Adipose tissue is contemplated as a dynamic organ that plays key roles in the human body. Adipogenesis is the process by which adipocytes develop from adipose-derived stem cells to form the adipose tissue. Adipose-derived stem cells’ differentiation serves well beyond the simple goal of producing new adipocytes. Indeed, with the current immense biotechnological advances, the most critical role of adipose-derived stem cells remains their tremendous potential in the field of regenerative medicine. This review focuses on examining the physiological importance of adipogenesis, the current approaches that are employed to model this tightly controlled phenomenon, and the crucial role of adipogenesis in elucidating the pathophysiology and potential treatment modalities of human diseases. The future of adipogenesis is centered around its crucial role in regenerative and personalized medicine.

Lung adenocarcinomas (LUADs) with somatic mutations in the KRAS oncogene comprise the most common molecular subtype of lung cancer in smokers and present with overall dismal prognosis and resistance to most therapies. Our group recently demonstrated that tobacco carcinogen-exposed mice with knockout of the airway lineage G-protein coupled receptor, Gprc5a , develop LUADs with somatic mutations in Kras . Earlier work has suggested that cancer stem cells (CSCs) play crucial roles in clonal evolution of tumors and in therapy resistance. To date, our understanding of CSCs in LUADs with somatic Kras mutations remains lagging. Here we derived CSCs (as spheres in 3D cultures) with self-renewal properties from a murine Kras -mutant LUAD cell line we previously established from a tobacco carcinogen-exposed Gprc5a −/− mouse. Using syngeneic Gprc5a −/− models, we found that these CSCs, compared to their parental isoforms, exhibited increased tumorigenic potential in vivo , particularly in female animals. Using whole-transcriptome sequencing coupled with pathways analysis and confirmatory PCR, we identified gene features ( n = 2,600) differentially expressed in the CSCs compared to parental cells and that were enriched with functional modules associated with an augmented malignant phenotype including stemness, tumor-promoting inflammation and anti-oxidant responses. Further, based on in silico predicted activation of GSK3β in CSCs, we found that tideglusib, an irreversible inhibitor of the kinase, exhibited marked anti-growth effects in the cultured CSCs. Our study underscores molecular cues in the pathogenesis of Kras -mutant LUAD and presents new models to study the evolution, and thus high-potential targets, of this aggressive malignancy.

: Stem cells are undifferentiated cells with the ability to proliferate and convert to different types of differentiated cells that make up the various tissues and organs in the body. They exist both in embryos as pluripotent stem cells that can differentiate into the three germ layers and as multipotent or unipotent stem cells in adult tissues to aid in repair and homeostasis. Perturbations in these cells’ normal functions can give rise to a wide variety of diseases. In this review, we discuss the origin of different stem cell types, their properties and characteristics, their role in tissue homeostasis, current research, and their potential applications in various life-threatening diseases. We focus on neural stem cells, their role in neurogenesis and how they can be exploited to treat diseases of the brain including neurodegenerative diseases and cancer. Next, we explore current research in induced pluripotent stem cell (iPSC) techniques and their clinical applications in regenerative and personalized medicine. Lastly, we tackle a special type of stem cells called cancer stem cells (CSCs) and how they can be responsible for therapy resistance and tumor recurrence and explore ways to target them.

Background Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among adult males globally. The poor prognosis of PCa is largely due to late diagnosis of the disease when it has already progressed to an advanced stage marked by androgen-independence, thus necessitating new strategies for early detection and treatment. We construe that these direly needed advances are limited by our poor understanding of early events in the progression of PCa and that would thus represent ideal targets for early intervention. To begin to fill this void, we interrogated molecular “oncophenotypes” that embody the transition of PCa from an androgen-dependent (AD) to–independent (AI) state. Methods To accomplish this aim, we used our previously established AD and AI murine PCa cell lines, PLum-AD and PLum-AI, respectively, which recapitulate primary and progressive PCa morphologically and molecularly. We statistically surveyed global gene expressions in these cell lines by microarray analysis. Differential profiles were functionally interrogated by pathways, gene set enrichment and topological gene network analyses. Results Gene expression analysis of PLum-AD and PLum-AI transcriptomes (n = 3 each), revealed 723 differentially expressed genes (392 upregulated and 331 downregulated) in PLum-AI compared to PLum-AD cells. Gene set analysis demonstrated enrichment of biological functions and pathways in PLum-AI cells that are central to tumor aggressiveness including cell migration and invasion facilitated by epithelial-to-mesenchymal transition (EMT). Further analysis demonstrated that the p38 mitogen-activated protein kinase (MAPK) was predicted to be significantly activated in the PLum-AI cells, whereas gene sets previously associated with favorable response to the p38 inhibitor SB203580 were attenuated (i.e., inversely enriched) in the PLum-AI cells, suggesting that these aggressive cells may be therapeutically vulnerable to p38 inhibition. Gene set and gene-network analysis also alluded to activation of other signaling networks particularly those associated with enhanced EMT, inflammation and immune function/response including, but not limited to Tnf , IL-6 , Mmp 2 , Ctgf , and Ptges . Accordingly, we chose SB203580 and IL-6 to validate their effect on PLum-AD and PLum-AI. Some of the common genes identified in the gene-network analysis were validated at the molecular and functional level. Additionally, the vulnerability to SB203580 and the effect of IL-6 were also validated on the stem/progenitor cell population using the sphere formation assay. Conclusions In summary, our study highlights pathways associated with an augmented malignant phenotype in AI cells and presents new high-potential targets to constrain the aggressive malignancy s...

