KFO 337:  Phenotypic Therapy and Immune Escape in Cancer (PhenoTImE): pre-clinical and translational advance of the CRU 337

• Subject Area: Medicine
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405344257

While genetic evolution undoubtedly contributes to the survival of cancer cells to therapy, accumulating clinical and experimental evidence highlights the role of non-genetic mechanisms for therapy resistance. Tumor cell subpopulations can dynamically switch their identity (and therapy vulnerability) depending on the respective therapeutic, immunologic, and microenvironmental context. Interestingly, the underlying biologic principles seem to be similar across cancer types, but the molecular key regulators are yet to be identified. PhenoTImE created a collaborative research infrastructure at the University Hospital Essen assembling eight interdisciplinary groups consisting of basic and clinician scientists and providing a complementary set of technologies, expertise, and early career development measures. During the last 2 years, we found that drug-tolerant persister cells from different cancers share similar epigenetic and metabolic rewiring strategies providing an important survival benefit. We developed patient-derived cell systems, tumor explant and mouse models for the longitudinal characterization of dynamic cell state transitions in melanoma, pancreatic ductal adenocarcinoma, and glioblastoma and identified first candidate mechanisms that reciprocally drive non-genetic drug and immune resistance. Concrete upstream tumor-intrinsic regulators include histone demethylases and FGFR/AKT signaling. In addition, the oncogenic PI3K/PTEN/AKT pathway, the HLA-II expression state of tumor cells, the paracrine IFN-γ level, and chemotactic molecules such as CXCL1 evolved as key targets controlling tumor cell state-depended T cell and neutrophil activation. En route to enhancing our mechanistic understanding by preclinical models, we also made significant progress in improving resistance biomarkers for potential translation into the clinic. Although the experiments of the first funding period (FP1) are still ongoing, some findings and technologies established already allow proposing an extended set of aims and research perspectives for FP2. We learned that therapy resistance -once fully developed- might be difficult to control due to emerging molecular complexity and cell state heterogeneity. Thus, we hypothesize that therapy and immune escape might be better tackled, if resistant cell states are co-targeted during the initial therapy phase or at therapy onset. We will focus on the characterization of tumor cell states in their natural tissue environment and on co-manipulation of drug and immune resistance in pre-clinical models at therapy onset. Our data will be integrated into consortial bioinformatic pipelines together with public datasets, always in a clinicopathologic-prognostic context. PhenoTImE as a research platform has demonstrated high significance for the Essen oncology priority becoming an important starting point for additional translational research activities and clinical trials in near future.

• DFG Programme: Clinical Research Units
• International Connection: Australia, Belgium, Israel, USA

Projects

• Adaptive epigenetic and metabolic regulation of redox circuits in drug persisting pancreatic cancer cells (Applicant Siveke, Jens T. )
• Building health intelligence with complex data on tumor cell states and therapy resistance (Applicants Horn, Susanne ;  Schadendorf, Dirk )
• Coordination Funds (Applicant Roesch, Alexander )
• Deconvoluting mitochondria plasticity and functionality in PDAC metastasis and therapy response (Applicant Grüner, Barbara )
• Dissecting and targeting HLA class II-positive melanoma cell states in therapy resistance (Applicant Paschen, Annette )
• Epigenetic maintenance of the redox balance in therapy-persisting tumor cell states (Applicant Roesch, Alexander )
• Identification and functional characterization of long non-coding RNAs as epigenetic determinants of therapy resistance in BRAF-driven cancers (Applicant Remke, Marc )
• Immune response persisting melanoma cells: Mechanisms of immune escape (Applicant Becker, Jürgen Christian )
• Targeting clonally expanding drug-resistant tumor cells in recurrent glioblastoma – FP 2: Co-clinical exploitation of epigenetic maintenance. (Applicant Scheffler, Björn )
• Unraveling the plasticity and tumor-promoting role of neutrophils as a function of tumor heterogeneity (Applicants Gunzer, Matthias ;  Helfrich, Ph.D., Iris )

• Spokesperson: Professor Dr. Dirk Schadendorf
• Leader: Professor Dr. Alexander Roesch
• Project Heads: Professor Dr. Jürgen Christian Becker; Professorin Dr. Barbara Grüner; Professor Dr. Matthias Gunzer; Professorin Iris Helfrich, Ph.D.; Dr. Susanne Horn; Professorin Dr. Annette Paschen; Professor Dr. Björn Scheffler; Professor Dr. Jens T. Siveke