Englander Institute for Precision Medicine

FORMATION OF MALIGNANT, METASTATIC SMALL CELL LUNG CANCERS THROUGH OVERPRODUCTION OF cMYC PROTEIN IN TP53 AND RB1 DEPLETED PULMONARY NEUROENDOCRINE CELLS DERIVED FROM HUMAN EMBRYONIC STEM CELLS.

TitleFORMATION OF MALIGNANT, METASTATIC SMALL CELL LUNG CANCERS THROUGH OVERPRODUCTION OF cMYC PROTEIN IN TP53 AND RB1 DEPLETED PULMONARY NEUROENDOCRINE CELLS DERIVED FROM HUMAN EMBRYONIC STEM CELLS.
Publication TypeJournal Article
Year of Publication2023
AuthorsChen HJoyce, Gardner EE, Shah Y, Zhang K, Thakur A, Zhang C, Elemento O, Varmus H
JournalbioRxiv
Date Published2023 Oct 09
Abstract

We recently 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 cMYC 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 cMYC 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.

DOI10.1101/2023.10.06.561244
Alternate JournalbioRxiv
PubMed ID37873210
PubMed Central IDPMC10592623
Grant ListK99 CA226353 / CA / NCI NIH HHS / United States
R00 CA226353 / CA / NCI NIH HHS / United States
U01 CA224326 / CA / NCI NIH HHS / United States

Weill Cornell Medicine Englander Institute for Precision Medicine 413 E 69th Street
Belfer Research Building
New York, NY 10021