iPSCs Archives - Sanford Burnham Prebys

Tag: iPSCs

Institute News

Scientists “turn back time” on cancer using new stem cell reprogramming technique

AuthorMonica May
Date

August 21, 2020

human cells

Discovery opens new research avenues that may help catch cancer early and identify potential preventive treatments

Scientists at Sanford Burnham Prebys Medical Discovery Institute have reprogrammed cancer cells back into their pre-cancer identity—opening new doors for studying how cancer develops and how it might be prevented. The research, published in Stem Cell Reports, may lead to tests that identify cancer early on, when it can be more easily treated, and uncover preventive treatments that stop cancer before it starts.

“We believe we have been able to contribute to one of the major goals of modern cancer research: creating next-generation models for studying how cancer develops from its earliest state,” says Evan Snyder, MD PhD, professor and director of the Center for Stem Cells & Regenerative Medicine at Sanford Burnham Prebys and senior author of the study. “We essentially took an adult cancer that has accumulated many mutations and pushed it back to the earliest stages of development, allowing us to emulate a tumor’s premalignant state. Then we watched cancer emerge from normal cells before our eyes.”

Turning back the clock on cancer 

In the study, the scientists set out to transform cells from anaplastic thyroid tumors—an aggressive, fast-growing cancer that is nearly always diagnosed at late stages—into induced pluripotent stem cells (iPSCs). These cells model the embryonic cells that are present at the earliest stages of human development and can become any cell in the body. While iPSCs are used today to create unlimited supplies of cells for research and therapeutic purposes—usually to correct abnormalities—the scientists recognized that tumor-derived iPSCs could be used to study the development of cancer.

However, this feat turned out to be easier said than done. The standard reprogramming method didn’t work, requiring the researchers to hunt for a different method that would induce the cancer cells to reset. Inhibiting a protein called RAS was the key ingredient that coaxed these thyroid cancer cells to become normal iPSC cells.

“We have named the pathway that is critical for making a cancer cell act as if it were a normal cell its ‘reprogram enablement factor,’” explains Snyder. “That factor will likely be different for every cancer and, in fact, may help in defining that cancer type.

“For this cancer type, which we examined in our study as a proof-of-concept, the reprogram enablement factor turned out to be blunting an overactive RAS pathway,” Snyder continues. “Our results suggest that losing control of RAS was the ‘big bang’ for this cancer—the very first event that leads to out-of-control cell growth and development of a tumor.”

The scientists next plan to reprogram additional cancers—including brain and lung cancer—into iPSCs to determine their “reprogram enablement factors.” If successful, they will next map the molecular changes that occur immediately before and after the tumors develop, which could reveal early signals of cancer and new preventive or early treatment measures.

“Unlike other cells, cancer cells are notoriously resistant to reprogramming,” says Snyder. “Our study is the first to successfully reprogram cancer cells into completely normal iPSCs, which opens new doors for cancer research.”

A team effort

The first author of the study is Yanjun Kong of Sanford Burnham Prebys and Shanghai Jiao Tong University. Yang Liu of Sanford Burnham Prebys is a co-corresponding author. Additional study authors include Ryan C. Gimple of UC San Diego; Rachael N. McVicar, Andrew P. Hodges and Jun Yin of Sanford Burnham Prebys; and Weiwei Zhan of Shanghai Jiao Tong University.

This study was funded by the Stem Cell Research Center & Core Facility at Sanford Burnham Prebys and by the China Scholarship Council (201606230202). The study’s DOI is 10.1016/j.stemcr.2020.07.016.

Institute News

First supercentenarian-derived stem cells created

AuthorMonica May
Date

March 19, 2020

telomere DNA illustration

Advance primes scientists to unlock the secrets of healthy aging.

People who live more than 110 years, called supercentenarians, are remarkable not only because of their age, but also because of their incredible health. This elite group appears resistant to diseases such as Alzheimer’s, heart disease and cancer that still affect even centenarians. However, we don’t know why some people become supercentenarians and others do not.

Now, for the first time, scientists have reprogrammed cells from a 114-year-old woman into induced pluripotent stem cells (iPSCs). The advance, completed by scientists at Sanford Burnham Prebys and AgeX Therapeutics, a biotechnology company, enables researchers to embark on studies that uncover why supercentenarians live such long and healthy lives. The study was published in Biochemical and Biophysical Research Communications.

“We set out to answer a big question: Can you reprogram cells this old?” says Evan Snyder, MD, PhD, professor and director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys, and study author. “Now we have shown it can be done, and we have a valuable tool for finding the genes and other factors that slow down the aging process.”

