Written by: Maddi Langweil
Cancer can make its way through the body by shapeshifting through even the narrowest places, like a skilled driver navigating traffic. It has a sly way of adapting to its environment by finding detours around every blockade clinicians place in its path.
A study from the lab of Nilay Sethi, MD, PhD, in Dana-Farber’s Center for Gastrointestinal Oncology, reveals an understanding of colorectal cancer’s maneuvers and how they can close those side streets, specifically by reprogramming cancer’s internal GPS.
“We have noticed that we are not getting the same clinical response in colorectal cancers when targeted therapies are used as we are in lung and breast cancer,” Sethi says. “That’s what led us to trying to understand the shape-shifting property we see emerging in resistance to those treatments.”
Identifying sly maneuvers
The colon is lined with cells that turn over every five to seven days and are replaced with new ones, like a conveyor belt.
At the bottom of the colon’s lining are stem cells that divide and support the production of mature cells, which offer different functions in digestion such as absorption of nutrients and secretion of mucus to line our GI tract.
“The lining of our gut is notably adaptable, which is very regulated in our bodies and helps our bodies respond to injury, but when cancer starts, it’s able to take advantage of that plasticity,” Sethi says. “That’s what makes cancers so dangerous.”
When cancer starts, there’s a noticeable shift in the cells — stem-cell-like properties emerge with specific abnormalities. There are remnants of normal activity, but mature cells are no longer being created.
Rather, the stem cells divide into cells that are not mature enough to function but still capable of replicating rapidly.
The gene responsible for blocking cell maturation is Sox9, as discovered by Sethi and his team in a previously published study. In this new study, Sethi has found clues about how to combat the effects of Sox9 and restore the creation of mature, functioning cells.
“We want to uncover how differentiation can be restored in colorectal cancer,” Sethi says. Rather than trying to kill tumor cells outright, Sethi’s lab aims to retrain them, coaxing malignant stem-like cells to resume normal functions.
Colorectal cancer can evade targeted treatments, but Dana-Farber researchers are identifying ways to block those methods by reprogramming how the cancer spreads — using epigenetic reprogramming.
Blocking the move
The team collaborated with Jun Qi, PhD, a chemical biologist at Dana-Farber. Together, they used a novel system to observe the activity of Sox9 and screen a library of small molecules in search of a way to reprogram the activity of Sox9 epigenetically. Epigenetic reprogramming interferes with markers on genes to turn the genes on and off without changing the DNA.
“This is a resetting of genes to on or off,” Sethi says. “In the case of Sox9, it can redirect the cell identity or cell fate.”
They found a hit with promise. Histone deacetylases (HDAC) are epigenetic markers involved in maintaining the stem-like state co-opted by cancer. HDAC inhibitors, which already are approved for the treatment of several cancers though not for colon cancer, could be used to interrupt that process and enable stem cells to produce mature, functional cells.
The discovery suggests that HDAC inhibitors could be used to re-sensitize tumor cells to other therapeutics in cases where the cancer has used Sox9 to shapeshift and evade treatment. Because many cancers exploit similar shape-shifting mechanisms, this finding may open the door to a broader strategy: re-differentiating rather than destroying tumor cells.
“We found that HDAC inhibition was the most powerful at reducing plasticity,” Sethi says. “However, we know that there’s heterogeneity amongst patients, even with the same cancer. Some colon cancer patients may respond better to HDAC inhibitors than others.”
Cancer may have insidious methods to evade treatment, but Sethi and his team are investigating those tactics, targeting them, and returning to the lab bench.
“There’s an incredible amount of effort being made to solve this problem,” says Sethi.
By reversing cancer’s loss of identity, Sethi and colleagues hope to pioneer a new therapeutic category, one that restores normalcy rather than only fighting malignancy.