Researchers at IRB Barcelona unravel a role for tumour suppressor genes in restricting the growth of neighbouring cell populations.

The study might have implications for understanding the early events of tumorigenesis and the selection of the tumour-initiating cells.
The healthy development of an organism depends on its tissues and organs growing to the right size, stopping when they need to, and maintaining stability in their form and function. Correct development depends on the availability of nutrients to the cells in their environment, a process that is tightly controlled by signalling mechanisms that occur within and between the cells that form these structures. Disruptions in this signalling can lead to unbalanced growth within a tissue or organ, and can give rise to conditions such as cancer.

The TOR and PI3K signalling pathways regulate tissue growth according to nutrient availability, and are frequently over-activated in human cancer. In the study published, Institute for Research in Biomedicine (IRB Barcelona) PhD student Ana Ferreira and Group Leader and ICREA Research Professor Marco Milán report that the over-activation of these two pathways not only causes the excess growth of cells and tissues, but also restrict the growth of neighbouring cell populations.

They present evidence that the proteoglycan Dally, a protein that is known to modulate the spreading, stability and activity of the growth-promoting signalling molecule called Dpp (in flies) or TGF-β (in humans), is regulated by these two pathways and mediates the effects on neighbouring populations. “They do so by competing for Dpp”, says Ana Ferreira, first author of the paper and funded by a PhD fellowship from Portugal’s Fundação para a Ciência e a Tecnologia.

‘PTEN, a gene that negatively regulates the PI3K pathway, is one of the most commonly lost tumour suppressors in human cancer. Understanding whether this pathway also affects TGF-β spreading in mammals may help us to gain insight into the early events of tumorigenesis and the selection of the tumour-initiating cells,’ she confirms.

‘Tumour initiating cells might be selected by their ability to compete for limiting growth factors and their capacity to restrict the growth of neighbouring cell populations,’ says Marco Milán, head of the Development and Growth Control Laboratory at IRB Barcelona. ‘Seventy percent of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis. It will be interesting to determine whether this mechanism, identified in fruit flies, is also active in humans.’ IRB Barcelona

By collecting samples from the portal vein — which carries blood from the gastrointestinal tract, including from the pancreas, to the liver — physicians can learn far more about a patient’s pancreatic cancer than by relying on peripheral blood from a more easily accessed vein in the arm.

Primary tumours shed cancerous cells, known as circulating tumour cells (CTCs), into the blood. These have been widely studied as prognostic biomarkers for various cancers. Because these cells are often larger, irregularly shaped and tend to cluster together, they get trapped in smaller vessels.

The authors hypothesized that most cells released from a gastrointestinal tumour would flow into the portal vein and then get sequestered by the narrow vessels in the liver. These cells would not reach the peripheral venous system. CTCs from gastrointestinal tumours are rarely identified in the peripheral blood until the cancer is widely metastatic.

To test this theory, researchers from the University of Chicago used an ultrasound-guided endoscope and a small needle to take blood from the portal vein during routine diagnostic endoscopies. They found CTCs in 100 percent of 18 patients with suspected tumours in the pancreas and bile ducts. Tests using peripheral blood samples, the standard method, detected tumours cells in only 4 of the 18 patients.

To test this theory, researchers from the University of Chicago used an ultrasound-guided endoscope and a small needle to take blood from the portal vein during routine diagnostic endoscopies. They found CTCs in 100 percent of 18 patients with suspected tumors in the pancreas and bile ducts. Tests using peripheral blood samples, the standard method, detected tumors cells in only 4 of the 18 patients.
‘We demonstrated that this method is potentially quite valuable as well as non-invasive, feasible and safe,’ said study director Irving Waxman, MD, professor of medicine and surgery and director of the Center for Endoscopic Research and Therapeutics at the University. ‘We had no complications related to portal vein blood acquisition.’ University of Chicago

IRB Barcelona has identified GEMC1 as a master gene for the generation of multiciliated cells—cells with fine filaments that move fluids and substances—which are found exclusively in the brain, respiratory tract, and reproductive system.

Defects in multiciliated cells lead to ciliopathies—rare and complex diseases that are poorly understood and for which not all causative genes have been identified.

The genomic sequencing of hundreds of patients with diverse types of ciliopathies has revealed that “in many cases the gene responsible is not known”, says Travis Stracker, head of the Genomic Instability and Cancer Lab at the IRB Barcelona. “So many people do not have a molecular diagnosis,” stresses the researcher. “Our work seeks to contribute to bridging this knowledge gap”.

A study on mice by Travis Stracker and his team, in collaboration with Vincenzo Costanzo’s laboratory at the FIRC Institute of Molecular Oncology (IFOM) in Milan, in which they reveal a gene candidate for a subtype of human ciliopathy. The gene in question, GEMC1, is indispensable for the generation of multiciliated cells specific to tissues such as the brain, trachea, lungs and oviducts.

