Selected Articles from This Issue

Abstract

Ceramide kinase (CERK) and its enzymatic product, ceramide-1-phosphate (C1P), have been implicated in oncogenesis, but molecular mechanisms underlying CERK/C1P-mediated oncogenesis have not been elucidated. While investigating CERK functionality in non–small cell lung cancer (NSCLC), Vu and colleagues discovered that CERK is more abundant in KRASG12 mutant NSCLC tumor samples. Further interrogation revealed that CERK inhibitor NVP-231 increases reactive oxygen species levels and ferroptotic cell death uniquely in KRASG12 mutant NSCLC cells. Accordingly, an in vivo model in which the authors used CRISPR/Cas9 to generate NSCLC cells with single CERK alleles demonstrated that limiting CERK abundance sensitizes KRASG12 mutant NSCLC cells to cisplatin. Voltage-dependent anion channel 1 (VDAC1) abrogation using siRNA reverses CERK inhibition-driven cytotoxicity and cisplatin sensitivity in vitro. Mechanistically, the authors found that CERK inhibition prevents AKT mitochondrial localization, reducing AKT-mediated VDAC1 phosphorylation and subsequent β-tubulin/VDAC1 interactions on mitochondrial outer membranes. Overall, this study demonstrates that KRASG12 mutant NSCLC survival is reliant on CERK, and that CERK dependence may be therapeutically targetable using existing chemotherapeutics.While increased Ecdysoneless (ECD) mRNA and protein abundance has been observed in breast cancer and other tumor types, molecular mechanisms by which ECD might promote breast cancer tumorigenesis have not been fully clarified. To query how ECD functions in breast cancer, Mohapatra and colleagues generated a mouse model in which an ECD transgene is overexpressed specifically in mammary epithelium (ECDTg). Mammary ECD overexpression produces mammary tumors with heterogeneous histological characteristics that occasionally metastasize to the lungs. Transcriptomic analyses of ECDTg and control tumors revealed that ECD overexpression enhances c-MYC transcriptional programming, particularly augmenting metabolic c-MYC target gene transcription. The authors demonstrated that ECD increases c-MYC abundance by facilitating c-MYC mRNA splicing and maturation. Furthermore, doxycycline disrupts ECD and c-MYC expression, unveiling a potential therapeutic vulnerability in ECD-overexpressing tumors. Taken together, this study defines novel, physiologically relevant ECD functions in mammary cancer and presents potential ECD-driven therapeutic targets.Small cell lung cancer (SCLC) is an aggressive disease for which current therapeutic options provide limited benefits, necessitating therapeutic target discovery. While it is known that MUC1-C facilitates tumorigenesis in several cancers, it has not been studied in SCLC. To assess the role of MUC1-C in SCLC, Fushimi and colleagues abrogated MUC1-C expression in classic, variant, and non-neuroendocrine SCLC cell lines using doxycycline-inducible shRNA and performed transcriptomic analyses. The authors found that MUC1-C enhances MYC transcriptional programming in each SCLC subtype. Further studies revealed that MUC1-C is required for MYC localization to the NOTCH2 promoter and enhancer, and that ablating MUC1-C or MYC expression decreases expression of NOTCH2 and master transcription factors that dictate SCLC subtypes. Genetic and pharmacological disruption of MUC1-C, as well as CRISPR-Cas9-mediated NOTCH2 elimination, inhibit SCLC cell tumorsphere formation in vitro and tumor growth in vivo, suggesting the MUC1-C/MYC/NOTCH2 axis drives stemness and tumor progression in SCLC. In sum, this study defines a novel, potentially therapeutically targetable molecular mechanism underlying SCLC tumor progression.Proteosome inhibitor bortezomib demonstrates effectiveness in many multiple myeloma patients upon initial treatment. However, patients often relapse after initial therapy and develop drug resistance. Previously, Shigeki Miyamoto's group discovered that bone marrow stromal cells (BMSC) produce cleaved forms of hyaluronan and proteoglycan link protein 1 (HAPLN1) that activate NF-κB to engender bortezomib resistance. How cleaved HAPLN1 matrikines are generated in multiple myeloma remains unknown. To test if BMSC-derived HAPLN matrikines might derive from proteolytic cleavage, Miyamoto and co-authors performed a qRT-PCR–based matrix metalloproteinase (MMP) screen in BMSC derived from healthy donors and multiple myeloma patients. The screen revealed heightened MMP2 expression in multiple myeloma patient BMSC, and gelatin zymography activity assays demonstrated increased MMP2 activity in multiple myeloma patient BMSC. Subsequent in vitro assays showed that MMP2 cleaves HAPLN1 into products similar in size to the previously discovered matrikines. Abrogating HAPLN1 and MMP2 expression via shRNA-expressing lentivirus transduction in multiple myeloma patient BMSC decreases NF-κB activation and fosters bortezomib sensitivity in multiple myeloma cells. Altogether, this study unveils a novel molecular mechanism by which BMSC support multiple myeloma cell bortezomib resistance.