Modeling spontaneous Breast cancer metastasis TO the Bone with a first-of-its-kind 3D device that recapitulates physiological tissue-level complexity.

Project Information

B2B

Grant agreement ID: 801159

DOI

10.3030/801159

Project closed

EC signature date 25 May 2018

Start date 1 July 2018

End date 31 December 2022

Funded under

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Total cost

€ 3 799 371,25

EU contribution

€ 3 799 371,25

Coordinated by

CONSIGLIO NAZIONALE DELLE RICERCHE
Italy

Periodic Reporting for period 3 - B2B (Modeling spontaneous Breast cancer metastasis TO the Bone with a first-of-its-kind 3D device that recapitulates physiological tissue-level complexity.)

Reporting period: 2021-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

The EU-funded project B2B is doing research for researchers, to bring recent advances in fluidic systems and 3D printing to the biomedical sector and develop a breakthrough in vitro alternative to animal models that is more clinically relevant in the study of cancer metastasis. B2B was inspired by the frustrations and difficulties that the biomed researchers have to face day by day. In cancer research, for example, scientists are missing reliable models to advance their research. The general discontent is related to the faults of available models, unable to capture the complexity of the human disease.
Animal models, on the one hand, offer a unique venue to insert a tumour in a complex system made of connected organs. But human-derived cancer becomes surrounded by a non-human physiological system. Therefore, the growth, development and response to drugs might differ, resulting in false positives that waste researchers’ time and money. The human metastatic process is even harder to reproduce in an animal model as it requires multiple connected organs.
On the other hand, the available in vitro approaches are generally bi-dimensional and lack the 3D complexity of a living organ. For example, standard cell cultures on a monolayer are an isolated system in which cells don’t behave differently according to the position and exposure, a behaviour far from the heterogeneity typical of cancer cells.
To not jeopardize the reliability of the results and to understand the mechanism of metastasis, in vitro models should include all the factors that affect the process and better resemble the human physiology.
The device developed within B2B will become the first cancer model that brings in vitro the 3D upgrade in clinically-relevant dimensions (macro-size tumour tissues), all in a connected system entirely based on human physiology.

The new technology should overcome the drawbacks of today’s in vitro and in vivo models by mimicking the human physiology as a system of connected organs. The connection via a fluidic system is particularly critical in B2B, as it will use macro-to-micro bioprinted vases that should reproduce the different sizes, branching and features of the blood vessels and at the same time be directly connected to the capillaries from the tumour tissues.
B2B has selected the metastatic process of breast cancer to the bone as its first application, since it represents a major hurdle in the fight of breast cancer. Breast cancer is the most common in women worldwide (25.4% of the total number of new cases diagnosed in 2018) and its most common metastatic site is indeed the bone (70% of the cases). In the B2B device, a patient-derived breast cancer lesion will be connected to an in vitro reconstructed bone, a marrow-containing ossicle. However, the technology developed in B2B is versatile and the same system might be applied in the future to study other types of cancers with similar features.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

B2B is developing a breakthrough in vitro alternative that is more clinically relevant than tumor spheroids and closer to human physiology than animal models.
In the B2B multidisciplinary team, scientists involved in cancer research work side by side with engineers and material scientists to develop an ad hoc technology that will simplify and enhance their research.
During the first half of the project, all the partners are working to fine-tune each one of the components of the final device:

i) In the breast cancer chamber, the setup of a primary tumor lesion has been implemented with one patient-derived cancer model. Furthermore, The Consortium has formally demonstrated the potential of the primary tumor of the B2B device to spontaneously generate CTCs and, as a consequence, metastasis.

ii) In the bone chamber, in vitro mineralized constructs have been combined with additional cell types for the purpose of recapitulating and studying complex cell interactions that may be relevant for bone metastasis.

iii) For the micro-network, made by self-assembled capillaries, the B2B team has established conditions to enable their growth together with breast cancer or chondrogenic cells.

iv) For the macro-vascular network, built as a set of vessels bio-printed into and around the micro-vascularized organoids, the consortium has collected several data to optimize their design, their coating polymer and ensure the formation of an endothelial surface.

At this stage, the Consortium has successfully designed and 3D printed the second prototype of the B2B device, in which several fluidical and biological tests have been carried out to optimize the platform usability and susceptibility to contaminations. The study has been enriched with simulation and computational analysis of the blood-like flow into the device network.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

B2B has selected the metastatic process of breast cancer to the bone as its first application since it represents a major hurdle in the fight of breast cancer. Breast cancer is the most common in women worldwide (25.4% of the total number of new cases diagnosed in 2018) and its most common metastatic site is indeed the bone (70% of the cases). In the B2B device, a patient-derived breast cancer lesion will be connected to an in vitro reconstructed bone, a marrow-containing ossicle. However, the technology developed in B2B is versatile and the same system might be applied in the future to study other types of cancers with similar features.

With B2B, we want to develop an in vitro alternative that is more clinically relevant than the available models and that is specifically conceived to study the metastatic process. It’s a bottom-up project that responds to the scientists’ request for a reliable model; therefore the new technology should first bring tangible benefits to researchers, enabling them to finally validate hypotheses that never saw the light of day. Nevertheless, on the long-term we expect a great impact in the society as a whole, since achieved results might reduce failures during preclinical studies, resulting in new therapies that will reach the market in a faster and more cost-competitive way.

The distinguishing factor of B2B, and the one that brings most of its complexity, is the size of the involved tissues, which require a 3D approach and an extensive network of capillaries to penetrate the whole mass (range of cm3).
From there, the need to integrate the macro- and micro-networks, which is is one of the most innovative points in B2B and that should result in a vascular system with a smooth transition from the macro- to the micro-scale. This is, to the best of our knowledge, the first time that it would be implemented. The B2B platform, therefore, won't just be an incremental new technology but a truly revolutionary one, that proposes a new in vitro model that outperforms the animal models.

3D rendering with the metastasis travelling in the vascular network within the B2B device the