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B2B partners at the University of Basel have recently released a review article highlighting recent discoveries about the exquisite regulatory role of blood vessels in bone development and repair.  

As highlighted by our collaborators Andrea Banfi and Nunzia Di Maggio from the Cell and Gene Therapy Laboratory at the Basel University Hospital and the University of Basel, blood vessels in the proximity of the main site of longitudinal growth of the long bones features a specialized endothelium that regulates the proliferation and differentiation of bone cells through the secretion of molecular signals.

Furthermore, it is a hub for the bidirectional molecular crosstalk between the different cell populations of the bone microenvironment. These vessels are a key target for current approaches aiming at coupling the formation of blood vessels and bone for bone repair. Open questions remain about their presence and feature in not stereotyped tissues, like engineered bone grafts, and the opportunities for their clinical stimulation by pharmacological treatments. 

The metastatic spread of cancer is achieved by the dissemination of circulating tumor cells (CTCs) in the blood. To date, cancer research has not paid much attention to the question of when tumors shed such CTCs. Researchers previously assumed that tumors release CTCs continuously. However, a new study by our partners at ETH Zurich, the University Hospital Basel, and the University of Basel has now come to a surprising conclusion: CTCs that later form metastasis mainly arise during the sleep phase of the affected individuals. The results of the study have just been published in the journal Nature. 

“When the affected person is asleep, the tumor awakens,” summarises the B2B partner and study leader Nicola Aceto, Professor of Molecular Oncology at ETH Zurich. During the study, which included 30 female cancer patients and mouse models, Prof. Aceto’s team found that the tumor generates more circulating cells when the organism is asleep. Cells that leave the tumor at night also divide more quickly and therefore have a higher potential to form metastases, compared to circulating cells that leave the tumor during the day. 

“Our research shows that the escape of circulating cancer cells from the original tumor is controlled by hormones such as melatonin, which determine our rhythms of day and night,” says Zoi Diamantopoulou, the study’s lead author and a postdoctoral researcher at ETH Zurich. 

The researchers’ next step will be to figure out how these findings can be incorporated into existing cancer treatments to optimize therapies. As part of further studies with patients, ETH Professor Nicola Aceto wants to investigate whether different types of cancer behave similarly to breast cancer and whether existing therapies can be more successful if patients are treated at different times. 

Reference: Diamantopoulou Z, Castro-Giner F, Schwab FD, et al. The metastatic spread of breast cancer accelerates during sleep. Nature. 2022:1-7. doi: 10.1038/s41586-022-04875-y 

Progress in detection and treatment have drastically improved survival for early breast cancer patients. However, distant recurrence causes high mortality and is typically considered incurable. Cancer dissemination occurs via circulating tumor cells and up to 75% of breast cancer patients could harbor micrometastases at the time of diagnosis, while metastatic recurrence often occurs years to decades after treatment. During clinical latency, disseminated tumor cells (DTCs) can enter a state of cell cycle arrest or dormancy at distant sites, and are likely shielded from immune detection and treatment. While this is a challenge, it can also be seen as an outstanding opportunity to target dormant DTCs on time, before their transformation into lethal metastatic lesions.  

Recently, our partner Prof. Nicola Aceto and his team at the Institute for Molecular Health Sciences of the ETH Zurich, have reviewed and discussed progress made in the understanding of DTC and dormancy biology in breast cancer. Strides in the mechanistic insights of these features have led to the identification of possible targeting strategies, yet, their integration into the clinical trial design is still uncertain. The authors suggest that incorporating minimally invasive liquid biopsies and rationally designed adjuvant therapies, targeting both proliferating and dormant tumor cells, may help to address current challenges and improve precision cancer care. 

The study of spontaneous breast cancer metastasis in vivo with patient-derived material generally fails to reproduce the metastatic behavior observed in patients, whereas the major metastatic site is the bone, which is indeed the target organ selected to be featured in the B2B device. 

A recent study from our partners at Prof. Nicola Aceto’s lab (now at ETH Zurich) provides evidence that when using metastasis-derived Circulating Tumor Cells (CTCs) rather than primary tumor cells as the source of transplanted cells in the in vitro / in vivo models, the consequent metastatic profile mirror the disease status of the original patient at the moment of CTC isolation. 

