Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.
Samantha E HoffmanTodd W DowreyCarlos Villacorta MartinKevin BiBreanna TitchenShreya JohriLaura DelloStrittoMiraj PatelColin MackichanStephanie IngaJudy ChenGrace GrimaldiSara NapolitanoIsaac WakiroJingyi WuJason YeungAsaf RotemEwa T SicinskaErin ShannonThomas ClancyJiping WangSarah DenningLauren BraisNaomi R BessonKathleen L PfaffYing HuangKatrina Z KaoScott J RodigJason L HornickSébastien VigneauJihye ParkMatthew H KulkeJennifer ChanEliezer Van AllenGeorge F MurphyPublished in: Science advances (2023)
Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10 . Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.
Keyphrases
- neuroendocrine tumors
- single cell
- rna seq
- high throughput
- clinical trial
- genome wide
- small cell lung cancer
- induced apoptosis
- acute myeloid leukemia
- gene expression
- small molecule
- bone marrow
- public health
- dendritic cells
- mass spectrometry
- current status
- dna methylation
- cell cycle arrest
- cell proliferation
- transcription factor
- signaling pathway
- cell death
- genome wide identification
- oxidative stress
- human health
- genome wide analysis
- childhood cancer