#IDIBELLseminars: Tumor Microenvironment–Driven Heterogeneity in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive form of cancer, with a 5-year survival rate of less than 13%. PDAC tumors exhibit spatial heterogeneity, which present both therapeutic challenges and potential vulnerabilities, ultimately leading to poor clinical outcomes. The mechanisms underlying this heterogeneity are not yet fully understood.

In our study, we utilized a combination of preclinical models and multi-center clinical data, integrating transcriptomic, proteomic, and bioimaging analyses derived from patient samples. We discovered a crucial interaction between tumor-intrinsic transcription factors and extrinsic inflammatory macrophages, which promotes the plasticity of epithelial/classical-like and mesenchymal/basal-like tumors while fostering an immunosuppressive environment. Our comprehensive analyses indicate that tumor-specific epigenetic regulatory programs inhibit pro-inflammatory signaling in classical tumors. This mechanism counteracts the activation of pro-inflammatory AP1-CCL2-TNF-α axis, thereby favoring a therapy-responsive phenotypic state. The significance of this dichotomous regulatory network is further highlighted by the presence of regional TNF-α+ macrophages, which correlate with a reactive tumor phenotype and a decrease in CD8+ T cell infiltration in PDAC patients. Notably, combining anti-TNF-α immunotherapy with chemotherapy effectively increases the infiltration of CD3+/CD8+ T cells in basal-like PDAC, resulting in improved survival outcomes. Overall, our findings indicate that the intrinsic epigenetic programs of tumor cells, along with extrinsic microenvironmental factors, drive intratumoral subtype heterogeneity and contribute to the progression of PDAC.

Hosted by Elisa Espinet –  Pancreatic Cancer group

Since 2022     Extension of Max-Eder Group Leader position, Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, UMG

Since 2018     Max-Eder Group Leader, Department of Gastroenterology, Gastrointestinal      Oncology and Endocrinology, UMG

2016-2017      Junior Group Leader, Department of Gastroenterology, Gastrointestinal

Oncology and Endocrinology, UMG

2014-2016      Postdoctoral Fellow at Barrow Neurological Institute, Phoenix, USA

2011-2014       Postdoctoral Fellow at Philipps-University of Marburg