Some of Princeton's leading cancer researchers were startled to discover that what they thought was a straightforward investigation into how cancer spreads through the body -- metastasis -- turned up evidence of liquid-liquid phase separations: the new field of biology research that investigates how liquid blobs of living materials merge into each other, similar to the movements seen in a lava lamp or in liquid mercury.

"We believe this is the first time that phase separation has been implicated in cancer metastasis," said Yibin Kang, the Warner-Lambert/Parke-Davis Professor of Molecular Biology. He is the senior author on a new paper featured on the cover of the current issue of Nature Cell Biology.

Not only does their work tie phase separations to cancer research, but the merging blobs turned out to create more than the sum of their parts, self-assembling into a previously unknown organelle (essentially an organ of the cell).

Discovering a new organelle is revolutionary, Kang said. He compared it to finding a new planet within our solar system. "Some organelles we have known for 100 years or more, and then all of a sudden, we found a new one!"

This will shift some fundamental perceptions of what a cell is and does, said Mark Esposito, a 2017 Ph.D. alumnus and current postdoc in Kang's lab who is the first author on the new paper. "Everybody goes to school, and they learn 'The mitochondria is the powerhouse of the cell,' and a few other things about a few organelles, but now, our classic definition of what's inside a cell, of how a cell organizes itself and controls its behavior, is starting to shift," he said. "Our research marks a very concrete step forward in that."

It all sounds similar to a dance event - but are singles or couples dancing here? This was the question Ali Isbilir and Dr. Paolo Annibale at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) were trying to answer. However, their investigation did not involve a ballroom, but the cell membrane. The question behind their investigation: does a particular protein receptor on the surface of cancer and immune cells appear alone or connect in pairs?

The receptor is called "CXCR4" - the subject of heated debate among experts in recent years due to its mysterious relationship status. Does it appear in singles or pairs on the cell membrane? And what makes the difference? The research team of the Receptor Signaling Lab at the MDC, has now solved the puzzle of its relationship status for the first time. Their findings were recently published in the journal "Proceedings of the National Academy of Sciences" (PNAS).

CXCR4 is an important receptor on immune and cancer cells
"When CXCR4 is found in large numbers on cancer cells, it also ensures that they can migrate, thereby laying the foundation for metastases," says lead author Isbilir. Metastases are known to be difficult to treat; some patients die as a result of these secondary tumors.

CXCR4 is also involved in inflammations. The center of inflammation releases messenger substances from the chemokine class. In lymph nodes, chemokines ensure that immune cells form many CXCR4 receptors on their membrane. With the help of these receptors, immune cells can locate the center of inflammation and migrate to it. The name CXCR, which stands for "chemokine receptor," also refers to this ability. "Such receptors are the most important target structures in pharmaceutical research," emphasizes Professor Martin Lohse, the last author of the study. "Approximately one-third of all drugs address this class of receptors."

Researchers find that the phenomenon of chromothripsis results in rearranged genomes and extra-chromosomal DNA that helps mutated cells not only evade treatment, but become more aggressive.

Cancer is one of the world's greatest health afflictions because, unlike some diseases, it is a moving target, constantly evolving to evade and resist treatment.

In a paper published in Nature, researchers at University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, with colleagues in New York and the United Kingdom, describe how a phenomenon known as "chromothripsis" breaks up chromosomes, which then reassemble in ways that ultimately promote cancer cell growth.

Chromothripsis is a catastrophic mutational event in a cell's history that involves massive rearrangement of its genome, as opposed to a gradual acquisition of rearrangements and mutations over time. Genomic rearrangement is a key characteristic of many cancers, allowing mutated cells to grow or grow faster, unaffected by anti-cancer therapies.

"These rearrangements can occur in a single step," said first author Ofer Shoshani, PhD, a postdoctoral fellow in the lab of the paper's co-senior author Don Cleveland, PhD, professor of medicine, neurosciences and cellular and molecular medicine at UC San Diego School of Medicine.
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"During chromothripsis, a chromosome in a cell is shattered into many pieces, hundreds in some cases, followed by reassembly in a shuffled order. Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA elements promote cancer cell growth and form minute-sized chromosomes called 'double minutes.'"

A new and less invasive treatment developed by Cancer Research UK researchers is safer than standard major surgery for early-stage rectal cancer, giving patients a better quality of life with fewer life-altering side effects, results from a pilot study show.

Results from the TREC trial show that a combination of local keyhole surgery and radiotherapy, rather than major surgery that removes the whole rectum, prevents debilitating side effects, such as diarrhoea, or the need for a permanent colostomy bag.

Patients reported a better quality of life with the new treatment, with less impact on their family and social life, and felt more positive about their body image and the way their bowels work.

