It is widely accepted that lung neuroendocrine tumours (NETs) and lung neuroendocrine carcinomas (NECs) are different diseases and not simply a continuum of neoplasms with a common pathogenesis. However, over the past years it has been suggested that in both the lung and the thymus the progression or transition from NET to NEC, possibly through the accumulation of genetic anomalies, might be possible. In line with this hypothesis and through multi-omics factor analysis of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers, we have identified a group of atypical carcinoids that we have named “supra-carcinoids” with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, suggesting that the molecular link between lung NETs and NECs might be subtler than initially thought (Figure below). In the same study we identified clinically relevant molecular groups of pulmonary carcinoids (Alcala et al., Nat Commun 2019).

Multi-omics factor analysis (MOFA) of transcriptomes and methylomes of LNEN samples (typical carcinoids, atypical carcinoids, and LCNEC). Point colours correspond to the histopathological types; coloured circles correspond to predictions of histopathological types by a machine learning (ML) algorithm (random forest classifier); filled coloured shapes represent the three molecular clusters identified by consensus clustering. The density of clinical variables that are significantly associated with a latent factor (ANOVA q-value < 0.05) are represented by kernel density plots next to each axis: histopathological type for latent factor 1, sex and histopathological type for latent factor 2.

Another important contribution that we would like to highlight is the generation of a molecular map of lung neuroendocrine neoplasms (Figure below), which provides an interactive way to explore the molecular data and allows easy statistical interrogation, including generating new hypotheses, but also projecting data from studies including fewer samples, (so frequent when working with rare cancers) in order to draw meaningful conclusions (Gabriel et al. Gigascience 2020).

Two-dimensional projection of LNEN transcriptome data using UMAP. The representation was obtained from the TumorMap portal, using the hexagonal grid view, each hexagonal point representing a LNEN sample. Point colours correspond to the molecular clusters defined in the previous publications.

We are currently performing a full molecular characterization of atypical carcinoids and supra-carcinoids (an aggressive group of pulmonary carcinoids that we have recently identified) through a multi-omic integrative analysis (WGS, RNA-seq, and 850k methylation arrays) of 100 primary tumors. The molecular data will be correlated with morphological, epidemiological, and clinical features. Finally, together with T Dayton (in Clever’s lab) we are trying to depict the mechanisms of a possible progression from low to high-aggressive lung neuroendocrine neoplasms by modeling tumor initiation and progression, using state-of-the-art organoid in vitro models.

Reconstructing the evolutionary history of neuroendocrine tumor subtypes. Neuroendocrine Tumor Research Foundation (NETRF, US). 2023 Mentored Award. Coordinators. Active

Reconciling lung carcinoids histopathological and molecular classifications. Neuroendocrine Tumor Research Foundation (NETRF, US). 2022 Investigator Award. Coordinators. Active – IARC Press Release – NETRF 2022 Annual Report

Unveiling the evolutionary processes and molecular pathways underlying the development and progression of lung neuroendocrine neoplasms. Worldwide Cancer Research (WCR, UK). 2020 Grant Round. Coordinators. Active

Comprehensive molecular characterisation of lung supra-carcinoids. Neuroendocrine Tumor Research Foundation (NETRF, US). 2019 Investigator Award. Coordinators. Completed

Genomic characterisation of broncho-pulmonary carcinoids. Institut National Du Cancer (INCa, France). PRT-K17-047. Coordinators. Completed

The Orthopedia Homeobox transcription factor (OTP) in the diagnostics and tumorigenesis of lung carcinoids. KWF Kankerbestrijding (DCS, The Netherlands). Collaborators. Completed

Epigenomic characterisation of lung neuroendocrine tumours. Ligue Contre le Cancer (LNCC, France). Coordinators. Completed

Genomic and transcriptomic characterisation of atypical carcinoids of the lung. National Institutes of Health (NIH, US). R03 CA195253-01. Coordinators. Completed