Journal Pre-proof Pten loss expands the histopathological diversity and lineage plasticity of lung cancers initiated by Rb1/Trp53 deletion

High grade neuroendocrine (NE) tumors of the lung, like small cell lung cancer (SCLC), are recalcitrant cancers for which more effective systemic therapies are needed. Despite their histopathological and molecular heterogeneity, they are generally treated as a single disease entity with similar chemotherapy regimens. While marked clinical responses can be observed, they are short lived. Inter- and intra-tumoral heterogeneity is considered a confounding factor in these unsatisfactory clinical outcomes, yet the origin of this heterogeneity and its impact on therapeutic responses is not well understood. Here new genetically engineered mouse models are employed to test the effects of Pten loss on the development of lung tumors initiated by Rb1 and Trp53 tumor suppressor gene deletion. Complete Pten loss drives more rapid tumor development with a greater diversity of tumor histopathology ranging from adenocarcinoma to SCLC. Pten loss also drives transcriptional heterogeneity as marked lineage plasticity is observed within histopathological subtypes. Spatial profiling indicates transcriptional heterogeneity exists both within and between tumor foci with limited spatial intermixing of transcriptional clusters, implying that the growth environment influences gene expression. These results identify Pten loss as clinically relevant genetic alteration driving the molecular and histopatholgical heterogeneity of NE lung tumors initiated by Rb1/Trp53 mutations.