NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas.
Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionally, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Lydia
L
Meder
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Katharina
K
König
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Luka
L
Ozretić
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Anne M
AM
Schultheis
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Frank
F
Ueckeroth
Biocenter, University of Würzburg, Am Hubland, Würzburg, 97074, Germany.
Carsten P
CP
Ade
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Kerstin
K
Albus
Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Department of Prostate Cancer Research, Institute of Pathology, University Hospital Bonn, Sigmund-Freud Straße 25, Bonn, 53105, Germany.
Diana
D
Boehm
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Ursula
U
Rommerscheidt-Fuss
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Alexandra
A
Florin
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Theresa
T
Buhl
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Wolfgang
W
Hartmann
Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Clinic for Internal Medicine I, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Jürgen
J
Wolf
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Sabine
S
Merkelbach-Bruse
Biocenter, University of Würzburg, Am Hubland, Würzburg, 97074, Germany.
Martin
M
Eilers
Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Biocenter, University of Würzburg, Am Hubland, Würzburg, 97074, Germany.
Sven
S
Perner
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Lukas C
LC
Heukamp
Institute of Pathology, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.|Center for Integrated Oncology Bonn, University Hospital Bonn, Sigmund-Freud Straße 25, 53105, Bonn, Germany.|Lung Cancer Group Cologne, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
Reinhard
R
Buettner
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D051880:Receptors, Notch; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C065500:ASCL1 protein, human; C495901:TP53 protein, human
Lung cancer; achaete-scute homolog 1; neurogenic locus notch homolog; retinoblastoma protein; small cell lung cancer