Stories about: molecular profiling

Deconstructed ‘death receptors’ suggest new ways to tackle cancer, autoimmune disease

death receptors apoptosis cancer autoimmune
The 3-D structure of the Fas death receptor’s transmembrane region, consisting of three tightly packed helices shown here from three angles. Cancer-causing mutations deform this structure, preventing “time to die” signals from passing through. (Fu Q; et al. Molecular Cell, Feb. 5, 2016).

Programmed cell death, or apoptosis, helps keep us healthy by ensuring that excess or potentially dangerous cells self-destruct. One way cells know it’s time to die is through signals received by so-called death receptors that stud cells’ surfaces. When these signals go awry, the result can be cancer (uncontrolled cell growth) or autoimmune disease (cells self-destructing too readily).

Researchers at Harvard Medical School (HMS) and the Program in Cellular and Molecular Medicine at Boston Children’s Hospital deconstructed a death receptor called Fas to learn more about its workings, using nuclear magnetic resonance (NMR) spectroscopy to reveal its structure.

They found that for immune cells to hear the “time to die” signal, a portion of Fas called the transmembrane region must coil into an intricate three-part formation, allowing the signal to pass into the cell. The NMR imaging also revealed that the amino acid proline is critical for the formation’s stability. Cancer-causing mutations in the transmembrane region (one of them affecting proline itself) deformed this delicate structure and prevented signals from passing through.

This better understanding of the Fas death receptor, published last week in Molecular Cell, could lead to new approaches that bypass Fas to encourage apoptosis in cancer or, conversely, inhibit Fas in autoimmune disease.

Read more on HMS’s news site.

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Challenging the dogma on deadly brain stem gliomas

Nestled in the pons (the red area above), the area that controls breathing, DIPG tumors have been impossible to biopsy and analyze for therapeutic insights. Until now. (MEXT Integrated Database Project/Wikimedia Commons)

Brain tumors can be very difficult to treat, but at least we know what to do about them. For years, a mix of surgery, radiation and chemotherapy has been used to treat brain tumors like medulloblastoma.

These treatments are fairly successful, but for a rare, almost always fatal tumor called diffuse intrinsic pontine glioma (DIPG), we haven’t had any success—in fact, we haven’t known where to start.

The problem has to do with where DIPGs are located: nestled among the nerves in a portion of the brain stem, the pons, that controls critical functions like our breathing, blood pressure and heart rate.

“For 40 years, we lacked the neurosurgical techniques to biopsy DIPGs safely,” say Mark Kieran, MD, PhD, director of the Brain Tumor Program at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC). “In fact, one of the first lessons every oncologist is taught still is, ‘Don’t biopsy brain stem gliomas.’ The dogma was that the risk of severe or fatal damage was too great.” And because we couldn’t biopsy them, we couldn’t study them to learn what makes them tick.”

A lot can change in four decades. Techniques for operating on the brain have advanced considerably, as have the tools for probing tumors at the molecular level. So, looking to turn the dogma about DIPGs on its head, Kieran has launched a clinical trial that aims to use advanced surgical and diagnostic tools to target and individualize DIPG treatment.

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Childhood brain cancer: Learning to divide and conquer

Molecular fingerprints for two of the six tumor subtypes (courtesy Pomeroy and Cho)

Diversity is good in populations of people, but when it comes to cancer, it’s bad news. In the case of medulloblastoma—the most common malignant brain cancer in children—tumor diversity has been one of the greatest barriers to designing effective treatments.

Now, in the largest genomic study of human medulloblastomas ever, Children’s researchers and their collaborators have subdivided the cancer into six different diseases—each with distinct molecular “fingerprints.” Knowledge of these tumor subtypes will improve neurologists’ ability to direct and individualize treatment. One subtype, carrying the worst prognosis, had never before been characterized.

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Patients and genes: Getting personal through information technology

Not long ago I sat in a room with a young patient and her parents, struggling to devise a treatment that would slow down the growth of her aggressive tumor, which continued in spite of intensive chemotherapy. We knew that the tumor was distinct — it responded to certain combinations of chemotherapy but not others — but we knew little about what drove its growth, and less about how to target our treatment for cure.

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Personalized rational medicine for all

Electrospray needle of a mass spectrometer

As a medical student at the last century’s end, I was taught to practice evidence-based medicine, to use the scientific method instead of the largely anecdotal, experiential practice of the physicians that came before. At this century’s beginning, medicine has begun yet another tectonic shift, termed personalized medicine.

Striving to use information about individual patients to their own benefit is probably as old as medicine itself.

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