Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities
Parth Desai, Nobuyuki Takahashi, Rajesh Kumar, Samantha Nichols, Justin Malin, Allison L. Hunt, Christopher W. Schultz, Yingying Cao, Desiree Tillo, Darryl Nousome, Lakshya Chauhan, Linda Sciuto, Kimberly R. 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 Vilimas, Danielle Pinkiert, Chante Graham, Donna Butcher, Andrew Warner, Robin Sebastian, Mimi Mahon, Karen Baker, Jennifer Cheng, Ann M. Berger, Ross Lake, Melissa L. Abel, Manan Krishnamurthy, George Chrisafis, Peter Fitzgerald, Micheal Nirula, Shubhank Goyal, Devon Atkinson, Nicholas W. Bateman, Tamara Abulez, Govind Nair, Andrea B. Apolo, Udayan Guha, Baktiar Karim, Rajaâ El Meskini, Zoë Weaver Ohler, Mohit Kumar Jolly, Alejandro A. Schäffer, Eytan Ruppin, David E. Kleiner, Markku Miettinen, G. Tom Brown, Stephen M. Hewitt, Thomas P. Conrads, Anish Thomas
Abstract
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.