Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin

Yang, Dian; Denny, Sarah K.; Greenside, Peyton G.; Chaikovsky, Andrea C.; Brady, Jennifer J.; Ouadah, Youcef; Granja, Jeffrey M.; Jahchan, Nadine S.; Lim, Jing Shan; Kwok, Shirley; Kong, Christina S.; Berghoff, Anna Sophie; Schmitt, Anna; Reinhardt, Hans Christian; Park, Kwon-Sik; Kundaje, Anshul; Greenleaf, William J.; Sage, Julien; Winslow, Monte M.

doi:10.1158/2159-8290.cd-17-0987

Cited by 129 publications

(157 citation statements)

References 61 publications

(92 reference statements)

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“…Thus, the gene expression programs controlling axonal growth in neuronal cells are also present in SCLC cells. We previously performed gene expression analyses on purified cancer cell from primary tumors and metastases from two mouse models of SCLC (Denny et al , 2016, Yang et al , 2018). In these studies, we found a general increase in the expression of neuronal gene expression programs during tumor progression.…”

Section: Resultsmentioning

confidence: 99%

“…Detailed methods for whole mount immunofluorescence staining have been described (Yang et al , 2018). Subcutaneous tumors with 5-10% GFP positive labeled cells mixed with non-GFP labeled SCLC tumor cells were dissected and were fixed in 4% paraformaldehyde and sectioned with a vibrating blade microtome at 500 µm thickness.…”

Section: Methodsmentioning

confidence: 99%

“…These genetically engineered mouse models recapitulate cancer progression in a controlled manner and allow for the isolation of primary tumors and metastases directly from their native microenvironment. Recently, we and others have used mouse models to uncover gene expression programs that are enriched in SCLC metastases (Denny et al , 2016, Semenova et al , 2016, Wu et al , 2016, Yang et al , 2018). While SCLC cells display features of neuroendocrine cells, the gene expression programs in metastatic SCLC include not only genes normally expressed in pulmonary neuroendocrine cells but also those expressed in neurons (Carney et al , 1982, Cutz, 1982, Broers et al , 1987, Anderson et al , 1988).…”

Section: Introductionmentioning

confidence: 99%

“…Higher levels of the neuronal markers such as NSE (neuron-specific enolase) correlate with shorter survival and more metastatic disease in SCLC patients (Carney et al , 1982, Dong et al , 2019, van Zandwijk et al , 1992). Broad neuronal gene expression programs are enriched in metastases from mouse models of SCLC, however, whether SCLC cells actually gain neuronal characteristics and whether neuronal features are key regulators of metastatic ability has not been previously characterized (Denny et al , 2016, Wu et al , 2016, Yang et al , 2018, Böttger et al , 2019).…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Cai

et al. 2019

Preprint

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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...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Yang

Cai

et al. 2019

Preprint

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“…Interestingly, the distal regions that became accessible upon NFIB upregulation were similar to open regions found in neural tissue. Recently, the same group described two metastatic models in SCLC, one dependent and other independent of NFIB amplification [59]. NFIB was likewise reported as amplified and/or overexpressed in melanoma [60], breast [61], oesophagus [62] and salivary gland malignancies [63].…”

Section: Nfibmentioning

confidence: 99%

Tumour Suppressor Genes with Oncogenic Roles in Lung Cancer

Barros-Filho¹,

Guisier²,

Rock³

et al. 2019

Genes and Cancer

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Lung cancer is one of the most common cancers and the leading cause of cancerrelated deaths worldwide. High-throughput sequencing efforts have uncovered the molecular heterogeneity of this disease, unveiling several genetic and epigenetic disruptions driving its development. Unlike oncogenes, tumour suppressor genes negatively regulate cell cycle control and exhibit loss-of-function alterations in cancer. Although tumour suppressor genes are more frequently disrupted, oncogenes are more likely to be drug-targeted. Many genes are described as presenting both tumour suppressive and oncogenic functions in different tumour types or even within the natural history of the disease in a single tumour. In this chapter, we describe current knowledge of tumour suppressor genes in lung tissues, focusing on tumour suppressor/oncogene duality.

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Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy

et al. 2021

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Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first-and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells or bronchioalveolar stem cells, but not basal cells or club cells of the trachea. It is also demonstrated that these clones are able to retain their epigenetic differences through passaging orthotopically in mice and crucially that they have distinct drug vulnerabilities. This work serves as a blueprint for exploring how epigenetics can be used to stratify patients for precision medicine decisions.

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Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin

Cited by 129 publications

References 61 publications

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

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

Tumour Suppressor Genes with Oncogenic Roles in Lung Cancer

Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy

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