A growing body of research in SCLC has revealed greater phenotypic heterogeneity within this disease than previously realized. Circulating-tumor-cell-derived explant models (CDX) are providing researchers with a resource to facilitate personalization of SCLC treatment.
At the International Association for the Study of Lung Cancer’s 2021 Hot Topic Meeting: Small Cell Lung Cancer, the opening keynote speaker, Caroline Dive, PhD, CBE, FMedSci, Director of the CRUK Manchester Institute Cancer Biomarker Centre, University of Manchester, United Kingdom, discussed CDX models and recent developments in their use.
CTCs & SCLC
According to Dr. Dive, the story of CDX models starts in 2012 when she and colleagues first started examining circulating tumor cells (CTCs) from patients with SCLC (using the CellSearch platform) and noticed the high number of CTCs with a large dynamic range. They found that the change in pre-treatment CTC number was a surrogate of chemotherapy response and was prognostic for PFS and OS.
Based on this information, they wondered if CTCs could be harvested and used to generate mouse models of SCLC, and their curiosity led to this accomplishment about 2 years later. They called these models “CTC-derived patient explants,” or CDX models.
“We felt this could change the field, as getting biopsies from [patients with] SCLC is really difficult especially from the majority of patients with metastatic disease,” Dr. Dive said.
There are now more than 50 CDX mouse models, including several CDX pairs generated from samples taken before a patient receives treatment and again post treatment at disease progression. The CDX models (subcutaneous implantation of CTCs) seed secondary tumors in mice in organs where patients experience metastases. And researchers at the Dive Lab have developed what they believe might be the first robust, patient-derived brain metastasis model, a common clinical presentation.
As the CDX models were being developed, other researchers began to define molecular subtypes of SCLC. These included two neuroendocrine (NE) subtypes—ASCL1 and NEUROD1—and two non-neuroendocrine (non-NE) subtypes—YAP1 and POU2F3.
“Now that we have subtypes and know that SCLC is heterogeneous—but at the moment treatment is homogeneous—can we move finally toward personalized medicine for [patients with] SCLC?” Dr. Dive asked. “The answer to that is going to be ‘yes.’”
Research into SCLC has involved thinking about not just these subtypes but also intratumoral heterogeneity, what Dr. Dive called “floaters and stickers.”
The NE cells (the ‘floaters’ in tissue culture), which are the majority of cell types in SCLC, can undergo endogenous Notch pathway activation, and transition to non-NE cells. Both NE and non-NE cells (the ‘stickers’ in tissue culture) cooperate in vivo to achieve metastasis, which is an early event in SCLC.
Dr. Dive focused much of her presentation on work led by Kathryn L. Simpson, PhD, also of Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, and doctoral student Sarah M. Pearsall, who are using CDX models to study SCLC biology, specifically vascular mimicry (VM).
VM is a transendothelial differentiation whereby tumor cells form their own blood vessels, Dr. Dive explained. VM is typically promoted by hypoxia to restore oxygen delivery and is associated with stem cell phenotype and poor prognosis in several tumor types.
Dr. Dive’s team showed that VM vessels are evident in SCLC biopsy samples and that their frequency was associated with worse prognosis. Dr. Dive then went on to discuss new studies that explored SCLC plasticity, which phenotypes are VM competent and how VM-competent cells remodel their extracellular matrix to form vessel-like networks. Her team continues to study the molecular mechanisms that underpin VM with a view to dissecting the pathway to identify tractable targets to slow tumor growth and decrease metastatic propensity.
The GUCY Project
Dr. Dive also spent some time discussing research by her post-graduate student Maximilian W. Schenk on soluble guanylate cyclase (sGC) signaling in SCLC. Mr. Schenk used six paired pre-treatment and post-chemotherapy CDX models to investigate gene expression changes at disease progression in models with varying degrees of acquired chemoresistance.1 He discovered subunits of sGC (nicknamed GUCY1A1 and GUCY1B1) were upregulated genes in the CDX progression models with the greatest degree of acquired chemoresistance. He also found that expression of both of the sGC subunits were regulated by Notch signaling in SCLC cell lines. Further, using a CDX progression model with a GUCY subunit knockout, the team showed that loss of sGC signaling sensitized CDX17P to chemotherapy and extended survival.
Dr. Dive concluded that “CDX models were supporting SCLC research and that personalized treatment for this ‘born to be bad’ cancer clearly requires comprehensive understanding of its heterogeneous biology. But we all think we are getting closer.”
- 1. Schenk MW, Humphrey S, Mukarran Hossain ASM, et al. Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer. Nature Communications. Published online November 17, 2021.