Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung

Sutherland, Kate D.; Proost, Natalie; Brouns, Inge; Adriaensen, Dirk; Song, Ji‐Ying; Berns, Anton

doi:10.1016/j.ccr.2011.04.019

Cited by 418 publications

(421 citation statements)

References 43 publications

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“…4K). These observations confirm and extend previous reports (12)(13)(14)(15) suggesting that PNECs can be the cells of origin for SCLC, offering insight into the complex interactions between tumor suppressors in tumor development.…”

Section: Pulmonary Neuroendocrine Cells Have Very Limited Potential Tosupporting

confidence: 91%

“…Ade-CGRP-Cre is expressed in PNECs as well as in a small number of Clara cells and ciliated cells (13). Importantly, these mouse models recapitulate critical aspects of human SCLC.…”

Section: Discussionmentioning

confidence: 91%

“…Mouse models of SCLC have been reported in which tumor suppressors p53 and Rb are inactivated in the lung epithelium via intrabronchial injection of adenoviral Cre (12) or an adenovirus (Ade-CGRP-Cre) in which a ∼2-kb rat CGRP promoter was used to drive Cre expression (13). Ade-CGRP-Cre is expressed in PNECs as well as in a small number of Clara cells and ciliated cells (13).…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps the most important clinical connection comes from the observation that characteristic markers of PNECs are frequently expressed in human small-cell lung cancer (SCLC), a highly aggressive form of lung cancer related to cigarette smoking (11). This finding led to the speculation that PNECs could be the cells of origin for SCLC, an idea that has been supported by mouse studies (12)(13)(14)(15). Despite this insight, the ability to reliably trace the early events that underlie changes in PNEC behavior and their progression toward tumor development in a defined genetic setting has not been achieved.…”

mentioning

confidence: 99%

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Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Song

Yao

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

247

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Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanisms underlying them have been elucidated. Importantly, PNECs have long been speculated to constitute the cells of origin of human small-cell lung cancer (SCLC) and recent mouse models support this hypothesis. However, a genetic system that permits tracing the early events of PNEC transformation has not been available. To address these key issues, we developed a genetic tool in mice by introducing a fusion protein of Cre recombinase and estrogen receptor (CreER) into the calcitonin gene-related peptide (CGRP) locus that encodes a major peptide in PNECs. The CGRP CreER mouse line has enabled us to manipulate gene activity in PNECs. Lineage tracing using this tool revealed the plasticity of PNECs. PNECs can be colabeled with alveolar cells during lung development, and following lung injury, PNECs can contribute to Clara cells and ciliated cells. Contrary to the current model, we observed that elimination of PNECs has no apparent consequence on Clara cell recovery. We also created mouse models of SCLC in which CGRP CreER was used to ablate multiple tumor suppressors in PNECs that were simultaneously labeled for following their fate. Our findings suggest that SCLC can originate from differentiated PNECs. Together, these studies provide unique insight into PNEC lineage and function and establish the foundation of investigating how PNECs contribute to lung homeostasis, injury/repair, and tumorigenesis.progenitor | naphthalene | cell of origin | tumor suppressor gene

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Section: Pulmonary Neuroendocrine Cells Have Very Limited Potential Tosupporting

confidence: 91%

“…Ade-CGRP-Cre is expressed in PNECs as well as in a small number of Clara cells and ciliated cells (13). Importantly, these mouse models recapitulate critical aspects of human SCLC.…”

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Song

Yao

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

247

View full text Add to dashboard Cite

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“…Thus, it appears that MEK inhibitor insensitivity in SCLC arises from the loss of retinoblastoma protein 1 function. Loss or mutation of retinoblastoma protein 1 and p53 in pulmonary neuroendocrine cells is sufficient to cause a mouse model of SCLC [88,89]. When various isoforms of PI 3-kinase are overexpressed in SCLC they increase stem cell factor-stimulated activation of AKT, but not ERK1/2 [86].…”

Section: Mapk Pathway In Other Cancersmentioning

confidence: 99%

Signal control through Raf: in sickness and in health

2011

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The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the prototype mammalian mitogenactivated protein kinase (MAPK) signaling cascade that regulates a number of processes, including proliferation, differentiation, survival, migration, stress responses and apoptosis. How this seemingly linear cascade is modulated to achieve a specific cellular function has been a main focus of the field. In this review, we describe new as well as old findings in the regulation of the ERK1/2 pathway in normal and disease states via MAP3Ks.

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The expression of YAP1 and other transcription factors contributes to lineage plasticity in combined small cell lung carcinoma

Jimbo,

Ohbayashi,

Fujii

et al. 2024

The Journal of Pathology CR

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Lineage plasticity in small cell lung carcinoma (SCLC) causes therapeutic difficulties. This study aimed to investigate the pathological findings of plasticity in SCLC, focusing on combined SCLC, and elucidate the involvement of YAP1 and other transcription factors. We analysed 100 surgically resected SCLCs through detailed morphological observations and immunohistochemistry for YAP1 and other transcription factors. Component‐by‐component next‐generation sequencing (n = 15 pairs) and immunohistochemistry (n = 35 pairs) were performed on the combined SCLCs. Compared with pure SCLCs (n = 65), combined SCLCs (n = 35) showed a significantly larger size, higher expression of NEUROD1, and higher frequency of double‐positive transcription factors (p = 0.0009, 0.04, and 0.019, respectively). Notably, 34% of the combined SCLCs showed morphological mosaic patterns with unclear boundaries between the SCLC and its partner. Combined SCLCs not only had unique histotypes as partners but also represented different lineage plasticity within the partner. NEUROD1‐dominant combined SCLCs had a significantly higher proportion of adenocarcinomas as partners, whereas POU2F3‐dominant combined SCLCs had a significantly higher proportion of squamous cell carcinomas as partners (p = 0.006 and p = 0.0006, respectively). YAP1 expression in SCLC components was found in 80% of combined SCLCs and 62% of pure SCLCs, often showing mosaic‐like expression. Among the combined SCLCs with component‐specific analysis, the identical TP53 mutation was found in 10 pairs, and the identical Rb1 abnormality was found in 2 pairs. On immunohistochemistry, the same abnormal p53 pattern was found in 34 pairs, and Rb1 loss was found in 24 pairs. In conclusion, combined SCLC shows a variety of pathological plasticity. Although combined SCLC is more plastic than pure SCLC, pure SCLC is also a phenotypically plastic tumour. The morphological mosaic pattern and YAP1 mosaic‐like expression may represent ongoing lineage plasticity. This study also identified the relationship between transcription factors and partners in combined SCLC. Transcription factors may be involved in differentiating specific cell lineages beyond just ‘neuroendocrine’.

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Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung

Cited by 418 publications

References 43 publications

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Signal control through Raf: in sickness and in health

The expression of YAP1 and other transcription factors contributes to lineage plasticity in combined small cell lung carcinoma

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