%0 Journal Article
%T Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities.
%A Desai P
%A Takahashi N
%A Kumar R
%A Nichols S
%A Malin J
%A Hunt A
%A Schultz C
%A Cao Y
%A Tillo D
%A Nousome D
%A Chauhan L
%A Sciuto L
%A Jordan K
%A Rajapakse V
%A Tandon M
%A Lissa D
%A Zhang Y
%A Kumar S
%A Pongor L
%A Singh A
%A Schroder B
%A Sharma AK
%A Chang T
%A Vilimas R
%A Pinkiert D
%A Graham C
%A Butcher D
%A Warner A
%A Sebastian R
%A Mahon M
%A Baker K
%A Cheng J
%A Berger A
%A Lake R
%A Abel M
%A Krishnamurthy M
%A Chrisafis G
%A Fitzgerald P
%A Nirula M
%A Goyal S
%A Atkinson D
%A Bateman NW
%A Abulez T
%A Nair G
%A Apolo A
%A Guha U
%A Karim B
%A El Meskini R
%A Ohler ZW
%A Jolly MK
%A Schaffer A
%A Ruppin E
%A Kleiner D
%A Miettinen M
%A Brown GT
%A Hewitt S
%A Conrads T
%A Thomas A
%J Cell Rep Med
%V 5
%N 6
%D 2024 Jun 18
%M 38897168
%F 16.988
%R 10.1016/j.xcrm.2024.101610
%X 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.