Cancer cells reprogram their metabolism using different strategies to meet energy and anabolic demands to maintain growth and survival. Understanding the molecular and genetic determinants of these ...metabolic programs is critical to successfully exploit them for therapy. Here, we report that the oncogenic melanocyte lineage-specification transcription factor MITF drives PGC1α (PPARGC1A) overexpression in a subset of human melanomas and derived cell lines. Functionally, PGC1α positive melanoma cells exhibit increased mitochondrial energy metabolism and reactive oxygen species (ROS) detoxification capacities that enable survival under oxidative stress conditions. Conversely, PGC1α negative melanoma cells are more glycolytic and sensitive to ROS-inducing drugs. These results demonstrate that differences in PGC1α levels in melanoma tumors have a profound impact in their metabolism, biology, and drug sensitivity.
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► PGC1α is elevated in a subset of human melanoma tumors and derived cell lines ► PGC1α-positive melanoma cells exhibit increased mitochondrial metabolism ► PGC1α-positive melanoma cells exhibit increased ROS detoxification capacity ► PGC1α-negative melanoma cells are more glycolytic and sensitive to ROS-inducing drugs
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hematologic cancers that recur after allogeneic hematopoietic stem-cell transplantation are often difficult to treat. A small pilot study suggests that ipilimumab may induce durable responses in a ...subgroup of patients with these cancers.
Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only cure for many patients who have advanced hematologic cancers, principally through the induction of a graft-versus-tumor effect.
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Unfortunately, more than one third of patients who have undergone transplantation have a relapse of disease.
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The prognosis for these patients is poor; the majority die within 1 year after relapse despite salvage chemotherapy, donor-lymphocyte infusion, or retransplantation.
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Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role.
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The engagement of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed . . .
Hair graying is the most obvious sign of aging in humans, yet its mechanism is largely unknown. Here, we used melanocyte-tagged transgenic mice and aging human hair follicles to demonstrate that hair ...graying is caused by defective self-maintenance of melanocyte stem cells. This process is accelerated dramatically with Bcl2 deficiency, which causes selective apoptosis of melanocyte stem cells, but not of differentiated melanocytes, within the niche at their entry into the dormant state. Furthermore, physiologic aging of melanocyte stem cells was associated with ectopic pigmentation or differentiation within the niche, a process accelerated by mutation of the melanocyte master transcriptional regulator Mitf.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of ...effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis. Although metabolic reprogramming is tightly associated with tumour progression, ...the effect of metabolic regulatory circuits on metastatic processes is poorly understood. PGC1α is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress and reprograms melanoma metabolism to influence drug sensitivity and survival. Here, we provide data indicating that PGC1α suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1α expression inversely correlates with vertical growth in human melanoma specimens. PGC1α silencing makes poorly metastatic melanoma cells highly invasive and, conversely, PGC1α reconstitution suppresses metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1α levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1α directly increases transcription of ID2, which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 causes downregulation of metastasis-related genes, including integrins that are known to influence invasion and metastasis. Inhibition of BRAF
using vemurafenib, independently of its cytostatic effects, suppresses metastasis by acting on the PGC1α-ID2-TCF4-integrin axis. Together, our findings reveal that PGC1α maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel acting transcriptional programs. Consequently, components of these circuits define new therapeutic opportunities that may help to curb melanoma metastasis.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
UV-induced pigmentation (suntanning) requires induction of α-melanocyte-stimulating hormone (α-MSH) secretion by keratinocytes. α-MSH and other bioactive peptides are cleavage products of ...pro-opiomelanocortin (POMC). Here we provide biochemical and genetic evidence demonstrating that UV induction of POMC/MSH in skin is directly controlled by p53. Whereas p53 potently stimulates the POMC promoter in response to UV, the absence of p53, as in knockout mice, is associated with absence of the UV-tanning response. The same pathway produces β-endorphin, another POMC derivative, which potentially contributes to sun-seeking behaviors. Furthermore, several instances of UV-independent pathologic pigmentation are shown to involve p53 “mimicking” the tanning response. p53 thus functions as a sensor/effector for UV pigmentation, which is a nearly constant environmental exposure. Moreover, this pathway is activated in numerous conditions of pathologic pigmentation and thus mimics the tanning response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Skin neoplasms include the most common malignancies affecting humans. Many show an ultraviolet (UV)-induced pathogenesis and often affect the head and neck region.
