1. Spatially confined sub-tumor microenvironments in pancreatic cancer
- Author
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Robert E. Denroche, Kazeera Aliar, Melanie Boerries, Foram Vyas, Curtis W. McCloskey, Steven Gallinger, Thomas Kislinger, Faiyaz Notta, Prashant Bavi, Geoffroy Andrieux, Peter Bronsert, Molly Udaskin, Laura Tamblyn, Antoine Devisme, Sandra Fischer, Julie M. Wilson, Gun Ho Jang, Rama Khokha, Jennifer J. Knox, Grainne M. O'Kane, Nikolina Radulovich, Barbara Grünwald, Joan Miguel Romero, and Andrew Macklin
- Subjects
Male ,In situ ,Adenocarcinoma ,Biology ,Epithelium ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,Immune system ,Cancer-Associated Fibroblasts ,Pancreatic cancer ,Tumor Microenvironment ,medicine ,Humans ,Fibroblast ,Cell Proliferation ,Tumor microenvironment ,Gene Expression Profiling ,Cell Differentiation ,Middle Aged ,medicine.disease ,Survival Analysis ,Phenotype ,Extracellular Matrix ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Cancer research ,Female ,Stromal Cells ,Carcinoma, Pancreatic Ductal - Abstract
Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. "Reactive" subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich "deserted" subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.
- Published
- 2021
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