Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

Abstract

Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. The exact molecular mechanisms involved in this NE transdifferentiation remain elusive. In small cell lung cancer (SCLC), plasticity from NE to nonNE phenotypes is driven by NOTCH signaling. Herein we review current understanding of NE lineage plasticity dynamics, exemplified by prostate cancer, NSCLC, and SCLC.

Figure 1.. Lineage plasticity as a mechanism of disease progression in Castration Resistant Prostate Cancer (CRPC).

Schematic representation of the current state of knowledge. In this perspective, we explore how around 10% of CRPC transition to a lethal form of prostate cancer by becoming indifferent to ARSi. We posit that understanding the mechanism of how this occurs could help prevent this deadly turn to the most aggressive form of prostate cancer. Modified from Cyrta et al. (in press).

Figure 2.. Studying plasticity in Small Cell Lung Cancer in CDX models.

Schematic showing how the NE and non-NE (NNE) cells within a SCLC CDX tumor, derived from a patient’s circulating tumor cells, can be disaggregated and placed into short term culture. The NE cells grow as floating cell spheres whilst the non-NE cells adhere to plastic (far right bright image). These differential growth behaviors allow easy separation and separate or combined study of the two phenotypes.

Figure 3.. Framework for systematic discovery of genomic and epigenomic lineage plasticity drivers.

(Left) pre and post-treatment LUAD and PCa samples undergo whole genome sequencing ± (middle) long-range and epigenomic profiling. (right) Statistical analysis of recurrent and chromatin perturbing SNVs, indels, and structural variants nominate loci that are under positive selection and/or recurrent chromatin perturbations. Such loci (rightmost panel) may represent enhancer-promoter interactions that bring complex combinations of distant loci together to drive cell identity changes through the creation (or disruption) of transcriptional condensates.

Figure 4.. Lineage Plasticity as a therapy induced state.

A. In proposed models, there may be pre-existing differentiated cells that are simply selected for during the course of therapy. B. However, emerging data presented in this Perspective explores the lineage plasticity model as a series of events that can transition differentiated cells into a stem-like state and then under the right conditions into another differentiated state either reversible (middle) or irreversible (lower). In this perspective, we address the features that contribute to the formation of lethal resistant clones. We propose that key features include simple and complex genomic alterations (e.g. TP53, RB1, PTEN loss), epigenetic reprogramming (e.g., EZH2, SETD2, SWI/SNF) and genomic instability secondary to changes in the tumor microenvironment (e.g., hypoxia). These alterations occur over a time course in the context of selection based on distinct oncogenic therapies. We present examples of luminal tumors transdifferentiating to SCC (i.e., PCa and NSCLC) and an example of SCLC transdifferentiating to another mesenchymal state. Figure based Waddington’s original figure (Waddington, 1957) modified by Le Magnen et al. (2018).