To review literature on cutaneous ...neoplasms that show a predilection for the head and neck region and that are associated with molecular alterations.
Literature review.
Common nonmelanoma skin cancers, such as basal and squamous cell carcinomas, show a UV-induced pathogenesis. Basal cell carcinomas are characterized by molecular alterations of the Hedgehog pathway, affecting patched and smoothened genes. While squamous cell carcinomas show UV-induced mutations in several genes, driver mutations are only beginning to be identified. In addition, certain adnexal neoplasms also predominantly affect the head and neck region and show interesting, recently discovered molecular abnormalities, or are associated with hereditary conditions whose molecular genetic pathogenesis is well understood. Furthermore, recent advances have led to an increased understanding of the molecular pathogenesis of melanoma. Certain melanoma subtypes, such as lentigo maligna melanoma and desmoplastic melanoma, which are more often seen on the chronically sun-damaged skin of the head and neck, show differences in their molecular signature when compared to the other more common subtypes, such as superficial spreading melanoma, which are more prone to occur at sites with acute intermittent sun damage. In summary, molecular alterations in cutaneous neoplasms of the head and neck are often related to UV exposure. Their molecular footprint often reflects the histologic tumor type, and familiarity with these changes will be increasingly necessary for diagnostic and therapeutic considerations.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The LKB1-AMPK signaling pathway serves as a critical cellular sensor coupling energy homeostasis to cell growth, proliferation, and survival. However, how tumor cells suppress this signaling pathway ...to gain growth advantage under conditions of energy stress is largely unknown. Here, we show that AMPK activation is suppressed in melanoma cells with the B-RAF V600E mutation and that downregulation of B-RAF signaling activates AMPK. We find that in these cells LKB1 is phosphorylated by ERK and Rsk, two kinases downstream of B-RAF, and that this phosphorylation compromises the ability of LKB1 to bind and activate AMPK. Furthermore, expression of a phosphorylation-deficient mutant of LKB1 allows activation of AMPK and inhibits melanoma cell proliferation and anchorage-independent cell growth. Our findings provide a molecular linkage between the LKB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this “deterministic” ...hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic screen for enhancers of cell invasion, and (4) evidence of expression selection in human melanoma tissues. This integrated effort identified six genes that are potently proinvasive and oncogenic. Furthermore, we show that one such gene,
ACP5, confers spontaneous metastasis in vivo, engages a key pathway governing metastasis, and is prognostic in human primary melanomas.
► Integrates melanoma mouse models and human genomics data to derive cancer gene list ► Uses a function-based screening approach to identify oncogenic metastasis drivers ► Shows that ACP5 engages the FAK-signaling complex and is prognostic in melanoma ► Metastatic events present in early tumors can reflect their oncogenic capability
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In March of last year, Google's (Menlo Park, California) artificial intelligence (AI) computer program AlphaGo beat the best Go player in the world, 18-time champion Lee Se-dol, in a tournament, ...winning 4 of 5 games.1 At first glance this news would seem of little interest to a pathologist, or to anyone else for that matter. ''2 To beat Se-dol, Google's AlphaGo program used artificial neural networks that simulate mammalian neural architecture to study millions of game positions from expert human-played Go games. In a simple regression fit, we might determine a line that predicts an outcome y given an input x. With increased computational power, machine learning algorithms are able to fit a huge number of input variables (for example, moves in a game of Go) to determine a desired output (maximizing space gained on the Go board). On a practical level, there are financial barriers to incorporating slide scanners and computers into pathology workflow,6 although presumably hospitals would undertake these steps if computers could improve diagnostic accuracy or increase the efficiency of pathologists. Levenson et al10 showed that pigeons can be trained to distinguish malignant from benign breast tissue with 85% accuracy for individual birds and with an impressive 99% accuracy for a flock consensus. Currently, development of state-of-the-art computer vision algorithms requires millions of training images.11 For AlphaGo, it was feasible to generate millions of example games, but establishing a whole-slide image database of millions of images is currently not practical. Systematic analysis of breast cancer morphology uncovers...
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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