In the study, the scientists reprogrammed blood cells from three different people—the aforementioned 114-year-old woman, a healthy 43-year-old individual and an 8-year-old child with progeria, a condition that causes rapid aging—into iPSCs. These cells were then transformed into mesenchymal stem cells, a cell type that helps maintain and repair the body’s structural tissues—including bone, cartilage and fat.

The researchers found that supercentenarian cells transformed as easily as the cells from the healthy and progeria samples. As expected, telomeres—protective DNA caps that shrink as we age—were also reset. Remarkably, even the telomeres of the supercentenarian iPSCs were reset to youthful levels, akin to going from age 114 to age zero. However, telomere resetting in supercentenarian iPSCs occurred less frequently compared to other samples—indicating extreme aging may have some lasting effects that need to be overcome for more efficient resetting of cellular aging.

Now that the scientists have overcome a key technological hurdle, studies can begin that determine the “secret sauce” of supercentenarians. For example, comparing muscle cells derived from the healthy iPSCs, supercentenarian iPSCs and progeria iPSCs would reveal genes or molecular processes that are unique to supercentenarians. Drugs could then be developed that either thwart these unique processes or emulate the patterns seen in the supercentenarian cells.

“Why do supercentenarians age so slowly?” says Snyder. “We are now set to answer that question in a way no one has been able to before.”

The senior author of the paper is Dana Larocca, PhD, vice president of Discovery Research at AgeX Therapeutics, a biotechnology company focused on developing therapeutics for human aging and regeneration; and the first author is Jieun Lee, PhD, a scientist at AgeX.

Additional authors include Paola A. Bignone, PhD, of AgeX; L.S. Coles of Gerontology Research Group; and Yang Liu of Sanford Burnham Prebys and LabEaze. The work began at Sanford Burnham Prebys when Larocca, Bignone and Liu were members of the Snyder lab.

The study’s DOI is 10.1016/j.bbrc.2020.02.092.

Institute News

Measuring heart toxicity of cancer drugs in a dish

AuthorJessica Moore
Date

February 22, 2017

Heart muscle cells (actin filaments in green, nuclei in blue)

A class of cancer drugs known as tyrosine kinase inhibitors (TKIs) are often damaging to the heart, sometimes to the degree that they can’t be used in patients. These toxic effects are not always predictable using current preclinical methods, so they may not be discovered until they make it to clinical trials.

New research could make it possible to tell which TKIs cause heart toxicity without putting any humans at risk. The collaborative study, involving Wesley McKeithan, a PhD student in the Sanford Burnham Prebys Medical Discovery Institute (SBP) graduate program and Mark Mercola, PhD, adjunct professor at SBP and a professor at Stanford University, used lab-grown heart muscle cells to assess the drugs’ potential to cause damaging effects.

“This new method of screening for cardiotoxicity should help pharma companies focus their efforts on TKIs that will be safe,” says Mercola, who collaborated with Joseph Wu, MD, PhD, also a professor at Stanford, on the study published in Science Translational Medicine. “That could mean better new TKIs will make it to the market, since we will be able to predict whether or not they cause heart problems early in the development process.”

TKIs with tolerable cardiac side effects, which include imatinib (Gleevec) and erlotinib (Tarceva), are widely used to treat multiple types of cancer. Because tumors often become resistant to these drugs, new compounds in this class continue to be developed to provide replacement treatments. Other TKIs can harm the heart in a variety of ways, from altering electrical patterns to causing arrhythmias, reducing pumping capacity, or even increasing risk of heart attacks.  

Mercola and Wu’s team used heart muscle cells derived from induced pluripotent stem cells (iPSCs), which can be generated from adult skin or blood cells. After treating heart muscle cells with one of 21 TKIs, they assessed their survival, electrical activity, contractions (beating) and communication with adjacent cells. They used a new method for measuring heart cell contraction developed by the lab of Juan Carlos del Álamo, Ph.D., at UC San Diego to create a ‘cardiac safety index’, which correlates in vitro assay results with the drugs’ serum concentrations in humans. Importantly, the safety index values matched nicely with clinical reports on the cardiotoxicity of currently used TKIs.

The study also identified a possible way to protect heart muscle cells from impairment caused by TKIs—treating them with insulin or insulin-like growth factor. Although more research is needed, the findings suggest that it may be possible to alleviate some of the heart damage in patients receiving these chemotherapies.

Mercola adds, “By using cells derived from a broader group of individuals, this screening strategy could easily be adopted by the pharma industry to predict cardiotoxicity.”

This story is based in part on a press release from Stanford University School of Medicine.