Neil Macpherson

Researchers at the ��Ƶ have found that cancer cells can enhance tumour growth by hijacking enhancer DNA normally used when tissues and organs are formed.

The mechanism, called “enhancer reprogramming,” occurs in bladder, uterine, breast and lung cancer – and could cause these types of tumors to grow faster in patients.

Jennifer Mitchell (supplied image)

The research was conducted in the lab of Jennifer Mitchell, a professor in the department of cell and systems biology in the Faculty of Arts & Science, and published recently in the journal Nucleic Acids Research. It pinpoints the role that specific proteins play in regulating the enhancer region which may lead to improved treatments for these cancer types.

Living cells, even cancer cells, follow instructions in the genome to turn genes on and off in different contexts, says first author Luis Abatti, a PhD candidate in Mitchell’s lab.

“The genome is like a recipe book written in DNA that gives instructions on making all the parts of the body,” Abatti says.

“In each organ, only the recipes relevant to that organ should be followed – whether it’s the instructions for lung, breast or some other tissue. Like flipping pages in a recipe book, the DNA containing the instructions for turning genes on in the lung is open and used in the lung, for example, but closed and ignored in other types of cells.

Luis Abatti (supplied image)

“We know that some cancer cells are opening the wrong pages in the recipe book – ones that contain the SOX2 gene, which can cause tumours to grow uncontrollably. We wanted to find out: How does the gene become expressed in cancer cells?”

The researchers analyzed genome data to look for enhancer DNA that could activate SOX2 in cancer cells. The enhancer they found is open in many different types of patient tumours, meaning this could be a cancer enhancer active in bladder, uterus, breast and lung tumours. Unlike many cancer-causing changes, the enhancer reprogramming mechanism does not arise out of mutation due to DNA damage – it is caused by part of the genome opening when it should be staying closed.

The researchers then determined that the enhancer causes increased cancer cell growth because when they removed the enhancer in lab-grown cells, the cancer cells created fewer new tumour colonies.

To figure out why cells have a DNA region that makes cancer worse, the team examined mice without this DNA region and found they do not form a separate passage for air and food in their throat as they develop. Thus, this potentially dangerous cancer-enhancer region is likely in the human genome to regulate airway formation as the human body forms. However, if a developing cancer cell opens this region, it will form a tumour that grows faster and is more dangerous for the patient.

The researchers unravel the mechanism of how developmentally active enhancers become repurposed in a tumour (image: © Abatti et al, 2023, published by Oxford University Press on behalf of Nucleic Acids Research)

“We also found that two proteins known to have a role in the developing airways – FOXA1 and NFIB – are now regulating SOX2 in breast cancer,” says Mitchell, who is associate chair of research in the department of cell and systems biology and is cross-appointed to the department of laboratory medicine and pathobiology in the Temerty Faculty of Medicine.

The enhancer is activated by the FOXA1 protein and suppressed by the NFIB protein. This means that drugs suppressing FOXA1 or activating NFIB may lead to improved treatments for bladder, uterine, breast and lung cancer.

“Now that we know how the SOX2 gene is activated in certain types of cancers, we can look at why this is happening,” Mitchell says.

“Why did the cancer cells end up on the wrong page of the genome recipe book?”

The research received support from the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Ontario government.

Whales' eyes offer glimpse into their evolution from land to sea: U of T researchers

Christopher.Sorensen — Thu, 28 Jul 2022 15:37:02 +0000

Whales' eyes offer glimpse into their evolution from land to sea: U of T researchers

Christopher.Sorensen Thu, 07/28/2022 - 11:37

Cutline

(photo by Shasin Satuei from Pexel via Canva)

Neil Macpherson

Topic

Breaking Research

Cell and Systems Biology

Ecology & Evolutionary Biology

Faculty of Arts & Science

Research & Innovation

��Ƶ researchers have shed light on the evolutionary transition of whales' early ancestors from on-shore living to deep-sea foraging, suggesting that these ancestors had visual systems that could quickly adapt to the dark.

Their findings show that the common ancestor of living whales was already a deep diver, able to see in the blue twilight zone of the ocean, with eyes that swiftly adjusted to dim conditions as the whale rushed down on a deep breath of surface air.

"In the evolution of whale diving, there's been a long-standing question of when deep-sea foraging evolved," says Belinda Chang, a professor in the Faculty of Arts & Science's departments of ecology and evolutionary biology, and cell and systems biology. "And it seems that based on our data, this happened before toothed and baleen whales diverged. The common ancestor of all living cetaceans was deeper diving – and then later species evolved all the diverse foraging specializations we see in modern whales and dolphins today."

Chang worked with Sarah Dungan, a former member of Chang's lab who has a PhD in ecology and evolutionary biology from U of T, on a study describing their experiments, computational analysis and results in the Proceedings of the National Academy of Sciences.

Deep diving by marine mammals is one of the great evolutionary transitions, along with powered flight and living on land, and reveals much about how quickly life can adapt in a changing world.

Whales evolved from mammals that share a common ancestor with hippos and that were partially aquatic. The great mystery of their transition to deep-sea foraging was how quickly this ability developed. Dungan and Chang looked at whale fossils on a molecular level and focused on the rhodopsin protein, which absorbs light and sends a signal that travels through the retina to the brain.

“One of the most intriguing aspects of this iconic land-to-sea evolutionary transition is that the qualities of the visual environment completely changed,” says Chang. “This helped to define which genes would be the most interesting for us to target in our studies.”

Dungan applied robust data science models to rhodopsin proteins from a variety of living whales and related mammals. This computerized analysis revealed a gene sequence representing the rhodopsin found in the common ancestor of all living whales. She expressed this gene in lab-grown cells to “resurrect” the predicted protein and experiment on purified samples.

"The fossil record is the gold standard for understanding evolutionary biology,” says Dungan. “But despite what Jurassic Park would have you believe, extracting DNA from fossil specimens is rare because the condition tends to be poor. So, if you’re interested in how genes and DNA are evolving, you rely on mathematical modelling and a strong sample of genes from living organisms to complement what we understand from the fossil record."

Belinda Chang (back left) leads a lab that focuses on the evolutionary transition of animals' vision. Sarah Dungan (right of Chang) researched whale vision as a former member of Chang’s lab (photo by Diana Tyszko)

Dungan and Chang were astonished by the biochemical properties of the resurrected protein compared to land mammals. Early whale rhodopsin was more sensitive to the blue light that penetrates deepest into the ocean, to a degree that exceeded expectations. Its biochemical properties also suggested that the retinas of early whales could respond rapidly to changes in light levels.

Early whales eventually evolved into the many kinds of toothed whales and baleen whales we see today. As separate species of whale evolved, they established ecological niches at various levels of the sea and even in freshwater rivers. Dungan and Chang’s work shows that there were further evolutionary adaptations as members of both groups either surfaced from the early deep levels to hunt closer to the surface or specialized to become even more extreme divers.

"I’ve always been fascinated by whales,” says Dungan. “The idea that there was a land mammal like me that eventually evolved to live underwater blew my mind as a kid, even though I really didn't understand exactly what that meant at the time.

“It is amazing that now we can have this level of insight into the lifestyle of a long-extinct organism, just from doing laboratory experiments on one protein. Ancestral protein resurrection is an incredibly powerful way for us to interrogate how ancient organisms evolved that most people don't know about,” she adds.

Next, Dungan and Chang plan to resurrect the ancestral whale proteins that transmit the rhodopsin light signal from the retina to the brain to provide insights into the neurological adaptations associated with deep diving. They will probe ancient evolutionary adaptations associated with new behaviours and hope to gain greater insight into how animals may adapt to a changing world.