What makes pancreatic cancer so aggressive? New study sheds light

“We know that patients with the earliest stage of pancreatic cancer have a survival rate of only 30 percent. This suggests that even in that very early stage of invasive cancer there are already cells that have spread to distant parts of the body,” says study author Diane M. Simeone, M.D. Credit: Image courtesy of University of Michigan Health System

New research from the University of Michigan Comprehensive Cancer Center helps explain why pancreatic cancer is so lethal, with fewer than a third of patients surviving even early stage disease.

The researchers found a gene known to be involved in nearly 90 percent of pancreatic cancers promotes cancer growth and spread. The gene, ATDC, plays a key role in how a tumor progresses from a preinvasive state to an invasive cancer to metastatic cancer.

"We know that patients with the earliest stage of pancreatic cancer have a survival rate of only 30 percent. This suggests that even in that very early stage of invasive cancer there are already cells that have spread to distant parts of the body," says study author Diane M. Simeone, M.D., director of the Pancreatic Cancer Center at the University of Michigan Comprehensive Cancer Center.

"This study sheds important light on what it is about pancreatic cancer that makes it so aggressive early in the game," she adds. The study appears Jan. 15 in Genes and Development.

Researchers used a mouse model to replicate pancreatic cancer as it appears in humans. They also studied pancreatic cancer tissue samples and samples of pre-invasive pancreatic lesions. They found ATDC was expressed in a subset of the pre-invasive cells and played a role in the development of pancreatic cancer stem cells, the small number of cells in a tumor that fuel its growth and spread. This suggests that ATDC promotes a tumor's invasiveness and spread early in the course of disease.

The researchers suspect that ATDC may be a potent drug target. No drugs currently exist to target this pathway in part because researchers do not understand the crystal structure of the protein. Simeone's team, working with the University of Michigan Center for Structural Biology has made crystals of the protein and begun to create a three-dimensional structure that they can use as a model for drug development.

Preliminary data suggests that ATDC may also play a role in other cancer types, including bladder, ovarian, colorectal and lung cancers and multiple myeloma. But, Simeone notes, it's particularly critical to find new treatment options for pancreatic cancer. About 46,400 Americans will be diagnosed with pancreatic cancer this year, and more than 39,000 will die of the disease. Pancreatic cancer is expected to become the second-leading cause of cancer death in the United States by 2030.

Source: University of Michigan Health System

3-D culture system for pancreatic cancer has potential to change therapeutic approaches

A team of researchers has developed a method to grow pancreatic tissue in a three-dimensional culture system, called organoids. The scientists are able to use tissue not only from laboratory mouse models, but also from human patients. The technology promises to change the way pancreatic cancer research is done, offering a path to personalized treatment approaches in the future. Credit: D. Tuveson/ Cold Spring Harbor Laboratory

Cold Spring Harbor and Bethpage, N.Y. -- Pancreatic cancer is one of the most deadly forms of cancer, with only 6 percent of patients surviving five years after diagnosis. Today, Cold Spring Harbor Laboratory (CSHL) and The Lustgarten Foundation jointly announce the development of a new model system to grow both normal and cancerous pancreatic cells in the laboratory. Their work offers the potential to change the way pancreatic cancer research is done, allowing scientists to interrogate the pathways driving this devastating disease while searching for new drug targets.

In work published in Cell, the research team describes a three-dimensional "organoid" culture system for pancreatic cancer. Co-led by David Tuveson, CSHL Professor and Director of Research for The Lustgarten Foundation, and Hans Clevers, Professor and Director of the Hubrecht Institute and President of the Royal Netherlands Academy of Arts and Sciences, the team developed a method to grow pancreatic tissue not only from laboratory mouse models, but also from human patient tissue, offering a path to personalized treatment approaches in the future.

All cancer research relies on a steady supply of cells -- both normal and cancerous -- that can be grown in the laboratory. By comparing normal cells to cancer cells, scientists can then identify the changes that lead to disease. However, both types of pancreatic cells have been extremely difficult to culture in the laboratory.

Furthermore, the normal ductal cells that are able to develop into pancreatic cancer represent about 10 percent of the cells in the pancreas, complicating efforts to pinpoint the changes that occur as the tumor develops. Until now, scientists have been entirely unable to culture human normal ductal pancreatic cells under standard laboratory conditions. 

Because of these limitations, most pancreatic cancer research relies on genetically engineered mouse models of the disease, which can take up to one year to generate. "With this development, we are now able to culture both mouse and human organoids, providing a very powerful tool in our fight against pancreatic cancer," explains Tuveson.

The organoids are entirely made up of ductal cells, eliminating the surrounding cell types that often contaminate samples from the pancreas. They grow as hollow spheres within a complex gel-like substance filled with growth-inducing factors and connecting fibers. Once they have grown to a sufficient size, the organoids can be transplanted back into mice, where they fully recapitulate pancreatic cancer. "We now have a model for each stage in the progression of the disease," says Chang-Il Hwang, Ph.D., one of the lead authors working in The Lustgarten Foundation's Pancreatic Cancer Research Lab at CSHL directed by Dr. Tuveson.

