Luana Tomaipitinca

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4−/− mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.

Background: Publicly available genomic and transcriptomic data in searchable databases allow researchers to investigate specific medical issues in thousands of patients. Many studies have highlighted the role lipids play in cancer initiation and progression and reported nutritional interventions aimed at improving prognosis and survival. Therefore, there is an increasing interest in the role that fat intake may play in cancer. It is known that there is a relationship between BMI and survival in patients with cancer, and that there is an association between a high-fat diet and increased cancer risk. In some cancers, such as colorectal cancer, obesity and high fat intake are known to increase the risk of cancer initiation and progression. On the contrary, in patients undergoing treatment for melanoma, a higher BMI unexpectedly acts as a protective factor rather than a risk factor; this phenomenon is known as the obesity paradox. Objective: We aimed to identify the molecular mechanism underlying the obesity paradox, with the expectation that this could indicate new effective strategies to reduce risk factors and improve protective approaches. Methods: In order to determine the genes potentially involved in this process, we investigated the expression values of lipid-related genes in patients with melanoma or colorectal cancer. We used available data from 2990 patients from 3 public databases (IST [In Silico Transcriptomics] Online, GEO [Gene Expression Omnibus], and Oncomine) in an analysis that involved 3 consecutive validation steps. Of this group, data from 1410 individuals were analyzed in the IST Online database (208 patients with melanoma and 147 healthy controls, as well as 991 patients with colorectal cancer and 64 healthy controls). In addition, 45 melanoma, 18 nevi, and 7 healthy skin biopsies were analyzed in another database, GEO, to validate the IST Online data. Finally, using the Oncomine database, 318 patients with melanoma (312 controls) and 435 patients with colorectal cancer (445 controls) were analyzed. Results: In the first and second database investigated (IST Online and GEO, respectively), patients with melanoma consistently showed significantly (P<.001) lower expression levels of 4 genes compared to healthy controls: CD36, MARCO, FABP4, and FABP7. This strong reduction was not observed in patients with colorectal cancer. An additional analysis was carried out on a DNA-TCGA data set from the Oncomine database, further validating CD36 and FABP4. Conclusions: The observed lower expression of genes such as CD36 and FABP4 in melanoma may reduce the cellular internalization of fat and therefore make patients with melanoma less sensitive to a high dietary fat intake, explaining in part the obesity paradox observed in patients with melanoma.

BACKGROUND Publicly available genomic and transcriptomic data in searchable databases allow researchers to investigate specific medical issues in thousands of patients. Many studies have highlighted the role lipids play in cancer initiation and progression and reported nutritional interventions aimed at improving prognosis and survival. Therefore, there is an increasing interest in the role that fat intake may play in cancer. It is known that there is a relationship between BMI and survival in patients with cancer, and that there is an association between a high-fat diet and increased cancer risk. In some cancers, such as colorectal cancer, obesity and high fat intake are known to increase the risk of cancer initiation and progression. On the contrary, in patients undergoing treatment for melanoma, a higher BMI unexpectedly acts as a protective factor rather than a risk factor; this phenomenon is known as the obesity paradox. OBJECTIVE We aimed to identify the molecular mechanism underlying the obesity paradox, with the expectation that this could indicate new effective strategies to reduce risk factors and improve protective approaches. METHODS In order to determine the genes potentially involved in this process, we investigated the expression values of lipid-related genes in patients with melanoma or colorectal cancer. We used available data from 2990 patients from 3 public databases (IST [In Silico Transcriptomics] Online, GEO [Gene Expression Omnibus], and Oncomine) in an analysis that involved 3 consecutive validation steps. Of this group, data from 1410 individuals were analyzed in the IST Online database (208 patients with melanoma and 147 healthy controls, as well as 991 patients with colorectal cancer and 64 healthy controls). In addition, 45 melanoma, 18 nevi, and 7 healthy skin biopsies were analyzed in another database, GEO, to validate the IST Online data. Finally, using the Oncomine database, 318 patients with melanoma (312 controls) and 435 patients with colorectal cancer (445 controls) were analyzed. RESULTS In the first and second database investigated (IST Online and GEO, respectively), patients with melanoma consistently showed significantly (P<.001) lower expression levels of 4 genes compared to healthy controls: CD36, MARCO, FABP4, and FABP7. This strong reduction was not observed in patients with colorectal cancer. An additional analysis was carried out on a DNA-TCGA data set from the Oncomine database, further validating CD36 and FABP4. CONCLUSIONS The observed lower expression of genes such as CD36 and FABP4 in melanoma may reduce the cellular internalization of fat and therefore make patients with melanoma less sensitive to a high dietary fat intake, explaining in part the obesity paradox observed in patients with melanoma.