Every year, 11,500 people in the UK are diagnosed with a tumour located in the rectum, the last part of the intestine which connects to the anus. Standard treatment is a major operation to remove the whole rectum, even if the cancer is early stage. About 25% of these major surgeries are done on small, early-stage tumours, and while it is effective, the operation can lead to long-term side-effects that seriously impacts quality of life for survivors.

The risk of serious adverse effects on the blood status and bone marrow of patients during chemotherapy can be predicted by a model developed at Linköping University, Sweden. This research may make it possible to use genetic analysis to identify patients with a high probability of side effects. 

It is often difficult during cancer treatment to achieve a balance between getting rid of as many tumour cells as possible, while at the same time not causing serious side effects.

One of the common properties of tumour cells is that they grow rapidly and in an uncontrolled manner. The chemotherapy drugs that are used to treat cancer have for this reason been designed to kill rapidly growing cells. But the treatment also kills normal cells that grow rapidly. One of the more sensitive tissues is the bone marrow, where various types of blood cell are formed at a rapid rate. Approximately 25% of lung cancer patients who receive combination treatment with the drugs gemcitabine and carboplatin experience life-threatening side effects on the bone marrow during standard treatment. In many cases, the treatment must be discontinued.

We know that genetic factors play a role in the response of an individual to these treatments. Complicated interactions between many genes are probably involved. The scientists who carried out the study have therefore investigated whether genetic signatures exist that can be used to identify the patients at a high risk of experiencing severe side effects from the treatment. This would enable them to adapt treatment to the individual more accurately from the start: those with a low risk of side effects can be given higher doses, with a stronger effect on the cancer, while those with highest risk can be given another treatment. 
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The study, published in npj Systems Biology and Applications, is a collaboration between researchers in pharmacogenetics and bioinformatics. They determined the complete DNA sequences of 96 patients with non-small cell lung cancer who had been treated with gemcitabine/carboplatin. Sequencing of the whole genome in this way provides information about millions of genetic variants that may be interesting. The researchers wanted to see whether they could find in this huge amount of data functional groups of genes that were linked to the degree of toxicity that the treatment had had on the bone marrow of the different patients

It is not biology, but access to health care that is causing Black Non-Hispanic patients with squamous cell cancer of the head and neck to have lower survival rates

Studies have long reported that Black cancer patients have poorer outcomes than their white counterparts. But two University of Colorado Cancer Center researchers decided to investigate the data further and figure out why. What they found was that the outcome disparity was caused not by biology, but simply by differences in access to health care.

The researchers, Jessica McDermott, MD, an assistant professor in the Department of Medical Oncology, and Sana Karam, MD, PhD, an associate professor in the Department of Radiation Oncology, examined Medicare data for individuals suffering squamous cell cancer of the head and neck. All 13,117 patients in this study were diagnosed with their first and only malignant tumor at age 66 or older sometime between 2006 and 2015.

The data confirmed what has been widely reported for years -- that the Black head and neck cancer patients had worse outcomes than the white cancer patients.

"But then when we controlled for access to care, those differences suddenly disappeared," says McDermott. "When you closely examine the data, it becomes clear what is going on."
Their findings were published this week in the Journal of the National Comprehensive Cancer Network. The physicians hope their research will catch the attention of those who can help narrow those disparate outcomes.

McDermott and Karam identified two major differences for Black patients: first, they presented at later stages of cancer, and second, they were less likely to receive treatment.

"This is an interesting finding," says McDermott. "A lot of the reasons driving the disparate outcomes came down to socially related things - they were less likely to be married, lived in poor areas, had comorbidities [presence of two or more chronic diseases], were less likely to see a primary care provider in the year leading up to the diagnosis, and were more likely to present in the emergency room."

For most cancers, where and when a patient first presents can make a large difference both in the care received and in the outcome.

"Just a reminder that we are talking about a curable disease, a disease that, if treated properly, can be eradicated with a high degree of certainty," says Karam. "I hope that more targeted interventions can be developed as a result of our findings. The problem lies not so much in biological differences, but access. If Black patients get the treatment, they do just as well."

Women who have been treated for breast cancer may have a higher risk of developing cardiovascular disease and in some groups the risk of dying from cardiovascular disease is higher than the risk of dying from breast cancer. The new study shows that it is possible to spot those at the greatest risk using computer analysis of the CT scans that are taken for planning cancer treatments. Researchers say that identifying patients most at risk of cardiovascular disease could allow steps to be taken to lower the risk.

The research was presented by Professor Helena Verkooijen, from the Division of Imaging and Oncology at the University Medical Center Utrecht in The Netherlands. She said: "We've seen great improvement in breast cancer survival, thanks in part to better treatment. However, treatments have side effects and some treatments - such as radiotherapy and certain types of cancer drug - can increase the risk of cardiovascular disease. In my opinion, treating breast cancer means finding the right balance between maximising chances of tackling the tumour, while minimising the risks of side effects, including the risk of cardiovascular disease."