Traditionally, cancer cells are isolated during surgery or autopsies. Unfortunately, approximately 85 percent of cancer patients are ineligible for surgery at the time of diagnosis, either because the tumor is entwined in critical vasculature or the disease has progressed too far. Researchers therefore have had limited access to patient samples. The new research provides a way for scientists to grow organoids from biopsy material, which is comparatively easy to obtain. "Biopsies are the standard for diagnosis," says Dannielle Engle, Ph.D., also a lead author on the paper. "We can now rapidly generate organoids from any patient, which offers us the potential to study the disease in a much wider population."

The team is now working to create a repository of pancreatic tumor samples, coordinating with the National Cancer Institute. "We hope to make this available to the entire pancreatic cancer research community," says Tuveson. Additionally, Lindsey Baker, Ph.D., another lead author of the paper, has started holding an "organoid school" for other researchers, and has already taught six laboratories from around the world this technique.

Source: Cold Spring Harbor Laboratory

'Sugar-coated' microcapsule eliminates toxic punch of experimental anti-cancer drug

3BrPA (red) is illustrated encased in a sugar-based microshell. Credit: Jean-Francois Geschwind, Johns Hopkins

Johns Hopkins researchers have developed a sugar-based molecular microcapsule that eliminates the toxicity of an anticancer agent developed a decade ago at Johns Hopkins, called 3-bromopyruvate, or 3BrPA, in studies of mice with implants of human pancreatic cancer tissue. The encapsulated drug packed a potent anticancer punch, stopping the progression of tumors in the mice, but without the usual toxic effects.

"We developed 3BrPA to target a hallmark of cancer cells, namely their increased dependency on glucose compared with normal cells. But the nonencapsulated drug is toxic to healthy tissues and inactivated as it navigates through the blood, so finding a way to encapsulate the drug and protect normal tissues extends its promise in many cancers as it homes in on tumor cells," says Jean-Francois Geschwind, M.D., chief of the Division of Interventional Radiology at Johns Hopkins Medicine.

The Johns Hopkins team used a microshell made of a sugar-based polymer called cyclodextrin to protect the 3BrPA drug molecules from disintegrating early and to guard healthy tissue from the drug's toxic effects, such as weight loss, hypothermia and lethal hypoglycemic shock.

Geschwind, a professor in the Russell H. Morgan Department of Radiology and Radiological Science at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, and others at Johns Hopkins have been studying the experimental drug as a cancer treatment for over a decade because of its ability to block a key metabolic pathway of cancer cells.

Most cancer cells, he explains, rely on the use of glucose to thrive, a process known as the Warburg effect, for Otto Heinrich Warburg, who was awarded the Nobel Prize in Physiology for the discovery in 1931. By using the same cellular channels that funnel glucose into a cancer cell, 3BrPA can travel inside the cancer cell and block its glucose metabolic pathway, Geschwind says.

However, animal studies have shown that in its free, nonencapsulated state, the drug is very toxic, says Geschwind.

The toxicity associated with the free-form version of the drug, he says, has prevented physicians from using the drug as a systemic treatment in people, one that can travel throughout the whole body.

In a report about their study published online Oct. 17 in Clinical Cancer Research, the researchers described minimal or zero tumor progression in mice treated with the microencapsulated 3BrPA. By contrast, a signal of tumor activity increased sixty-fold in mice treated with the widely used chemotherapy drug gemcitabine. Activity increased 140-fold in mice who received the drug without encapsulation.

Specifically, daily injections of nonencapsulated 3BrPA were highly toxic to the animals, as only 28 percent of the animals survived the 28-day treatment. All of the mice who received the encapsulated drug survived to the end of the study.

Geschwind says the "extremely promising results" of the study make the encapsulated drug a good candidate for clinical trials, particularly for patients with pancreatic ductal adenocarcinoma. These cancers rank as the fourth most common cause of cancer-related deaths in the world, with a five-year survival rate of less than 5 percent. In the mouse studies, the encapsulated medication also reduced the metastatic spread of pancreatic cancer cells.

Source: Johns Hopkins Medicine

First steps in formation of pancreatic cancer identified

Shown is a region of a pancreas with preneoplastic lesions. Red labeling indicates macrophages, green labeling indicates pancreatic acinar cells that dedifferentiate, and grey labeling indicates further progressed pancreatic lesions. Credit: Image courtesy of Mayo Clinic

Researchers at Mayo Clinic's campus in Jacksonville say they have identified first steps in the origin of pancreatic cancer and that their findings suggest preventive strategies to explore.

In an online issue of Cancer Discovery, the scientists described the molecular steps necessary for acinar cells in the pancreas -- the cells that release digestive enzymes -- to become precancerous lesions. Some of these lesions can then morph into cancer.

"Pancreatic cancer develops from these lesions, so if we understand how these lesions come about, we may be able to stop the cancer train altogether," says the study's lead investigator, Peter Storz, Ph.D., a cancer biologist.

