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

Wei Zhang, Luc Girard, Yu An Zhang, Tomohiro Haruki, Mahboubeh Papari-Zareei, Victor Stastny, Hans K. Ghayee, Karel Pacak, Trudy G. Oliver, John D. Minna, Adi F. Gazdar

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 subtype, as well as cell lines from the GEM model. High NE SCLC lines grew as non-adherent floating aggregates or spheroids while Low NE lines had morphologic features of the variant subtype and grew as loosely attached cells. While the high NE subtype expressed one of the NE lineage master transcription factors ASCL1 or NEUROD1, together with NKX2-1, the entire range of NE markers, and lacked expression of the neuronal and NE repressor REST, the low NE subtype had lost expression of most NE markers, ASCL1, NEUROD1 and NKX2-1 and expressed REST. The low NE subtype had undergone epithelial mesenchymal transition (EMT) and had activated the Notch, Hippo and TGFβ pathways and MYC oncogene . Importantly, the high and low NE group of SCLC lines had similar gene expression profiles as their SCLC tumor counterparts. Conclusions: SCLC tumors and cell lines can exhibit distinct inter-tumor heterogeneity with respect to expression of NE features. Loss of NE expression results in major alterations in morphology, growth characteristics, and molecular properties. These findings have major clinical implications as the two subtypes are predicted to have very different responses to targeted therapies.

Original languageEnglish (US)
Pages (from-to)32-49
Number of pages18
JournalTranslational Lung Cancer Research
Volume7
Issue number1
DOIs
StatePublished - Feb 1 2018

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Small Cell Lung Carcinoma
Phenotype
Neoplasms
Tumor Cell Line
Cell Line
Neuroendocrine Cells
Epithelial-Mesenchymal Transition
Neuroendocrine Tumors
Growth
Oncogenes
Transcriptome
Transcription Factors
Gene Expression

Keywords

  • Epithelial-mesenchymal transition
  • Genetically engineered mouse model
  • Neuroendocrine tumors
  • Small cell lung cancer (SCLC)
  • Tumor heterogeneity

ASJC Scopus subject areas

  • Oncology

Cite this

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. / Zhang, Wei; Girard, Luc; Zhang, Yu An; Haruki, Tomohiro; Papari-Zareei, Mahboubeh; Stastny, Victor; Ghayee, Hans K.; Pacak, Karel; Oliver, Trudy G.; Minna, John D.; Gazdar, Adi F.

In: Translational Lung Cancer Research, Vol. 7, No. 1, 01.02.2018, p. 32-49.

Research output: Contribution to journalArticle

Zhang, W, Girard, L, Zhang, YA, Haruki, T, Papari-Zareei, M, Stastny, V, Ghayee, HK, Pacak, K, Oliver, TG, Minna, JD & Gazdar, AF 2018, 'Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes', Translational Lung Cancer Research, vol. 7, no. 1, pp. 32-49. https://doi.org/10.21037/tlcr.2018.02.02
Zhang, Wei ; Girard, Luc ; Zhang, Yu An ; Haruki, Tomohiro ; Papari-Zareei, Mahboubeh ; Stastny, Victor ; Ghayee, Hans K. ; Pacak, Karel ; Oliver, Trudy G. ; Minna, John D. ; Gazdar, Adi F. / Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. In: Translational Lung Cancer Research. 2018 ; Vol. 7, No. 1. pp. 32-49.
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abstract = "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 subtype, as well as cell lines from the GEM model. High NE SCLC lines grew as non-adherent floating aggregates or spheroids while Low NE lines had morphologic features of the variant subtype and grew as loosely attached cells. While the high NE subtype expressed one of the NE lineage master transcription factors ASCL1 or NEUROD1, together with NKX2-1, the entire range of NE markers, and lacked expression of the neuronal and NE repressor REST, the low NE subtype had lost expression of most NE markers, ASCL1, NEUROD1 and NKX2-1 and expressed REST. The low NE subtype had undergone epithelial mesenchymal transition (EMT) and had activated the Notch, Hippo and TGFβ pathways and MYC oncogene . Importantly, the high and low NE group of SCLC lines had similar gene expression profiles as their SCLC tumor counterparts. Conclusions: SCLC tumors and cell lines can exhibit distinct inter-tumor heterogeneity with respect to expression of NE features. Loss of NE expression results in major alterations in morphology, growth characteristics, and molecular properties. These findings have major clinical implications as the two subtypes are predicted to have very different responses to targeted therapies.",
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AU - Girard, Luc

AU - Zhang, Yu An

AU - Haruki, Tomohiro

AU - Papari-Zareei, Mahboubeh

AU - Stastny, Victor

AU - Ghayee, Hans K.

AU - Pacak, Karel

AU - Oliver, Trudy G.

AU - Minna, John D.

AU - Gazdar, Adi F.

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N2 - 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 subtype, as well as cell lines from the GEM model. High NE SCLC lines grew as non-adherent floating aggregates or spheroids while Low NE lines had morphologic features of the variant subtype and grew as loosely attached cells. While the high NE subtype expressed one of the NE lineage master transcription factors ASCL1 or NEUROD1, together with NKX2-1, the entire range of NE markers, and lacked expression of the neuronal and NE repressor REST, the low NE subtype had lost expression of most NE markers, ASCL1, NEUROD1 and NKX2-1 and expressed REST. The low NE subtype had undergone epithelial mesenchymal transition (EMT) and had activated the Notch, Hippo and TGFβ pathways and MYC oncogene . Importantly, the high and low NE group of SCLC lines had similar gene expression profiles as their SCLC tumor counterparts. Conclusions: SCLC tumors and cell lines can exhibit distinct inter-tumor heterogeneity with respect to expression of NE features. Loss of NE expression results in major alterations in morphology, growth characteristics, and molecular properties. These findings have major clinical implications as the two subtypes are predicted to have very different responses to targeted therapies.

AB - 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 subtype, as well as cell lines from the GEM model. High NE SCLC lines grew as non-adherent floating aggregates or spheroids while Low NE lines had morphologic features of the variant subtype and grew as loosely attached cells. While the high NE subtype expressed one of the NE lineage master transcription factors ASCL1 or NEUROD1, together with NKX2-1, the entire range of NE markers, and lacked expression of the neuronal and NE repressor REST, the low NE subtype had lost expression of most NE markers, ASCL1, NEUROD1 and NKX2-1 and expressed REST. The low NE subtype had undergone epithelial mesenchymal transition (EMT) and had activated the Notch, Hippo and TGFβ pathways and MYC oncogene . Importantly, the high and low NE group of SCLC lines had similar gene expression profiles as their SCLC tumor counterparts. Conclusions: SCLC tumors and cell lines can exhibit distinct inter-tumor heterogeneity with respect to expression of NE features. Loss of NE expression results in major alterations in morphology, growth characteristics, and molecular properties. These findings have major clinical implications as the two subtypes are predicted to have very different responses to targeted therapies.

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KW - Small cell lung cancer (SCLC)

KW - Tumor heterogeneity

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