Desai P, Takahashi N, Kumar R, Nichols S, Malin J, Hunt A, Schultz C, Cao Y, Tillo D, Nousome D, Chauhan L, Sciuto L, Jordan K, Rajapakse V, Tandon M, Lissa D, Zhang Y, Kumar S, Pongor L, Singh A, Schroder B, Sharma AK, Chang T, Vilimas R, Pinkiert D, Graham C, Butcher D, Warner A, Sebastian R, Mahon M, Baker K, Cheng J, Berger A, Lake R, Abel M, Krishnamurthy M, Chrisafis G, Fitzgerald P, Nirula M, Goyal S, Atkinson D, Bateman NW, Abulez T, Nair G, Apolo A, Guha U, Karim B, El Meskini R, Ohler ZW, Jolly MK, Schaffer A, Ruppin E, Kleiner D, Miettinen M, Brown GT, Hewitt S, Conrads T, and Thomas A
Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states., Competing Interests: Declaration of interests A.T. received grants to NCI from EMD Serono Research & Development, AstraZeneca, Gilead Sciences, and ProLynx during the conduct of the study., (Published by Elsevier Inc.)