Coronavirus disease 2019 (COVID-19) has infected millions of people worldwide and emerged to be the biggest global health threat claiming hundreds of thousands of lives at exponential rates. The severity of the disease increases with old age and presence of underlying health conditions, such as cancer. Managing cancer patients under these circumstances is rather challenging, given their compromised immunity and the overwhelmed health care services by COVID-19 community transmission. Thus, it is prudent to establish common guidelines for the monitoring and treatment of cancer patients. In this review, we comprehensively investigate the various aspects of cancer care during the COVID-19 pandemic, discuss challenges faced while treating cancer patients, and propose potential approaches to manage COVID-19 among this vulnerable population. We also discuss molecular aberrations and genetic changes associated with cancer and their role in affecting the virus' infectivity and severity. Lastly, we shed light on therapeutic approaches that can encompass both diseases without compromising one over the other.

Purpose: The dopamine D2-like receptors (DRD2) belong to the family of G-protein coupled receptors, which play crucial roles in various neurophysiological processes and in tumorigenesis. Several reports have described the role of DRD2 in cancer progression by influencing cellular invasion, migration, apoptosis and proliferation. Thereby, the pharmacological targeting of the DRD2 may serve as a potential therapeutic approach for cancer treatment. The imipridones ONC201 and ONC206 (Oncoceutics) are selective small molecule antagonists of DRD2 that inhibit Akt/Erk signaling pathway, and thus serve as promising anti-cancer agents for many tumors. Methods and Results: A MTT ([3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide]) cell growth assay was used to measure the in vitro anti-proliferative effects of ONC201 and ONC206 on different types of human cancer cells, namely HCT116 (colon), MCF7 (breast), UC6 (bladder), PC3 and DU145 (prostate). Cells were seeded 24 hours (h) before drug treatment, and then treated with either ONC201 or ONC206 at different concentrations ranging from 1 to 100 µM. Cell proliferation was measured at 24, 48 and 72 h post drug treatment. Our results show that both ONC201 and ONC206 had considerable, dose-dependent anti-proliferative effects on all the tested cell lines after three consecutive days of treatment. Furthermore, we assessed the effects of the two drugs on nervous system tumors, namely neuroblastoma (NB) and medulloblastoma (MB). Pediatric human NB cell lines (MYCN-amplified IMR-32 and the non MYCN-amplified SKNSH) exhibited a dose-dependent inhibition on cellular proliferation and increased apoptosis at 48 and 72 h after drug treatment. ONC206 was more potent than ONC201 at inhibiting cell proliferation in both cell lines. Cell migration was also inhibited with both drugs in the IMR-32 and SKNSH NB cell lines. Cell viability was assessed in human MB D556 and D283 cell lines, which was reduced at 48 and 74 h post treatment with both ONC201 and ONC206 compared to vehicle treated cells. Tumor-sphere formation efficiency was inhibited in a dose-dependent manner in both human NB (IMR-32 and SKNSH) and MB (D556 and D283) cells after treatment with either drug. Western blot analysis revealed differential protein expression of stem cell maintenance and tumorigenic proteins, including OCT-4, MYCN, L1-CAM, HSP90, FABP5, VEGFR2 and RAB5C after treatment with either ONC201 or ONC206. Conclusion: Our data show potent anti-stem cell maintenance as well as anti-proliferative, anti-migratory, anti-viability and pro-apoptotic activity of both ONC201 and ONC206 on cancer cell lines, with ONC206 showing greater potency than ONC201. Our future directions include utilizing a combinatorial multi-modality therapy to treat a panel of pediatric and adult neurological tumors with ONC 201/206 and other selective inhibitors of tumorigenic pathways to completely eliminate the highly resistant sub-population of cancer stem cells, and delay malignant recurrence. Citation Format: Reine Hanna, Reem Daouk, Farah Ballout, Sarra El-Soussie, Jad Abdallah, Wassim Abou-Kheir, Tamara Mary Abou-Antoun. Anti-cancer effects of novel imipridone DRD2 antagonists in a panel of human cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3797.

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