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A Memorial Sloan Kettering Cancer Center tumor atlas study of human small cell lung carcinoma (SCLC) using MIBI spatial proteomic imaging and single-cell transcriptomics revealed signatures linked to metastasis and poor prognosis


Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer

Chan, et al., Cancer Cell  8 Nov 2021: (39), 1479-1496.

Key Insights
  • A new molecular atlas of the disease that sheds light on what makes the cancer so aggressive
  • A rare subpopulation of stem-like cells with linkages to metastasis and poor prognostic outcomes was discovered
  • Features and cell populations associated with profibrotic, immunosuppressive tumor landscapes were discvoered
  • The high multplex and high resolution of MIBI-based spatial proteomics enabled deep spatial characterization of the tumor microenvironment and the ability to observe specific cell subpopulations and their relative spatial locations

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.

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