The need for new treatment and prevention strategies is pressing, Dr. Storz says. Pancreatic cancer is one of the most aggressive human cancers -- symptoms do not occur until the cancer is well advanced. One-year survival after diagnosis is only 20 percent. It is the fourth leading cause of cancer death in this country.

The scientists studied pancreatic cells with Kras genetic mutations. Kras produces a protein 

that regulates cell division, and the gene is often mutated in many cancers. More than 95 percent of pancreatic cancer cases have a Kras mutation.

The researchers detailed the steps that led acinar cells with Kras mutations to transform into duct-like cells with stem cell-like properties. Stem cells, which can divide at will, are also often implicated in cancer.

They found that Kras proteins in the acinar cells induce the expression of a molecule, ICAM-1, which attracts macrophages, a specific kind of immune cells. These inflammatory macrophages release a variety of proteins, including some that loosen the structure of the cells, allowing acinar cells to morph into different types of cells. These steps produced the precancerous pancreatic lesions.

"We show a direct link between Kras mutations and the inflammatory environment that drive the initiation of pancreatic cancer," Dr. Storz says.

But the process can be halted in laboratory mice, he adds. "We could do this two ways -- by depleting the macrophages or by treating the transformed cells with a blocking antibody that shuts down ICAM-1," says Dr. Storz. "Doing either one reduced the number of precancerous lesions."

Dr. Storz noted that a neutralizing antibody that blocks ICAM-1has already been developed. It is being tested for a wide variety of disorders, including stroke and rheumatoid arthritis.

"Understanding the crosstalk between acinar cells with Kras mutations and the microenvironment of those cells is key to developing targeted strategies to prevent and treat this cancer," he says.

Source: Mayo Clinic

Understanding, improving body's fight against pathogens

Significant reductions in the number of plasma cells in the spleen and bone marrow were observed in the absence of DOK3. Each dot in the figure represents one plasma cell detected. Credit: Image courtesy of A*Star Agency for Science, Technology and Research

Scientists from A*STAR's Bioprocessing Technology Institute (BTI) have uncovered the crucial role of two signalling molecules, DOK3 and SHP1, in the development and production of plasma cells. These discoveries, published in two journals PNAS and Nature Communications, advance the understanding of plasma cells and the antibody response, and may lead to optimisation of vaccine development and improved treatment for patients with autoimmune diseases such as lupus and tumours such as multiple myeloma.

While they exist in small populations in humans, the large amounts of antibodies secreted by plasma cells make them key to the body's immune system and its ability to defend itself against pathogens, such as bacteria and viruses. Proper maintenance of a pool of plasma cells is also critical for the establishment of lifelong immunity elicited by vaccination.

Dysregulation of plasma cell production and maintenance could lead to autoimmune diseases and multiple myeloma. Autoimmune diseases occur when the immune system does not distinguish between healthy tissue and antigens, which are found in pathogens. This results in expansion of plasma cells which produce excessive amounts of antibodies leading to destruction of one's own healthy tissue. The discoveries by scientists in BTI's Immunology Group have improved understanding of the mechanism by which plasma cells are developed from a major class of white blood cells called B cells.

For the first time, the molecule DOK3 was found to play an important role in formation of plasma cells. While calcium signalling typically controls a wide range of cellular processes that allow cells to adapt to changing environments, it was found to inhibit the expression of the membrane proteins essential for plasma cell formation. These membrane proteins include PDL1 and PDL2, and represent some of the key targets for the development of immunotherapy by pharmaceutical companies. DOK3 was able to promote the production of plasma cells by reducing the effects of calcium signalling on these membrane proteins. The absence of DOK3 would thus result in defective plasma cell formation.

In another study, BTI scientists discovered the importance of SHP1 signalling to the long term survival of plasma cells. While the molecule SHP1 has a proven role in prevention of autoimmune diseases, it was found that the absence of SHP1 would result in the failure of plasma cells to migrate from the spleen where they are generated to the bone marrow, a survival niche where they are able to survive for much longer periods. This could result in a reduction of the body's immune response and thus, an increased susceptibility to infections and diseases. The scientists in this study also successfully rectified the defective immune response caused by an absence of SHP1 by applying antibody injections, which might advance the development of therapeutics. On the other hand, targeting SHP1 might be a strategy to treat multiple myeloma where the accumulation of cancerous plasma cells in the bone marrow survival niches is undesirable.

Findings hold potential for improved treatment

The discovery of these new targets for modulating the antibody response allows the development of novel therapeutic strategies for patients with autoimmune diseases and cancer.Understanding the mechanism that governs plasma cell differentiation is also critical for the optimal design of vaccines and adjuvants, which are added to vaccines to boost the body's immune response.

Prof Lam Kong Peng, Executive Director of BTI, said, "These findings allow better understanding of plasma cells and their role in the immune system. The identification of these targets not only paves the way for development of therapeutics for those with autoimmune diseases and multiple myeloma, but also impacts the development of immunological agents for combating infections."

Source: A*Star Agency for Science, Technology and Research