Metastatic small cell lung cancer arises from TP53/RB1-deficient and MYC overproduction hESC-derived PNECs

• Published in: eLife Vol. 13
• Main Authors: Chen, Huanhuan Joyce, Gardner, Eric E, Shah, Yajas, Zhang, Kui, Thakur, Abhimanyu, Zhang, Chen, Elemento, Olivier, Varmus, Harold
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 22.07.2025; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Analysis; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Beta2 protein; Cancer Biology; Cell Differentiation; Diet; Doxycycline; Embryo cells; Embryonic stem cells; Genes; hESC; Human Embryonic Stem Cells; Human subjects; Humans; Lung cancer; Lung cancer, Small cell; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Metastases; Metastasis; Mice; Myc protein; Neoplasm Metastasis; Neuroendocrine Cells - metabolism; Neuroendocrine Cells - pathology; p53 Protein; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Retinoblastoma Binding Proteins - deficiency; Retinoblastoma Binding Proteins - genetics; SCLC; Short Report; Small cell lung carcinoma; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - pathology; Stem cells; Transgenes; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors; Ubiquitin-Protein Ligases - deficiency; United States; Ireland; Nebraska; lung cancer; SCLC; mouse; cancer biology; hESC
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.93170

We previously described our initial efforts to develop a model for small cell lung cancer (SCLC) derived from human embryonic stem cells (hESCs) that were differentiated to form pulmonary neuroendocrine cells (PNECs), a putative cell of origin for neuroendocrine-positive SCLC. Although reduced expression of the tumor suppressor genes TP53 and RB1 allowed the induced PNECs to form subcutaneous growths in immune-deficient mice, the tumors did not display the aggressive characteristics of SCLC seen in human patients. Here, we report that the additional, doxycycline-regulated expression of a transgene encoding wild-type or mutant MYC protein promotes rapid growth, invasion, and metastasis of these hESC-derived cells after injection into the renal capsule. Similar to others, we find that the addition of MYC encourages the formation of the SCLC-N subtype, marked by high levels of NEUROD1 RNA. Using paired primary and metastatic samples for RNA-sequencing, we observe that the subtype of SCLC does not change upon metastatic spread and that production of NEUROD1 is maintained. We also describe histological features of these malignant, SCLC-like tumors derived from hESCs and discuss potential uses of this model in efforts to control and better understand this recalcitrant neoplasm.