“Only if we understand the molecular and cellular mechanisms that give rise to cancer and metastases can we exert a decisive influence on the treatment and prevention of this disease,” says Mohamed Bentires-Alj.
This article was originally published in June 2015.
Published on 18/06/2020
Statistically, every third Swiss citizen is set to develop cancer once during his or her lifetime. But cancer does not constitute a single disease. As much as each patient differs from another, the types of cancer can vary greatly – in fact, there are more than two hundred different tumor types. Due to this variety, today’s cancer research is focused on investigating the molecular and cellular mechanisms that influence tumor development and growth as well as the formation of secondary tumors, so-called metastases.
“Only if we understand the fundamental molecular and cellular mechanisms by which the cancer develops and progresses to metastasis, can we make a great impact for the prevention and treatment of this disease,” says Mohamed Bentires-Alj, Group Leader at the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel.
This scientist, who has an educational background in pharmacy, has dedicated his research to breast cancer, the most common tumor type in women. The risk of breast cancer increases the earlier menstruation starts, the later a woman becomes pregnant, and the later she eventually reaches menopause. “Female hormones have an effect on the development of the breast, and likely also in the development of breast cancer,” says Bentires-Alj who also has been studying the mechanisms underlying the protective effect of an early pregnancy on breast cancer.
Cancer stem cells as a point of attack
Although more than 5500 women and around 40 men in Switzerland fall ill with breast cancer each year, two-thirds of these patients can now survive 10 years or more after therapy. Most fatal cases are due to metastases, when the tumor spreads to other body parts.
“One of the most important and exciting scientific challenges in cancer biology today is tumor heterogeneity. This issue remains unsolved, it is puzzling, and has enormous clinical implications. Tumor heterogeneity is the common thread of our research,” says Bentires-Alj. With the enzyme SHP2, Bentires-Alj was recently able to identify a marker that is associated with a poor prognosis for malignant tumors. “We discovered that SHP2 promotes breast cancer progression and maintains tumor-initiating cells.”
Here SHP2 plays a critical role in the so-called cancer stem cells. These are special cells inside a tumor that keep the tumor alive, and they were implicated in metastasis formation and in resistance to therapy. SHP2 thus serves as a promising point of attack for finding a new therapy.
Building bridges
Born in Morocco, Bentires-Alj is a strong supporter of knowledge transfer networks and interdisciplinarity. He considers it crucial that his findings eventually make their way into clinical applications. He says: “We are at the beginning of an era in which we see cancer as an organismal disease and in which basic scientific discoveries are making their way to the clinic.” In 2009, for example, he established the European Network of Breast Development and Cancer Labs, which he has chaired since its founding. It has received considerable recognition among professionals in the field. In the Basel region, too, he promotes the exchange of information among universities, hospitals and industry through his founding of the Basel Breast Consortium (BBC). BBC will now extend to institutes, industries and hospitals in all of Switzerland.
Bentires-Alj is convinced that industry is also seeking to deepen the ties with academic research: “Today we want to know exactly why tumors are heterogeneous and why a given therapy works and what possible undesirable side effects it could have before we bring a drug to market.” Following his postdoctoral training at Harvard Medical School in Boston, he intentionally chose to work at the FMI because the institute – which is affiliated with the Novartis Institutes for BioMedical Research (NIBR) and the University of Basel – has a reputation for closely collaborating with academia and industry. In the past few years, the FMI has pursued numerous collaborations with various NIBR research groups. For example, Bentires-Alj’s group has collaborations in the areas of Oncology and Autoimmunity, Transplantation and Inflammatory Diseases (ATI), with the Developmental and Molecular Pathways group (DMP) and the Center for Proteomic Chemistry (CPC), plus additional projects with the Pharmaceuticals division.
“The cooperation with Mohamed Bentires-Alj from the FMI is a great example of the collaborative culture we share between NIBR and our affiliated institutions,” said Dhaval Patel, Head of NIBR Europe. “By leveraging our complementary know-how and expertise in immunology and tumor biology we were able to gain new insights into the mechanism of breast cancer metastasis.” Further testimony to the collaborative spirit was a joint mentorship of a postdoctoral candidate, whose research project was recently published in Nature.
“Another factor that eases our collaboration is that I am already very well acquainted with many NIBR investigators because we worked together at Harvard,” says Bentires-Alj.
Putting immune cells to use
A particularly close collaboration exists with the scientists in the ATI group – a tie-up that may only seem to make sense at a second glance. Yet, the body’s immune system plays a key role in fighting cancer because antibodies can bind cancer cells. The immune response against tumors is being put to use by scientists in an increasing number of new ways. For example, one can harness the immune system to attack cancer cells. In addition some innovative compounds couple an active ingredient to antibodies, allowing specific targeting of tumor cells. This contrasts sharply with traditional chemotherapies, which target all the cells in the body – even healthy ones – and sometimes lead to severe side effects. Oncologists and immunologists have been working hand in hand for a long time. Since his early days as a scientist, Bentires-Alj has been very interested in both disciplines. “After my studies, I had to decide on what to specialize in and selected cancer research. But thanks to immuno-oncology I can tie my interest in both areas together.”
Things turn out differently …
The collaboration with the ATI group has since resulted in several key findings. These were published in Nature in November 2014 and have won broad acclaim. Bentires-Alj and his Novartis colleague Tobias Junt showed that a much-vaunted approach to treating metastatic breast cancer has extremely negative effects when the treatment is stopped.
The active ingredient that Junt and Bentires-Alj studied blocks the signaling molecule CCL2, which is known to attract white blood cells, the so-called monocytes, to the center of a tumor, where they promote its progression to metastases. “We wanted to bypass the challenging issue of cancer heterogeneity by interfering with the less heterogeneous tumor microenvironment, and it worked: While neutralization of CCL2 had no effect on primary tumor growth, it greatly decreased metastases,” says Bentires-Alj.
Bentires-Alj and Junt, however, wanted to find out what happens when this therapy is stopped. They were very surprised to see that discontinuing the therapy has devastating consequences, as they registered a sharp increase in the formation of metastases. The monocytes, which had been retained within the bone marrow by the inhibitor, now poured into the tumor and into already existing metastases as if there had been no therapy at all.
For Bentires-Alj, it is evident that research must be conducted thoroughly and cautiously. “It’s important to be very careful when you interfere with the tumor microenvironment,” he explains. True, some therapies that take advantage of the patient’s immune system can be very helpful, “but only if we fully understand the molecular mechanisms and can assess the long-term impact a procedure can have.” This, however, does not mean that CCL2-based treatments cannot be used at all. In fact, scientists are working together to use additional therapies to limit the observed effect and the findings of Bentires-Alj and Junt have provided good hints.