Autophagy plays a role in several physiological and pathological processes as it controls the turnover rate of cellular components and influences cellular homeostasis. The liver plays a central role in controlling organisms’ metabolism, regulating glucose storage, plasma proteins and bile synthesis and the removal of toxic substances. Liver functions are particularly sensitive to autophagy modulation. In this review we summarize studies investigating how autophagy influences the hepatic metabolism, focusing on fat accumulation and lipids turnover. We also describe how autophagy affects bile production and the scavenger function within the complex homeostasis of the liver. We underline the role of hepatic autophagy in counteracting the metabolic syndrome and the associated cardiovascular risk. Finally, we highlight recent reports demonstrating how the autophagy occurring within the liver may affect skeletal muscle homeostasis as well as different extrahepatic solid tumors, such as melanoma.

Cancer stem cells (CSC) represent a key cellular subpopulation controlling biological features such as cancer progression in all cancer types. By using melanospheres established from human melanoma patients, we compared less differentiated melanosphere-derived CSC to differentiating melanosphere-derived cells. Increased lipid uptake was found in melanosphere-derived CSC vs. differentiating melanosphere-derived cells, paralleled by strong expression of lipogenic factors Sterol Regulatory Element-Binding Protein-1 (SREBP-1) and Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). An inverse relation between lipid-storing phenotype and autophagy was also found, since microtubule-associated protein 1A/1B-Light Chain 3 (LC3) lipidation is reduced in melanosphere-derived CSC. To investigate upstream autophagy regulators, Phospho-AMP activated Protein Kinase (P-AMPK) and Phospho-mammalian Target of Rapamycin (P-mTOR) were analyzed; lower P-AMPK and higher P-mTOR expression in melanosphere-derived CSC were found, thus explaining, at least in part, their lower autophagic activity. In addition, co-localization of LC3-stained autophagosome spots and perilipin-stained lipid droplets was demonstrated mainly in differentiating melanosphere-derived cells, further supporting the role of autophagy in lipid droplets clearance. The present manuscript demonstrates an inverse relationship between lipid-storing phenotype and melanoma stem cells differentiation, providing novel indications involving autophagy in melanoma stem cells biology.

GSK‐3 is a ubiquitously expressed serine/threonine kinase existing as GSK‐3α and GSK‐3β isoforms, both active under basal conditions and inactivated upon phosphorylation by different upstream kinases. Initially discovered as a regulator of glycogen synthesis, GSK‐3 is also involved in several signaling pathways controlling many different key functions. Here, we discuss recent advances regarding (i) GSK‐3 structure, function, regulation, and involvement in several cancers, including hepatocarcinoma, cholangiocarcinoma, breast cancer, prostate cancer, leukemia, and melanoma (active GSK‐3 has been shown to induce apoptosis in some cases or inhibit apoptosis in other cases and to induce cancer progression or inhibit tumor cell proliferation, suggesting that different GSK‐3 modulators may address different specific targets); (ii) GSK‐3 involvement in autophagy modulation, reviewing signaling pathways involved in neurodegenerative and liver diseases; (iii) GSK‐3 role in oxidative stress and autophagic cell death, focusing on liver injury; (iv) GSK‐3 as a possible therapeutic target of natural substances and synthetic inhibitors in many diseases; and (v) GSK‐3 role as modulator of mammalian aging, related to metabolic alterations characterizing senescent cells and age‐related diseases. Studies summarized here underline the GSK‐3 multifaceted role and indicate such kinase as a molecular target in different pathologies, including diseases associated with autophagy dysregulation.