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Dayton Group

Organoid models of neuroendocrine development and cancer

At EMBL from September 2022.

The Dayton group leverages novel organoid models of neuroendocrine (NE) cells and tumours to recapitulate and dissect mechanisms of human disease including cancer initiation, progression, and drug response.

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The Dayton group leverages novel organoid models of neuroendocrine (NE) cells and tumours to recapitulate and dissect mechanisms of human disease including cancer initiation, progression, and drug response.

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Previous and current research

Our group uses organoids to understand: (1) differentiation and plasticity of NE cells, and (2) the biology of NE cancers (Figure 1).

Differentiation and plasticity of NE cells

Pulmonary NE cells account for only 0.5% of the lung epithelium. They secrete hormones and neuropeptides that influence lung physiology, and multiple studies show increased pulmonary NE cell numbers in human diseases, suggesting an important function. These cells are also a cell of origin for pulmonary NE neoplasms, a tumour type that constitutes 20-25% of invasive primary lung cancers.

We have pioneered a tractable and robust model system for the study and manipulation of human pulmonary NE cells and their progenitors in multicellular organoids that also contain all of the major airway cell types (Figure 2).

Biology of NE cancers

NE neoplasms comprise NE tumours (NETs) and NE carcinomas (NECs). While NETs generally proliferate and progress slowly, NECs are associated with a very poor prognosis. Irrespective of subtype, the treatment options for patients with unresectable, relapsed, or metastasized NE neoplasms are limited. We have developed novel patient-derived tumour organoids (PDTOs) of pulmonary NETs and of large cell NEC (LCNEC) that conserve and maintain the intratumoral heterogeneity and major gene expression patterns observed in matched tumour tissue. Using these PDTO models we:

  • Identified a subset of pulmonary NETs that expresses high levels of EGFR and depends on EGF for its growth in culture.
  • Identified a biomarker potentially predictive of therapeutic response of NE cancers to BCL2 inhibitors.

Future projects and goals

Broadly, we aim to tackle several outstanding questions: 

(1) Does heterogeneity in the molecular states that lie along the differentiation trajectories for NE cells influence genomic and phenotypic intratumour and inter-tumour heterogeneity in NE cancers? 

(2) How do NE cells respond to acute and chronic injury and how do these responses change when they acquire cancer-associated mutations? 

(3) How do cancer-associated mutations influence cell state and differentiation in NE cells and NE cell progenitors?

More specific goals include:

  • Development of genetic tools to manipulate and label NE cells and their progenitors
  • Define the NE cell response to environmental stimuli
  • Apply CRISPR-Cas9 gene editing to model NE tumour progression
  • Engineer organoid models of NE cancer initiation that enable natural evolution of a tumour in an in vitro system

Online presentations

June 2020 London Stem Cell Network Stem Cell Forum

ingfographic showing the schematic of media impact on neuroendocrine lung organoids and tumor/neoplasm organoids
Figure 1: Schematic outline of novel organoid models of human NE cells and NE cancers that recapitulate features of NE cell growth, differentiation, and transformation. Figure made with Biorender.
ingfographic showing IF staining for neuroendocrine cells in human lung/airway organoids after differentiation
Figure 2: Airway organoids containing NE cells and all major airway cell types were generated from human lung tissue and NE cell differentiation was recapitulated in vitro by addition of NE differentiation medium: whole-mount immunofluorescence of organoids for the NE marker, UCHL1 (green). Figure made with some images from Biorender.
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