Spatially confined sub-tumor microenvironments in pancreatic cancer
Menée à l'aide de 413 échantillons tumoraux prélevés sur 393 patients atteints d'un adénocarcinome canalaire du pancréas et à l'aide d'organoïdes et de données issues du projet "The Cancer Genome Atlas", cette étude identifie, au sein des tumeurs, des régions distinctes se caractérisant par leur phénotype immunitaire, l'état de différenciation de leurs fibloblastes associés au cancer et leurs fonctions chimioprotectrices ou pro-tumorales
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.
Cell , article en libre accès, 2020