Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies

Balanis, Nikolas G.; Sheu, Katherine M.; Esedebe, Favour N.; Patel, Saahil J.; Smith, Bryan; Park, Jung Wook; Alhani, Salwan; Gomperts, Brigitte N.; Huang, Jiaoti; Witte, Owen N.; Graeber, Thomas G.

doi:10.1016/j.ccell.2019.06.005

Cited by 129 publications

(145 citation statements)

References 78 publications

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“…Consistent with our findings, a recent study identified sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase in SCLC cells (53). A large meta-analysis of small cell neuroendocrine tumors also suggests susceptibility to disruption of lipid and sterol metabolism (54). Additional investigation into the latter will need to be performed to ascertain which of the many roles of the mevalonate pathway and its byproducts are truly critical in SCLC.…”

Section: Discussionsupporting

confidence: 87%

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

et al. 2020

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Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC. Significance: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.

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Section: Discussionsupporting

confidence: 87%

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

et al. 2020

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“…A recent study identified “SCLC-like” epithelial tumors in pan-cancer samples using a principal component analysis-based approach. They found that tumors across many lineages with a higher “SCLC-like” score had lower immune gene expression (49). We applied our NE scoring method across all cancer lineages (“pan-cancer” analysis) to compute NE scores and assess their relationship with immune phenotypes.…”

Section: Resultsmentioning

confidence: 99%

Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer

Cai

Liu

Huang

et al. 2020

Preprint

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Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed “variant” due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings provide a new framework to guide design of treatment regimens in SCLC.

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“…Its targets were opposing altered in inflamed TME in part of tumors( Figure.4C), including neurogenesis-related genes: CHRNB2, neuronatin (NNAT), neuronal pentraxin 1 (NPTX1), extracellular matrix organization: CAPN6, KRT6A; cellular traffic: KIF1A, SLC34A2( Figure.4A, D). These results revealed that miR-650 may be involved the formation of neuroendocrine phenotype of non-inflamed TME by inhibiting the expression of neurogenesisrelated genes [17].…”

Section: Figure3mentioning

confidence: 86%

Pan-cancer analysis identified inflamed microenvironment associated multi-omics signatures

Wang

Liu

Ran

et al. 2020

Preprint

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BackgroundImmunotherapy has revolutionized cancer therapy. However, responses are not universal. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, how different tumors shape their tumor microenvironment remains a critical unsolved problem. A deeper insight into the molecular characteristics of inflamed tumor microenvironment may be needed. Materials and methodsHere, based on single-cell RNA sequencing technology and TCGA pan-cancer cohort, we investigated multi-omics molecular features of tumor microenvironment phenotypes. Based on single-cell RNA-seq analysis, we classified pan-cancer tumor samples into inflamed or noninflamed tumor and identified molecular features of these tumors. Analysis of integrating identified gene signatures with a drug-genomic perturbation database identified multiple drugs which may be helpful for converting non-inflamed tumors to inflamed tumors. ResultsOur results revealed several inflamed/non-inflamed tumor microenvironments-specific molecular characteristics. For example, inflamed tumors highly expressed miR-650 and lncRNA including MIR155HG and LINC00426, these tumors showed activated cytokines-related signaling pathways. Interestingly, non-inflamed tumors tended to express several genes related to neurogenesis. Multiomics analysis demonstrated the neuro phenotype transformation may be induced by hypomethylated promoters of these genes and down-regulated miR-650. Drug discovery analysis revealed histone deacetylase inhibitors may be a potential choice for helping favorable tumor microenvironment phenotype transformation and aiding current immunotherapy. ConclusionOur results provide a comprehensive molecular-level understanding of tumor cell-immune cell interaction and may have profound clinical implications.

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Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies

Cited by 129 publications

References 78 publications

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer

Pan-cancer analysis identified inflamed microenvironment associated multi-omics signatures

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