Spatially confined sub-tumor microenvironments in pancreatic cancer
Open accessPublished version of a preprint
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.
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Fibroblast status during tumorigenesis and progression can be influenced by genetic mutations present in PDAC cells.
“fibroblast status throughout tumorigenesis and progression can be influenced by genetic mutations present in the PDAC cells154,155”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [155]
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- Authors
- Grünwald, B. T., Devisme, A., Andrieux, G., Vyas, F., Aliar, K., McCloskey, C. W., Macklin, A., Jang, G. H., Denroche, R., Romero, J. M., Bavi, P., Bronsert, P., Notta, F., O’Kane, G., Wilson, J., Knox, J., Tamblyn, L., Udaskin, M., Radulovich, N., Fischer, S. E., Boerries, M., Gallinger, S., Kislinger, T., & Khokha, R.
- Affiliations
- University Health Network (CA)
- University of Freiburg (DE)
- Ontario Institute for Cancer Research (CA)
- Corresponding author
- Boerries, Melanie
- Kislinger, Thomas
- Khokha, Rama
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 184
- Issue
- 22
- Pages
- 5577-5592.e18
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W3206996158
- Cited by
- 433
- References
- 56
- Citations by year
- 2026: 76 · 2025: 95 · 2024: 97 · 2023: 98 · 2022: 61 · 2021: 5
- FWCI
- 24.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Alexander von Humboldt-Stiftung (DEU‐1199182‐FLFP, DEU 1199182)
- Princess Margaret Cancer Foundation (DEU 1199182 FLF-P, ALTF 116-2018)
- Ontario Institute for Cancer Research
- Government of Ontario
- Pancreatic Cancer Canada Foundation
- Deutsche Forschungsgemeinschaft (FKZ 01ZZ1801B, SFB850)
- Bundesministerium für Bildung und Forschung (01ZZ1801B, Fkz. 01ZZ1801B)
- Terry Fox Research Institute
- Canadian Cancer Society Research Institute
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- pancreatic cancer, tumor microenvironment, intratumoral heterogeneity, fibroblast plasticity, antitumor immunity, chemotherapy response, tumor cell phenotype, multi-omics integration, single-cell transcriptomics
- MeSH terms
- Cancer-Associated Fibroblasts, Adenocarcinoma, Cell Differentiation, Epithelium, Extracellular Matrix, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms, Phenotype, Gene Expression Regulation, Neoplastic, Survival Analysis, Stromal Cells, Gene Expression Profiling, Carcinoma, Pancreatic Ductal, Cell Proliferation, Tumor Microenvironment
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