Synthetic cell-based analysis of biophysical adaptations in the tumor immune microenvironment

• Applicant: Dr. Oskar Staufer
• Subject Area: Biophysics ; Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525255627

Cancer cells adapt their phenotype as well as their surrounding microenvironment to evade elimination by the immune system. A fundamental understanding of this adaptive evasive behavior is urgently required to develop more effective immunotherapeutic strategies. However, the mechanisms underlaying immune evasion have mostly been studied with a focus on biochemical processes, although cumulating evidence suggests that the biophysical context needs to be considered to reach mechanistic insights. Within tumors, physical cues, such as adhesion forces and stiffness gradients, act in concert with biochemical signaling pathways to potentiate immune evasion. The molecular complex interplay between mechanical and biochemical stimuli, together with a lack of suitable tools that allow to probe and tune both stimuli simultaneously but independently, has hindered progressive understanding of adaptivity in immune evasion. Within this program, I will tackle the complexity challenge of physico-chemical stimuli in the tumor immune microenvironment (TIME) by a systematic analysis based on bottom-up assembled artificial cells. Towards this, I aim to develop artificial cells that allow to measure adhesion forces, alter tumor tissue stiffnesses and simultaneously trigger immune-related biochemical signaling in cancer cells. To perform this analysis in a tumor-like environment, the artificial cells will be incorporated into 3D tumoroids to form hybrid in vitro tissues with defined artificial TIMEs. Three distinct artificial cell systems will be developed to correlate signaling, adhesion and stiffness phenomena during immune evasion: 1. giant unilamellar vesicles equipped with immune proteins to trigger reverse signaling in cancer cells (signaling) 2. Droplet-supported lipid bilayers coupled to DNA-based cadherin force sensors (adhesion) and 3. Silica colloidosomes with integrated enzymatic machineries to secrete artificial extracellular matrix into the tumoroids (stiffness). The developed synthetic cells will lay the technological fundament to decouple biochemical from mechanical effects in the TIME and study their functional interplay by quantitative light imaging and molecular profiling. The success of this ambitious program relies on the powerful synergy between my expertise in cellular biophysics, synthetic biology and molecular immunology. Hosted between the resource rich setting of Saarland University (Centre for Biophysics), the Helmholtz Institute for Pharmaceutical Research and the Leibniz Institute for New Materials, I will contribute fundamental knowledge on the development of life-like artificial systems to interrogate immune processes. More broadly, this interdisciplinary project will open up perspectives for artificial cell technologies capable of mimicking and manipulating tissue patterns and functions. The support from the Emmy Noether program will allow me to establish a unique profile at the intersection of immunophysics and synthetic biology.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: System for parallel plate compression analysis
• Instrumentation Group: 4190 Spezielle Geräte der Mikrosystemtechnik