Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities

Parth Anil Desai; Nobuyuki Takahashi; Rajesh Kumar; Samantha Nichols; Justin Malin; Allison L. Hunt; Christopher William Schultz; Yingying Cao; Desiree Tillo; Darryl Nousome; Lakshya Chauhan; Linda C. Sciuto; Kimberly Rae Jordan; Vinodh N. Rajapakse; Mayank Tandon; Delphine Lissa; Yang Zhang; Suresh Kumar; Lőrinc Sándor Pongor; Abhay Pratap Singh; Brett Schroder; Ajit Kumar Sharma; Tiangen Chang; Rasa J Vilimas; Danielle Pinkiert; Chante Graham; Donna O. Butcher; Andrew Warner; Robin Sebastian; Mimi Mahon

doi:10.1016/j.xcrm.2024.101610

Cancer BiologyCell Reports MedicineJun 1, 2024

Peer-reviewed journal article

Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities

Parth Anil Desai iD, Nobuyuki Takahashi iD, Rajesh Kumar iD, Samantha Nichols iD, Justin Malin iD, Allison L. Hunt iD, Christopher William Schultz iD, Yingying Cao iD, Desiree Tillo iD, Darryl Nousome iD, Lakshya Chauhan iD, Linda C. Sciuto iD, Kimberly Rae Jordan iD, Vinodh N. Rajapakse iD, Mayank Tandon iD, Delphine Lissa iD, Yang Zhang iD, Suresh Kumar, Lőrinc Sándor Pongor iD, Abhay Pratap Singh iD, Brett Schroder, Ajit Kumar Sharma iD, Tiangen Chang iD, Rasa J Vilimas iD, Danielle Pinkiert iD, , Anish Thomas iD

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Abstract

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the 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 tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Together, our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.