The surface of multiciliated cells is covered by hundreds of cilia. These tiny, hairlike structures serve to circulate cerebrospinal fluid, remove mucus from the respiratory tract, and transport ovum through the oviduct, among other functions. Defects in the generation or function of these cells causes a subtype of ciliopathies called Mucociliary Clearance Disorders.

Specifically, GEMC1-deficient mice produced by Stracker reproduce the symptoms of a rare disease called RGMC (Reduced Generation of Multiple Motile Cilia)—a condition that causes hydrocephaly, severe respiratory infections, and infertility. The work, led by IRB Barcelona PhD student Berta Terré and IFOM postdoctoral researcher Gabriele Piergiovanni, reports that GEMC1 regulates the only two genes known to date that underlie this disease, Multicilin and Cyclin O, thus making it a potential candidate gene for RGMC.

In addition, the study has revealed that GEMC1 is one of the most important genes in the gene signalling cascade for the production of multiciliated cells. This means that this gene affects many others that depend on its expression. The gene expression analysis of this first study has revealed at least 10 new candidate genes related to cilia, as well as dozens that were already known or suspected of being involved in the function of cilia. IRB Barcelona

An international team that includes researchers at Sahlgrenska Academy has found a new genetic cause of osteoporosis. The findings set the stage for eventually curing the disease.

Osteoporosis is a common condition that leads to fractures with half of all women experiencing a fracture during their lifetime.

The discovery of a genetic variant has permitted researchers to link a particular gene to bone density and fractures. Follow-up studies have described the mechanisms by which the protein coded by the gene affects bone density.

Sahlgrenska Academy Professor Claes Ohlsson, who participated in the study, says, “Given that the EN1 gene has never been associated with osteoporosis before, we have a brand new pathway for developing drugs that can inhibit the condition.”

Directed by Canadian scientists, the international study initially examined highly detailed genetic data from 10,000 individuals and subsequently replicated the EN1 discovery in 500,000 others. The inclusion of so many subjects allowed the researchers to establish correlations between rare genetic changes and pathological conditions.

 “The study is clear evidence that uncommon genetic variants can have a significant impact on widespread diseases,” Professor Ohlsson says. “We have discovered a new mechanism for regulating bone density and fractures.” Sahlgrenska Academy, University of Gothenburg

While searching for  a non-invasive way to detect prostate cancer cells circulating in blood, Duke Cancer Institute researchers have identified some blood markers associated with tumour resistance to two common hormone therapies.

In a study, the Duke-led team reported that they isolated multiple key gene alterations in the circulating prostate tumour cells of patients who had developed resistance to abiraterone or enzalutamide.

Enzalutamide is a drug that blocks the male androgen receptor, and abiraterone is a drug that lowers testosterone levels. Both drugs are approved to treat hormone-resistant prostate cancer, but the tumours typically develop resistance within a few years. 

The study, focusing on a small number of patients and using sophisticated blood analysis technology, demonstrated that circulating tumour cells detected in blood have the potential to reveal important genetic information that could guide treatments selection in the future, and suggest targets for new therapies.

“We have developed a method that allows us to examine the whole genome of rare circulating cancer cells in the blood, which is unique in each patient, and which can change over time during treatment,” said senior author Andrew Armstrong, M.D., a medical oncologist and co-director of Genitourinary Clinical-Translational Research at the Duke Cancer Institute (DCI).

“Among the genomic changes in the patients’ individual cancers, we were able to find key similarities between the cancer cells of men who have hormone-resistant prostate cancer,” Armstrong said. “Our goal is to develop a ‘liquid biopsy’ that would be non-invasive, yet provide information that could guide clinical decisions.”

Armstrong and colleagues from the DCI and the Duke Molecular Physiology Institute used a process called array-based comparative genomic hybridization to analyse the genome of the circulating tumour cells of 16 men with advanced, treatment-resistant prostate cancer. The technique enabled them to determine which genes had extra copies and which regions were deleted.

Focusing both on genes that have previously been implicated in tumour progression, plus other genes important to cancer biology, the researchers found changes in multiple genetic pathways that appear to be in common among the men’s circulating tumour cells.

“Our research provides evidence supporting the ability to measure gains and losses of large scale sections of the circulating tumour cells genome in men with prostate cancer,” said co-author Simon Gregory, Ph.D., director of the Section of Genomics and Epigenetics in the Duke Molecular Physiology Institute. “We are now evaluating this method combined with higher resolution DNA mutational studies and measurements of RNA splice variants in CTCs to determine their clinical relevance to patients and treatment resistance.”

Should these common alterations be similarly identified in larger studies, they could be used as biomarkers as part of a blood-based liquid biopsy to help determine what treatments would be most effective. The findings could also point to new targets for drug development.

One such large prospective clinical validation study is underway now at the Duke Cancer Institute, which is examining how the mutations develop in the context of enzalutamide or abiraterone therapy, and how the mutations relate to other key genetic events.

Duke University corporate.dukehealth.org/news-listing/duke-team-identifies-blood-biomarkers-drug-resistant-cancer-tumor-cells?h=nl