January 18 Research Roundup: Skin Cancer, Turning Cancer Cells Into Fat Cells, and a Longevity Test
There are plenty of great scientific research stories out this week. Here’s a look at just a few of them.
The Genetics of Skin Cancer
Squamous cell carcinoma is the second most common form of cancer in the U.S. and has the highest mortality rate of non-melanoma skin cancers. The researchers, Katie DeCicco-Skinner and her team, described the interaction between a cell signaling pathway called MET and the TpI2 gene and how it contributes to skin cancer progression.
“It’s critical we obtain a better understanding of the biological mechanisms by which skin cancers develop,” DeCicco-Skinner stated. “The incidence of all skin cancers has drastically increased over the last several decades and yet much is still unknown about the genetic causes that lead to development or progression of these cancers.”
How Mesenchymal Stem Cells Repair Damaged Organs
Mesenchymal stem cells (MSCs) are typically found in bone marrow in adults. They play a key role in repairing damaged organs. A group of researchers led by Prasad Shastri and Melika Sarem of the Institute for Macromolecular Chemistry at the University of Freiburg published research into how MSCs function in the journal Stem Cell Research & Therapy. They worked with Oliver Otto, at the University of Griefswald.
MSCs work with other MSCs to turn into complex tissues, like cartilage or bone. They form microscopic clusters in a process called condensation. It was identified as an important step for skeletal development, but the exact mechanism wasn’t understood. The researchers found that reducing the number of cells that participated in condensation led to the activation of an intrinsic differentiation program. This causes MSCs to become cartilage cells.
“Since MSCs harvested from adult bone marrow are a heterogeneous population of cells and their ability to undergo differentiation into cartilage or bone cells varies from donor to donor, our findings have significant implication for MSC-based strategies for engineering cartilage and bone tissue,” stated Shastri.
Turning Breast Cancer Cells into Fat
In laboratory mice, researchers with the University of Basel in Switzerland were able to stimulate human breast cancer cells to transform into fat cells. They exploited a pathway called epithelial-mesenchymal transition (EMT), which cancer uses, as well as the opposite pathway, MET, which stands for mesenchymal-to-epithelial transition. They published their research in the journal Cancer Cell.
The authors wrote, “The models used in this study have allowed the evaluation of disseminating cancer cell adipogenesis in the immediate tumor surroundings. The results indicate that in a patient-relevant setting combined therapy with rosiglitazone and trametinib specifically targets cancer cells with increased plasticity and induces their adipogenesis.”
Not all cancer cells turned into a fat cell, but the ones that did, didn’t change back. Senior author Gerhard Christofori, stated, “The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating. As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells.”
They speculate that this process, which used FDA-approved drugs, could lead to new therapies using these approaches in combination with conventional chemotherapy to suppress the primary tumor growth and the formation of metastases.
Dementias Linked to Leaky Blood Vessels in the Brain
Dementias, such as Alzheimer’s disease, are associated with the accumulation of proteins called amyloid and tau. They are also associated with brain inflammation. Now, researchers with the University of Southern California have published research showing that leaky brain capillaries are signs of early onset Alzheimer’s, and that people with this leakage have worse memory problems regardless of the presence of amyloid and tau. They published their research in the journal Nature Medicine.
Their study looked at 161 older adults over five years. “The fact that we’re seeing the blood vessels leaking, independent of tau and independent of amyloid, when people have cognitive impairment on a mild level, suggests it could be a totally separate process or a very early process,” stated senior author Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine at USC. “That was surprising that this blood-brain barrier breakdown is occurring independently.”
In some aging patients, the blood-brain barrier appears to become less tightly meshed. “If the blood-brain barrier is not working properly, then there is the potential for damage,” stated co-author Arthur Toga, director of the USC Stevens Neuroimaging and Informatics Institute. “It suggests the vessels aren’t properly providing the nutrients and blood flow that the neurons need. And you have the possibility of toxic proteins getting in.”
Using DNA to Predict Longevity
The team analyzed genetic data from more than 500,000 people as well as records of their parents’ lifespans. They isolated 12 areas of the human genome that had a significant impact on lifespan, including five previously unreported sites. The ones with the greatest impact had already been associated with fatal diseases such as heart disease and smoking-related illnesses. However, to their surprise, genes linked to cancers but not with smoking did not show up in the study.
“If we take 100 people at birth, or later, and use our lifespan score to divide them into ten groups,” stated Peter Joshi, an AXA Fellow at the University of Edinburgh’s Usher Institute, “the top group will live five years longer than the bottom on average.”
Slowing Liver Cancer by Blocking PD-L1 Production
The advent of immuno-oncology is built on the ability to block PD-L1 and PD-1 with so-called checkpoint inhibitors. Researchers at the University of California, San Francisco (UCSF) were interested in whether they could prevent the production of PD-L1 and PD-1 altogether. They published their work in the journal Nature Medicine.
Using a mouse model of liver cancer, the researchers evaluated differences in RNA and protein production in tumors driven by the oncogene KRAS and faster-growing tumors driven by KRAS and another oncogene dubbed MYC. They used ribosome profiling, which allowed them to isolate all the proteins being actively created in the ribosomes. They were then able to transcribe the RNA being translated into proteins and identifying the differences. The MYC gene hijacks the cells’ translational activities to create a deadlier cancer proteome.
“This is a new avenue for liver cancer intervention,” stated senior author Davide Rugerro. “There is a particular subset of proteins, more beneficial to cancer cells than to normal cells, called the ‘cancer proteome.’ Once we know the mechanisms by which cells shift to favor that proteome, we can develop drugs to target it.”
The team also used a drug called eFT508, which inhibits eIF4D, a cellular translation factor that connects RNA with ribosomes. Pfizer and Darmstadt, Germany’s Merck KGaA are funding a collaboration to test a combination of the drug with those company’s checkpoint inhibitors.