A cellular and spatial atlas of TP53-associated tissue remodeling in lung adenocarcinoma

TP53 is the most frequently mutated gene across many cancers and is associated with shorter survival in lung adenocarcinoma (LUAD). To define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multi-omic cellular and spatial tumor atlas of 23 treatment-naïve human lung tumors. We found that TP53 -mutant ( TP53 mut) malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across resectable LUAD patient tumors, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, pro-metastatic expression programs in TP53 mut tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274 - PDCD1 and PVR - TIGIT , are also enriched in TP53 mut LUAD tumors, which may influence response to checkpoint blockade therapy. Our methodology can be further applied to investigate mutation-specific TME changes in other cancers. ### Competing Interest Statement As.R. is an equity holder in Celsius Therapeutics and Nucleai. A.N.H. has received research support from Amgen, Blueprint Medicines, BridgeBio, Bristol Myers Squibb, C4 Therapeutics, Pfizer, Eli Lilly, Novartis, Nuvalent, Roche/Genentech, Scorpion Therapeutics, and served as a paid consultant for Engine Biosciences, Nuvalent, Oncovalent, Tolremo Therapeutics and TigaTx. R.B. has received research support from the NCI, NBIB, NHLBI and DOD; industry grants from Genentech, Roche, Merck, Siemens, NorthPond, Bicycles Therapeutics. R.B. holds equity and patents licensed to Navigation Sciences. O.R.-R. has given numerous lectures on the subject of single-cell genomics to a wide variety of audiences and, in some cases, has received remuneration to cover time and costs. A.R. is a co-founder and equity holder of Celsius Therapeutics and an equity holder in Immunitas. She was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov until July 31, 2020. A.R., O.R.-R., J.J.-V., and M.S. have been employees of Genentech since 2020, and have equity in Roche. B.E.J receives post-marketing royalties for a patent on epidermal growth factor receptor testing, research support from Cannon Medical Systems, paid Consultant to Novartis, Boston Pharmaceuticals, Checkpoint Therapeutics, Chugai, Daichi Sankyo, Foundation Medicine, G1 Therapeutics, Genentech, GSK, Hengrui Therapeutics, Janssen, Jazz Pharma, Lilly, Bluedot Bio, Unpaid Member of a Steering Committee for Pfizer.