Lineage-specific intolerance to oncogenic drivers restricts histological transformation

Abstract

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC following treatment with targeted therapies. Here we designed models to follow the conversion of LUAD to SCLC and found the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells, transcriptionally resembling the pulmonary basal lineage. These findings suggest histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.

The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1

“…Although the work reported here is exclusively based on prostate cancer models, the platform is, in principle, adaptable to other epithelial lineages in which short-term organoid culture and orthotopic transplantation methods have been developed. One disease that closely approximates the lineage transitions observed in prostate cancer is EGFR - or ALK -mutant lung adenocarcinoma where epithelial to NE transition is seen as a mechanism of escape from EGFR or ALK inhibition, particularly in patients with co-occurring loss of function mutations in TP53 and RB1 , and recently demonstrated in an EGFR-driven GEMM 7,8,11,55,56 . KRAS G12C -mutant lung adenocarcinoma is a second example where transition to squamous histology is a resistance mechanism for RAS inhibitor therapy 10,57 .…”

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

“…In particular, it may be important to determine whether hESC-derived SCLC cells with varied genotypes are liable to metastasize to specific sites such as the brain and bone, which are commonly affected in patients with SCLC, but were not sites for metatastic growth in the experiments reported here. Finally, the role of other tumor suppressor genes, such as PTEN – implicated in the development of mouse models of histological transformation of LUAD to SCLC that we have recently reported (44) – should also be examined in this human ESC-derived model.…”