The study included around 14,000 breast cancer patient who were treated with radiotherapy in three large hospitals in The Netherlands between 2005 and 2016.Professor Verkooijen and her colleagues used a measure called coronary artery calcium (CAC) score. This is a calculation of the amount of calcium in the walls of the heart's arteries and it is known to be strong risk factor in cardiovascular disease because calcifications can lead to narrowing or blocking of the blood vessels.

The researchers developed a deep learning algorithm that could gauge the presence and extent of coronary artery calcifications from the CT scans that were already being carried out to help plan each woman's radiotherapy treatment. This allowed them to automate the measurement of CAC for all the women with only minimal extra workload.

Is increased coffee consumption associated with improved survival in patients with advanced or metastatic colorectal cancer?

In a study of 1171 patients with advanced or metastatic colorectal cancer, increased coffee consumption  was associated with lower risk of disease progression and death. Significant associations were noted for both caffeinated and decaffeinated coffee.

Among patients with advanced or metastatic colorectal cancer, the study found that increased coffee intake was associated with lower risk of disease progression and death.

Mackintosh et al. Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer. JAMA Oncol, 2020. doi:10.1001/jamaoncol.2020.3938 [Article]

Scientists at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) report today the development of new models to study molecular characteristics of tumors of the lung and pancreas that are driven by mutations in a gene named NTRK1. 

In healthy bodies, NTRK1 has critical functions in the development of nerve cells, particularly those that send signals to the brain about pain, temperature, and touch. In some cancers, these powerful genes malfunction to send signals to cells, instructing them to grow constantly.

The study, published in the journal Cell Reports, was led by Martin McMahon, PhD, senior director of preclinical translation at HCI and professor of dermatology at the U of U, and Aria Vaishnavi, PhD, a postdoctoral fellow in McMahon's lab. McMahon's team focuses on cell-cell communication, like the signaling promoted in some cancers by NTRK1.

One way to examine this experimentally is to devise a way to model human cancers in mice. This process produces a new tool, a "mouse model," which allows scientists to analyze in a laboratory setting how a cancer develops, how it behaves over time, and to test potential new drugs and treatment targets. The researchers hope the new NTRK1 mouse models reported today will accelerate progress toward finding more effective treatments for patients with NTRK1-driven lung and pancreas cancers.

A conversation with Ignacio Garrido-Laguna, MD, PhD, a physician-scientist at HCI, associate professor of internal medicine at the U of U, and director of the HCI Phase I Clinical Research Program, inspired the idea for this study. Garrido-Laguna was caring for a pancreatic cancer patient who was participating in a clinical trial at HCI (NCT02568267). The patient's tumor had a mutation in NTRK1 and then had a remarkable response to the NTRK1 inhibitor drug being evaluated. Hence, it made sense to Garrido-Laguna and McMahon that the response might be related to inhibition of the mutated NTRK1.

McMahon posited that if NTRK1 signaling was responsible, disruption of that signaling might be beneficial. "Pancreatic cancers have proven to be a particularly recalcitrant to treatments, so we wanted to thoroughly evaluate such a dramatic response as we work to identify new potential treatments for this disease," said McMahon. Moreover, since the responses to the NTRK1 inhibitors are often short-lived, McMahon and colleagues wanted to design new combination therapies that prevented the onset of lethal drug resistance.

Breast Cancer patients are 60 percent more likely to die of cancer after surviving a heart attack, a new study finds.

Led by researchers at NYU Grossman School of Medicine, the study shows how heart attacks, by blocking blood flow through arteries, trigger a specific, pro-cancer immune reaction.

Designed by evolution to attack invading bacteria and viruses, the immune system also recognizes cancer cells as abnormal and worthy of attack, say the study authors. But heart attack, along with other blood flow-reducing events like stroke and heart failure - were found to come with changes to immune cells that rendered them less able to respond to tumors.

Published online in Nature Medicine, the analysis of more than 1700 early-stage breast cancer patients found that those who also experienced heart attack, stroke, or heart failure had a greater risk than those that did not of cancer recurrence, cancer spread, and of dying from breast cancer.

The new work also found that mice with breast cancer saw a two-fold increase in tumor volume over 20 days after ligation (cutting off) of blood flow in the coronary artery, which simulated a heart-attack, when compared to mice with cancer but normal blood flow.

"By blunting the immune system's assault on cancer cells, a heart attack appears to provide an environment that enables tumor growth," says corresponding author Kathryn Moore, PhD, the Jean and David Blechman Professor of Cardiology, and Director of the Cardiovascular Research Center at NYU Langone Health. "While further studies will be needed, our results provide support for the aggressive clinical management of cardiovascular risk factors, not only to reduce risk of cardiovascular disease, but possibly breast cancer progression."

As one in eight American women will develop breast cancer during their lifetimes, and with nearly three million breast cancer survivors in the United States, the need for a better understanding the interplay between cancer and cardiovascular disease is urgent, adds Moore.