This method can be completed with CRISPR-based genetic screens for unbiased identification of disease-relevant genes, including specific genetic dependencies for each step of the metastatic process in vivo. For example, the results of this approach allowed us to pinpoint previously unappreciated genes whose expression regulates CTC cluster formation, as well as genes that regulate the intravasation of both single and clustered CTCs and organ-specific metastasis.  

Therefore, this novel CTC-based tool helps to study spontaneous breast cancer metastasis in a highly clinically relevant fashion. This model, in combination with a CRISPR-based approach, represents a new tool to reclassify driver genes involved in the spread of human cancer, providing insights into the biology of metastasis and paving the way to test targeted treatment approaches.  

Our partner React4Life has won the European Innovation Radar prize for ‘Innovative Health Tech’ for their organ-on-a-chip solution that supports the development of personalised drugs and can accelerate the development of new therapies.

The European Commission has awarded prizes to some of the most promising innovations in Europe that have emerged from EU-funded research and innovation projects. The Innovation Radar is a Commission initiative, which highlights innovations emerging from research and innovation projects financed by the EU under Horizon 2020 and Horizon Europe, the EU’s research and innovation programmes for 2014-2020 and 2021-2027 respectively. This annual competition has been held since 2015, awarding prizes to the best EU-supported innovators who have developed solutions that can reach the market.

Drug absorption, distribution, metabolism, and excretion are biological processes that involve several organs (i.e. intestine, liver, kidneys), finally determining the drug levels in tissues and thus its correct function. If not adequate, these processes can cause the failure of drugs and impair their approval. For this reason, their correct evaluation of drug metabolism is a fundamental step in the drug discovery pipeline. New in vitro models, not as complex as the one proposed by the B2B project, come in handy to speed up the study of drug absorption and metabolism.

A recent review by the group of Silvia Scaglione, the B2B project coordinator, provides an overview of recent advances in in vitro models that mimic the intestinal barrier for pharmaceutical screening: 2D traditional monolayers, complex multicellular 3D systems which display a good correlation with clinical data, and emerging fluid-dynamic platforms that closely recapitulate the intestinal physiological cues, but still need to be standardized.

The ossicle generated by the team of Prof. Farrell at the Erasmus University Medical Center is derived from cells from patients, children who underwent surgery to have their cleft palate reconstructed. “If there are leftover bone chips from the surgery, we can then take them and isolate the marrow stromal cells. After growing these cells in the lab, we can generate pellets and turn them into cartilage.” The original material is harvested for the reconstruction surgery and the leftover material, if not used for research purposes, would have been thrown away. This is done with implicit consent according to the regulations of the medical ethical committee of Erasmus MC. Patients, or their responsible carers, are informed about this possibility and if they disagree, they can opt-out from the waste material being used in this manner.

“We wouldn’t be able to do our work without those cells; they are the only source for the tissue, so precious for us,” says Dr. Farrell. The experiments in his lab need a constant supply of bone-generating cells, but this type of cells can’t be immortalized. “We can grow them in the lab and replicate them, but only up to a certain extent. Afterward, they became exhausted and we need a new supply – that’s why the tissue donation is so important for us.” The analysis performed by Eric and his group concern only general biological features of the cells; no sensitive or genetic data are collected. The anonymous donors feel generally comfortable with this procedure, yet, with simple action, they provide a valuable contribution to our research.

In tissue engineering, the combination of multiple cell types and the employment of 3D cell culture is becoming the new norm, as it better resembles human physiology. “What makes B2B stand out among other multicellular 3D culture is the scale”, says Dr. Eric Farrell from the Erasmus University Medical Center. “In B2B the tissues have a physiologically relevant dimension (cm³), and thanks to that, we can reproduce gradients of oxygen and nutrient diffusion – which are ultimately responsible for important features in the spread of the disease. This makes the B2B device unique.”

According to Dr. Farrell, several aspects of the device might find applications outside the project’s scope; for example, the study of extravasation and migration of breast cancer cells might be applied to other types of cancers. “The innovative vascular component surely will find other applications as it is very relevant in human physiology. More difficult is the substitution of the bone chamber with another type of organ, not cancerogenic,” says Eric.  “What we are learning about the bone is not easily transferable to other tissues. One would need to start again from scratch, study the generation process for the tissue as we are doing now for the ossicle.” says Prof. Farrell “But by assembling together all the components of the B2B device we are learning so many important lessons, especially at the interfaces.” Indeed, the experience gained with B2B will serve as a roadmap for similar devices, regardless of the tissues featured within.