Posts Tagged ‘infertility’

Newest precision medicine tool: Prostate cancer organoids

The researchers, whose results were published today in Cell, successfully grew six prostate cancer organoids from biopsies of patients with metastatic prostate cancer and a seventh organoid from a patient’s circulating tumor cells. Organoids are three-dimensional structures composed of cells that are grouped together and spatially organized like an organ. The histology, or tissue structure, of the prostate cancer organoids is highly similar to the metastasis sample from which they came. Sequencing of the metastasis samples and the matched organoids showed that each organoid is genetically identical to the patient’s cancer from which it originated.

“Identifying the molecular biomarkers that indicate whether a drug will work or why a drug stops working is paramount for the precision treatment of cancer,” said Yu Chen, MD, PhD, Assistant Attending Physician in the Genitourinary Oncology Service and Human Oncology and Pathogenesis Program at MSK. “But we are limited in our capacity to test drugs — especially in the prostate cancer setting, where only a handful of prostate cancer cell lines are available to researchers.”

With the addition of the seven prostate cancer organoids described in the Cell paper, Dr. Chen’s team has effectively doubled the number of existing prostate cancer cell lines.

“We now have a new resource at our disposal that captures the molecular diversity of prostate cancer. This will be an invaluable tool we can use to test drug sensitivity,” he added.

The use of organoids in studying cancer is relatively new, but the field is exploding quickly according to Dr. Chen. In 2009, Hans Clevers, MD, PhD, of the Hubrecht Institute in the Netherlands demonstrated that intestinal stem cells could form organoids. Dr. Clevers is the lead author on a companion piece also published in Cell today that describes how to create healthy prostate organoids. Dr. Chen’s paper is the first to demonstrate that organoids can be grown from prostate cancer samples.

The prostate cancer organoids can be used to test multiple drugs simultaneously, and Dr. Chen’s team is already retrospectively comparing the drugs given to each patient against the organoids for clues about why the patient did or didn’t respond to therapy. In the future, it’s possible that drugs could be tested on a patient’s organoid before being given to the patient to truly personalize treatment.

After skin cancer, prostate cancer is the most common cancer in American men — about 233,000 new cases will be diagnosed in 2014. It is also the second leading cause of cancer death in men; 1 in 36 men will die of the disease.

Despite its prevalence, prostate cancer has been difficult to replicate in the lab. Many mutations that play a role in its growth are not represented in the cell lines currently available. Cell lines can also differ from their original source, and because they are composed of single cells, they do not offer the robust information that an organoid — which more closely resembles a living organ — can provide.

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Rare stem cells hold potential for infertility treatments

Researchers studying infertility in mouse models found that, unlike similar types of cells that develop into sperm, the stem cells that express PAX7 can survive treatment with toxic drugs and radiation. If the findings hold true in people, they eventually could lead to new strategies to restore or protect fertility in men undergoing cancer treatment.

“Unfortunately, many cancer treatments negatively impact fertility, and men who receive such treatments are at high risk of losing their fertility. This is of great concern among cancer patients,” said Dr. Diego H. Castrillon, Associate Professor of Pathology and Director of Investigative Pathology. “The PAX7 stem cells we identified proved highly resistant to cancer treatments, suggesting that they may be the cells responsible for the recovery of fertility following such treatments.”

Infertility, which the Centers for Disease Control estimates affects as many as 4.7 million men in the United States, is a key complication of cancer treatments, such as chemotherapy and radiation therapy.

The new findings, presented in the Journal of Clinical Investigation, provide valuable insight into the process of sperm development. Known as spermatogenesis, sperm development is driven by a population of “immature” stem cells called progenitors in the testes. These cells gradually “mature” into fully differentiated sperm cells. Dr. Castrillon and his team tracked progenitor cells that express the protein PAX7 in mouse testes, and found that these cells gradually give rise to mature sperm.

“We have long known that male fertility is driven by rare stem cells within the testes, but the precise identity of these stem cells has been disputed,” said Dr. Castrillon, who holds the John H. Childers, M.D. Professorship in Pathology. “Our findings suggest that these rare PAX7 cells are the key cells within the testes that are ultimately responsible for male fertility.”

Importantly, even after exposure to toxic chemotherapy or radiation treatments, the PAX7-expressing cells continued to divide and thus could contribute to restoring sperm development.

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A shift in the code: New method reveals hidden genetic landscape

The letters in the human genome carry instructions to make proteins, via a three-letter code. Each trio spells out a “word;” the words are then strung together in a sentence to build a specific protein. If a letter is accidentally inserted or deleted from our genome, the three-letter code shifts a notch, causing all of the subsequent words to be misspelled. These “frameshift” mutations cause the protein sentence to become unintelligible. Loss of a single protein can have devastating effects for cells, leading to dysfunction and sometimes to serious diseases.

DNA insertions and deletions vary in length and sequence. Each indel can range in size from one DNA letter to thousands, and they are often highly repetitive. Their variability has made it challenging to identify indels, despite major advancements in genome sequencing technology. They are, in effect, regions of the genome that have remained hidden from view as researchers search for the mutations that cause disease.

A team of CSHL scientists, including Assistant Professors Mike Schatz, Gholson Lyon, and Ivan Iossifov, and Professor Michael Wigler, has devised a way to mine existing genomic datasets for indel mutations. The method, which they call Scalpel, begins by grouping together all of the sequences from a given genomic region. Scalpel — a computer formula, or algorithm — then creates a new sequence alignment for that area, much like piecing together parts of a puzzle.

“These indels are like very fine cuts to the genome — places where DNA is inserted or deleted — and Scalpel provides us with a computational lens to zoom in and see precisely where the cuts occur,” says Schatz, a quantitative biologist. Such information is critical to understand the mutations that cause disease. In work published today in Nature Methods, the team used Scalpel to search for indels in patient samples. Lyon, a CSHL researcher who is also a practicing psychiatrist, worked with his team to analyze a patient with severe Tourette syndrome and obsessive-compulsive disorder, identifying and validating more than a thousand indels to demonstrate the accuracy of the method.

The CSHL team performed a similar analysis to search for indels that are associated with autism. They explored a dataset of 593 families from the Simons Simplex Collection, a group composed entirely of families with one affected child but no other family members with the disorder. While the researchers discovered a total of 3.3 million indels across the 593 families, most appeared to be relatively harmless. Still, a few dozen mutations stood out to be specifically associated with autism. “All this adds to our body of knowledge about the spontaneous mutations that cause autism,” says Schatz.

But the tool can be applied much more broadly. “We are collaborating with plant scientists, cancer biologists, and others, looking for indels,” says Schatz. “This is a powerful tool, and we are looking forward to revealing new pieces of the genome that make a difference, throughout the tree of life.”

This work was supported by US National Institutes of Health, US National Science Foundation, the CSHL Cancer Center Support Grant, the Stanley Institute for Cognitive Genomics, and the Simons Foundation.

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