Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer

Girard²,

Transl. Lung Cancer Res.

et al. 2018

184

224

Background: Small cell lung cancer (SCLC) is a deadly, high grade neuroendocrine (NE) tumor without recognized morphologic heterogeneity. However, over 30 years ago we described a SCLC subtype with "variant" morphology which did not express some NE markers and exhibited more aggressive growth. Methods:To quantitate NE properties of SCLCs, we developed a 50-gene expression-based NE score that could be applied to human SCLC tumors and cell lines, and genetically engineered mouse (GEM) models. We identified high and low NE subtypes of SCLC in all of our sample types, and characterized their properties. Results:We found that 16% of human SCLC tumors and 10% of SCLC cell lines were of the low NE

“…These included NFIB (74), SLFN11 (75,76), BCL2 (28), SOX2 and EZH2 (70,77). Figure 9 is a summary of the main differences between the NE high and low subtypes.…”

Section: Discussionmentioning

confidence: 99%

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

Girard²,

Transl. Lung Cancer Res.

et al. 2018

184

224

“…More generally, the transition from a neuroendocrine state to a state where neuroendocrine differentiation is decreased but neuronal differentiation is increased may be related to the exceptional plasticity of SCLC cells (reviewed in (Yuan et al , 2019)). Epithelial-to-mesenchymal transition (EMT) is thought to contribute to migration, metastasis, and resistance to treatment in many cancer contexts and may play a role in SCLC (Allison Stewart et al , 2017, Krohn et al , 2014, Canadas et al , 2014, O’Brien-Ball and Biddle, 2017, Singh and Settleman, 2010). Vascular mimicry (or epithelial-to-endothelial transition (EET) (Yuan et al , 2019)) may also contribute to tumor growth and response to treatment in SCLC (Williamson et al , 2016).…”

Section: Discussionmentioning

confidence: 99%

Axon-like protrusions promote small cell lung cancer migration and metastasis

Yang

Cai

et al. 2019

Preprint

14Metastasis is the main cause of death in cancer patients but remains a poorly understood 15 process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic types of 16 human cancer. SCLC cells normally express neuroendocrine and neuronal gene programs but 17 accumulating evidence indicates that these cancer cells become relatively more neuronal and less 18 neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human 19 SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The 20 formation of these protrusions is controlled by multiple neuronal factors implicated in 21 axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like 22 protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option 23 of developmental neuronal programs is a novel molecular and cellular mechanism that 24 contributes to the high metastatic ability of SCLC. 25 65 cells that have transitioned to a more neuronal cell state. 66 5 68 To investigate SCLC migration, we developed an assay in which SCLC cells, which 69 classically grow in culture as floating spheres or aggregates, are grown as a monolayer under 70 Matrigel ((Denny et al., 2016) and Methods). Unexpectedly, we noticed that cells from some 71 SCLC cell lines (N2N1G, 16T, 6PF) derived from the Rb f/f ;p53 f/f (DKO) and Rb f/f ;p53 f/f ;p130 f/f 72 (TKO) genetically engineered mouse models form long cellular protrusions into cell-free spaces 73 ( Figure 1A-B). To determine whether these structures specifically project into cell-free areas or 74 they also exist within monolayers, we cultured a minor fraction of fluorescently-labeled, RESULTS 67 SCLC cells can form long cellular protrusions in culture and in vivo 75GFP positive SCLC cells with control SCLC cells. We found that SCLC cells also form protrusions 76 when they are in close contact with surrounding cancer cells (Figure S1A). Similar mixing 77 experiments performed in subcutaneous allografts also documented the growth of protrusions by 78 SCLC cells in vivo (Figure 1C-D). Finally, similar structures also extend from SCLC micro-79 metastases in the liver in the autochthonous TKO mouse model and after intravenous 80 transplantations of SCLC cells (Figure S1B-C). 81Human SCLC patient-derived xenografts (PDXs) recapitulate many important features of the 82 human disease (e.g. (Gardner et al., 2017, Saunders et al., 2015). To label rare cancer cells 83 within human SCLC PDXs and identify whether they had protrusions in unperturbed tumors, we 84 used DiI tracing. DiI is a lipophilic dye that diffuses within cell membranes and has been widely 85 employed to label projections from individual neurons (Heilingoetter and Jensen, 2016, Mufson 86 et al., 1990). Protrusions from SCLC cells were easily identifiable in two out of three PDX 87 models ( Figure 1E-F). In the 2D monolayer culture system, not all human SCLC cell lines 88 formed protrusions, but NCI-H446 cells formed long protru...

“…Beyond BRCA1/2 mutations, various strategies are being explored to select patients who are likely to benefit from PARP inhibitors, such as molecular characterization of aberrations in DNA repair genes, 34 gene-expression signatures, 35 HDR score, 36 loss of heterozygosity scoring system, 37 prior sensitivity to platinum, 30 PARP1 expression, 38,39 SLFN11 expression, and epithelial-to-mesenchymal transition. 40 Broadly speaking, PARP1 expression is elevated in SCLC but only a subset respond to single-agent PARP inhibition. 16 On the basis of our experiments, Merkel cell carcinoma displays similar traits to SCLC, suggesting that better predictive markers and further testing, including PARP inhibitor combinations may enhance the effectiveness of single-agent PARP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Poly ADP‐ribose polymerase‐1 as a potential therapeutic target in Merkel cell carcinoma

Ferrarotto

Cardnell

et al. 2018

Head & Neck

Self Cite