Deciphering the role of poroelasticity in tumor dynamics using multiscale acoustic probing – PoroTume

Despite deeper understanding of cancer metabolism, 90% of experimental drugs fail in clinical studies, mostly due to lack of efficacy. This stems from the lack of predictability of in vitro and in vivo models that are used to design generic drugs at preclinical stages, and from the limited histophysiological clues that can guide clinicians in adapting the generic therapy to each patient. At the same time, it is now well established that the mechanical properties of tumours control their physiology. Tumours have a complex structure containing several cell types, connected together by transmembrane bonds or extracellular matrix interactions. From a mechanical point of view, this structure can be recapitulated as an elastic frame invaded by biological fluids, with a behaviour resembling that of poroelastic materials. As such tumours are comparable to sponges soaked with biological fluids, where permeability drives resistance to fluid flow and cohesivity dictates the elasticity of the skeletal frame. The role of elasticity and permeability in growth, invasivity and response to drugs is largely unknown due to the lack of characterisation techniques. POROTUME aims at deciphering the link between poroelasticity and mechanisms of drug action to obtain an integrated description of tumour biology.

It is necessary to recreate the mechanical complexity of tumours in in vitro models with a reductionist approach to test innovative therapies and implement new characterization techniques. Organoids are powerful in vitro models that are widely used in standardized preclinical studies to accelerate the translation of novel therapeutics to the clinic, but also as a tool to understand precisely tumour physics and biology. Formed from the controlled assembly of individual cells, they describe closely the complex tumour organisation, physiopathology and microenvironment. However these models challenge the standard microscopy techniques that use of fluorescent tags, which alter normal cell functions and eventually kill cells, hindering the study of drug kinetics over standard therapeutic time scales. Most importantly, they provide a contrast that does not reveal mechanical properties. For this, the impact of tumour mechanics on the response to drugs has been largely ignored, and novel imaging techniques that would incorporate mechanical properties as the contrast mechanism are sorely needed. Inspired by early theories of poroelasticity, we want to translate their experimental implementation in large scale geological systems to a tinier scale on organoids using optoacoustic techniques.

We will implement non-invasive mapping of the poroelasticity by detecting mechanical signals from the quasi-static range with opto-mechanical force sensors to the hypersonic range using light-scattering technologies. The analysis of the mechanics observed at contrasted time scales will allow probing elasticity and resistance to fluid flow. The poroelastic properties of organoids have never been studied, and the application of opto-acoustic techniques to life science is only starting to emerge. We therefore need to do the spadework for deciphering the link between poroelastic parameters and the structure of the organoid. We will compare the opto-acoustic measurements on organoids of increasing complexity in terms of composition and resistance to drug action to identify the key features of organoids. On these models, we will evaluate the impact of clinically relevant drug therapies using poroelasticity as a quantitative indicator, thereby optimizing dosimetry and exposure time to the treatment. The knowledge generated by POROTUME will improve the predictability of in vitro models, and open new mechano-sensitive therapeutic routes. Furthermore, our results will define new mechanical indicators complementing histological data. The technologies we use hold great potential for in vivo translation and should provide new tools to guide clinicians in personalizing a therapy.