two major questions should deserve increased attention in future studies attempting to delineate the metabolic landscape of CSCs, and its connection with therapeutic resistance. First, the metabolic demand of CSCs plausibly varies in relation to the switch from quiescence to proliferation and vice versa, thus adding an element of dynamicity that deserves tailored investigations. Second, the molecular output of lipid reprogramming is still unclear. Even though pioneering studies are beginning to connect lipid metabolism to CSCs via intermediate molecular cascades (e.g. the Hippo pathway), we foresee the existence of a broader network of canonical signal transduction pathways whose activity, and consequent impact on CSC properties, can be tuned by alterations in lipid content.