Identification of ALDH1A3 as a Viable Therapeutic Target in Breast Cancer Metastasis-Initiating Cells

The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates; however, this has failed to positively affect the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers, CD44 or Vimentin) were compared in tumors derived from BM, lung metastases (LM), or bone metastases (BoM) of patients as well as mice after injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small-molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment

PROSES ADAPTASI DAN MEKANISME KOPING PASIEN KANKER PARU MENURUT TEORI CALLISTA ROY : Adaptation Process and Coping Mechanisms of Lung Cancer Patients According to Callista Roy’s Theory in Salatiga, Central Java

Pendahuluan Penderita kanker paru dapat mengalami masalah psikologis saat menghadapi penyakitnya dan stres yang berkepanjangan dapat menyebabkan penurunan kemampuan fungsi, koping, kecemasan dan mempengaruhi kualitas hidupnya. Model Adaptasi Callista Roy adalah model perawatan yang menjelaskan bagaimana orang dapat meningkatkan kesehatan mereka dengan mempertahankan perilaku adaptif dan mengubah perilaku yang maladaptif. Penelitian ini bertujuan untuk mengetahui dan mendeskripsikan proses adaptasi dan mekanisme koping pada pasien kanker paru berdasarkan teori Callista Roy di RS Paru dr. Ario Wirawan Salatiga, Jawa Tengah. Metode: penelitian ini menggunakan pendekatan kualitatif deskriptif  melalui teknik wawancara mendalam dan terstruktur dengan partisipan serta menggunakan instrumen panduan wawancara. Partisipan dalam penelitian ini berjenis kelamin laki-laki dengan jumlah tiga orang. Hasil penelitian menunjukkan bahwa partisipan dapat menerima keberadaan diri terhadap penyakit, rutin melakukan pengobatan di rumah dan di rumah sakit serta mendapatkan dukungan positif dari keluarga dan masyarakat. Kesimpulan: proses adaptasi yang dilakukan partisipan terhadap penyakit kanker paru memunculkan mekanisme koping adaptif dimana ketiga partisipan dapat menerima keberadaan diri terhadap penyakit, rutin melakukan pengobatan, serta mendapatkan dukungan positif dari keluarga maupun masyarakat berupa doa dan semangat

Multi-kinase inhibitor c1 triggers mitotic catastrophe of glioma stem cells mainly through melk kinase inhibition

Glioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as a therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Previously, we identified that the mitotic kinase maternal embryonic leucine-zipper kinase (MELK) is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we demonstrate evidence that the role of MELK in the GSC survival is specifically dependent on its kinase activity. With in silico structure-based analysis for protein-compound interaction, we identified the small molecule Compound 1 (C1) is predicted to bind to the kinase-active site of MELK protein. Elimination of MELK kinase activity was confirmed by in vitro kinase assay in nano-molar concentrations. When patient-derived GSCs were treated with C1, they underwent mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed with shRNA-mediated MELK knockdown. In addition, C1 treatment strongly induced tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuated growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors. © 2014 Minata et

Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors

Aggressive cancers such as glioblastoma (GBM) contain intermingled apoptotic cells adjacent to proliferating tumor cells. Nonetheless, intercellular signaling between apoptotic and surviving cancer cells remain elusive. In this study, we demonstrate that apoptotic GBM cells paradoxically promote proliferation and therapy resistance of surviving tumor cells by secreting apoptotic extracellular vesicles (apoEVs) enriched with various components of spliceosomes. apoEVs alter RNA splicing in recipient cells, thereby promoting their therapy resistance and aggressive migratory phenotype. Mechanistically, we identified RBM11 as a representative splicing factor that is upregulated in tumors after therapy and shed in extracellular vesicles upon induction of apoptosis. Once internalized in recipient cells, exogenous RBM11 switches splicing of MDM4 and Cyclin D1 toward the expression of more oncogenic isoforms. © 2018 Elsevier Inc.Pavlyukov et al. show that apoptotic GBM cells secrete vesicles enriched with components of spliceosomes to alter RNA splicing in surviving tumor cells and promote their aggressiveness. They identify RBM11 as one such factor that switches MDM4 and cyclinD1 toward the more oncogenic isoforms in recipient cells