Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options.

As the largest organ of the human body, our skin serves as a physical barrier between the individual and the environment. The skin preserves body fluid, guards against irradiation and pathogens and conducts sensations. The epidermis is composed of several epithelial layers. The basal cells attach to the basement membrane above the dermis, joined by hemidesmosomes and adherens junctions, and are home to the epidermal stem cells (EpdSCs), which undergo long-term self-renewal and continuously fuel the upward flux of differentiating cells, forming the skin barrier. 1 EpdSC progenies transition through the multiple differentiated layers, starting with the suprabasal spinous layer, rich in desmosomes 2 ; then the granular layer, containing keratohyalin and lamellar granules; and finally the stratum corneum, composed of flattened denucleated corneocytes with heavily crosslinked keratin cables and a cornified envelope, eventually sloughed off the skin surface. 3 Connecting to the epidermis are many epidermal appendages, among which the most abundant are the sweat glands and the pilosebaceous units. Sweat glands are responsible for thermoregulation, 4,5 while the pilosebaceous unit is composed of

Accumulating evidence indicates a critical role of autophagy in regulating vascular smooth muscle cell (SMC) homeostasis in atherogenesis. However, little is known about the modulatory role of autophagy in PDGF-BB-induced SMC transition towards the synthetic phenotype and extracellular matrix remodeling. We recently demonstrated that acid sphingomyelinase (ASM, encoded by Smpd1 gene) controls autophagy maturation in coronary arterial SMCs. Here, we demonstrate that PDGF-BB stimulation causes a myofibroblast-like non-canonical synthetic phenotype transition in Smpd1−/− SMCs. These non-canonical phenotypic changes induced by PDGF-BB in Smpd1−/− SMCs were characterized by increased expression of fibroblast-specific protein (FSP-1), massive deposition of collagen type I, decreased cell size, elevated inflammatory status with enhanced cytokine release and adhesion molecule expression. Mechanistically, PDGF-BB induces prolonged Akt activation that causes decreased autophagosome biogenesis and thereby exaggerates p62/SQSTM1 accumulation in Smpd1−/− SMCs. More importantly, Akt inhibition or p62/SQSTM1 gene silencing attenuates PDGF-BB-induced phenotypic changes in Smpd1−/− SMCs. This first demonstration of a p62/SQSTM1-dependent myofibroblast-like phenotypic transition in Smpd1−/− SMCs suggests that ASM-mediated autophagy pathway contributes to maintaining the arterial smooth muscle homeostasis in situation of vascular remodeling during atherosclerosis.

Amitriptyline is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase (ASM). Amitriptyline is well known for its cardiovascular side effects and toxicity in psychiatric patients. However, the mechanisms underlying the cardiovascular side effects of amitriptyline remain largely undefined. This study aimed to determine the effects of amitriptyline on angiogenic capability of vascular endothelial cells in physiological settings and identify its mechanism of action.The ex vivo aortic ring angiogenesis and in vitro-cultured endothelial cell tube formation assay were used to assess the effects of amitriptyline on endothelial angiogenic capability. It was demonstrated that amitriptyline impaired the angiogenesis of aortic rings, which was similar to that found in aortic rings with haploinsufficiency of the ASM gene. In cultured mouse microvascular endothelial cells (MVECs), amitriptyline impaired the proliferation and tube formation under basal condition, which were accompanied by attenuated angiogenic signalling pathways such as endothelial nitric oxide synthase, Akt and Erk1/2 pathways. Mechanistically, amitriptyline inhibited autophagic flux without affecting autophagosome biogenesis at basal condition. ASM gene silencing or autophagy inhibition mimics the inhibitory effects of amitriptyline on endothelial cell proliferation and tube formation. Collectively, our data suggest that amitriptyline inhibits endothelial cell proliferation and angiogenesis via blockade of ASM-autophagic flux axis. It is implicated that the cardiovascular side effects of amitriptyline may be associated with its inhibitory action on physiological angiogenesis.

Stem cells are fundamental units of tissue remodeling whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward-stratifying progenies, skin relies on its secretory functions to form the outermost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. KLF5 binds to and transcriptionally regulates genes encoding rate-limiting sphingolipid metabolism enzymes. Remarkably, skin barrier defects elicited by KLF5 ablation can be rescued by dietary interventions. Finally, we found that KLF5 is widely suppressed in human diseases with disrupted epidermal secretion, and its regulation of sphingolipid metabolism is conserved in human skin. Altogether, we established KLF5 as a disease-relevant transcription factor governing sphingolipid metabolism and barrier function in the skin, likely representing a long-sought secretory lineage-defining factor across tissue types.