Posted on

A Death Wish That Allows Worms to Thrive — and What It Tells Us About Cancer Biology

Source: Memorial Sloan Kettering - On Cancer
Date: 03/28/2019
Link to original
Image of article

In biology, how cells die is as important as how they live. Cell death provides a counterbalance to cell division, maintaining the proper number of cells throughout an organism’s lifetime. Gaining a better understanding of how cells die is also important for cancer research. It can teach us how the body naturally fends off cancer — by preventing runaway cell growth — as well as point to new ways to target and kill tumor cells.

The lab of Sloan Kettering Institute cell biologist Michael Overholtzer explores the mechanisms of different kinds of cell death. More than a decade ago, while studying breast cancer cells, he was the first to observe a type of cell death called entosis, in which one cell engulfs and kills another.

In a study published in March 2019 in Cell Reports, Dr. Overholtzer described for the first time the role of entosis in the development of a tiny worm called C. elegans. The discovery is significant because until now very little has been known about the role that entosis plays in natural developmental processes.

“Understanding cell death in normal development can provide new clues about how it works and why it evolved,” says Dr. Overholtzer, who was recently named dean of the Gerstner Sloan Kettering Graduate School of Biomedical Sciences. “We hope this research will help us find ways to harness it for cancer treatment.”

Characterizing Different Kinds of Cell Death

The most well-studied form of cell death is called apoptosis. Apoptosis is a type of programmed cell death sometimes likened to cellular suicide, in which a cell breaks down in a regulated, systematic fashion. Apoptosis can occur in response to cell damage, but it’s also a normal part of development in embryos. For example, apoptosis in the hands and feet allows individual fingers and toes to form, by killing cells in the spaces in between them.

In the March 2019 study, the researchers focused on the development of the gastrointestinal and reproductive tracts of the C. elegans worm, a popular lab model for studying development. Research from a team at Rockefeller University had suggested that forms of cell death other than apoptosis were important in the formation of parts of the worm’s body. Dr. Overholtzer’s team decided to continue this line of inquiry.

In particular, the researchers looked at the role of cell death in the formation of the cloaca, the dual-purpose orifice at the hind end of worms, as well as many other organisms, from which excrement is discharged. In males, it is also where sperm are released. It turns out that entosis is vital to ensuring that the genital tract connects to the cloaca. Without it, male worms are sterile.

A Mysterious Process

Unlike apoptosis, entosis requires two cells. It might sound more like a murder than a suicide, but cells that undergo death by entosis still have a death wish. They actually burrow themselves into the other cell, where they are broken down and eaten.

“This is a really enigmatic process,” Dr. Overholtzer says. “Why would a cell decide to do this? It turns out that in the worm, it’s required for normal development.”

In the C. elegans embryo, a type of cell called a linker cell pulls the developing genital tract into the cloaca. The linker cell then burrows into another cell, where it is destroyed by entosis. Destruction of the linker cell creates an opening that allows sperm to enter the cloaca.

“There’s an ongoing question in biology, which is, ’Where do all these different cell death programs come from and why do they exist?’” he notes. “For entosis, this study demonstrates that a process observed initially in breast cancer cells also has a role in normal development.”

Further research will focus on figuring out whether entosis contributes to other developmental processes, as well as molecular changes in the cell that lead to death by entosis. The researchers also plan to study a piece of the linker cell that is left behind after the cell undergoes entosis, called the lobe. “These pieces stick around for a long time, so we think they may have some purpose,” Dr. Overholtzer concludes.

Posted on

Understanding Biology’s Blueprint: 8 Questions with Kat Hadjantonakis

Source: Memorial Sloan Kettering - On Cancer
Date: 12/30/2019
Link to original
Image of article

Earlier this year, Anna-Katerina “Kat” Hadjantonakis was named Chair of the Sloan Kettering Institute’s Developmental Biology Program. She succeeded Kathryn Anderson, who had led the program since it launched in 2003.

We spoke with Dr. Hadjantonakis about the field of developmental biology and how she got interested in this area of research.

What is developmental biology, and what does it have to do with cancer?

Developmental biologists study the genes, proteins, and other biological phenomena that control how cells multiply, change their identity, and reorganize themselves to give rise to different tissues and organs. This provides a blueprint to understand how our bodies form.

Cancer happens when normal developmental processes go awry. To learn how to fix them, you first need to know how they’re supposed to work.

What is the focus of your research?

My lab uses primarily mammalian models to learn how cells know what to become and how groups of these cells generate the blueprints of organs. We study tissue called the endoderm, which becomes organs, including the lungs, liver, and pancreas. We study how endodermal cells give rise to distinct organs with different functions.

Did you always know you wanted to be a scientist?

I went to school in the UK, and the education system requires that you narrow down your interests early. I excelled at biology and math, so I decided to go in that direction. I also excelled at fine art, especially photography, but sadly was unable to pursue that interest in parallel. I’m dyslexic and have always been better with processing images than words. I did my undergraduate and PhD degrees at Imperial College London. I’ve now come full circle because my lab uses a lot of microscopy, an adaptation of photography.

What led you to MSK?

When I was a postdoc at Columbia University, I met Kathryn at a meeting on mouse genetics. She told me MSK was creating the Developmental Biology Program and that I should consider applying. I was the first person hired after the program started.

Now that you’re Chair of the program, what are your plans for it?

Our first goal is to recruit three or four junior faculty members who will be leaders in their fields. We want people who work on the cutting edge of research, address important unsolved problems, and are collaborative and good institutional citizens. Kathryn is a true role model, and it’s fabulous that she’s staying on as faculty. I have some big shoes to fill.

Where in the UK did you grow up?

I grew up in London, but both of my parents were Greek. Even though I sound British, I have a long, unpronounceable Greek name. Growing up, I used to visit Greece every summer. I speak Greek, but with a British accent.

Do you still make art?

I don’t have time to practice art, but I live in the Chelsea neighborhood, the nexus of many art galleries. So I try to take advantage of those cultural opportunities.

What are your other hobbies?

Listening to music. I used to have a subscription to the Metropolitan Opera, but I relinquished it. Their performances started too early. My schedule is unpredictable, and I often failed to make it across town in time after work.

I cycle as much as I can. I see it as an efficient mode of transport and a decent form of exercise — a surrogate for not getting to the gym as often as perhaps I should! I ride a Citi Bike to work, weather permitting. When I first came to New York, I was petrified to ride here. I used to cycle in London and in Toronto, where I trained. The city has done a lot with building bike lanes and raising awareness of cyclists. I’m now brave enough to venture onto the streets. 

Posted on

Scientists accidentally engineer mice with unusually short and long tails

Source: Cell Press
Date: 01/17/2019
Link to original
Image of article

Researchers from two groups studying mouse development have accidentally created mice with unusually long and unusually short tails. Their findings, publishing January 17 in the journal Developmental Cell, offer new insight into some of the key aspects controlling the development of tails in mice and have implications for understanding what happens when developmental pathways go awry.

“The same regulatory networks that control mechanisms regulating how a body pattern is formed are often coopted for other developmental processes,” says Moisés Mallo, a researcher at Instituto Gulbenkian de Ciência in Lisbon, Portugal, and senior author of one of the two papers. “Studying these networks can give us relevant information for understanding other developmental, or even pathological, processes.”

Both groups’ findings are related to a gene called Lin28, which was already known to have a role in regulating body size and metabolism, among other functions.

“We were trying to make mouse models of Lin28-driven cancer, but we were surprised to find that these mice had super long tails. They had more vertebrae,” says George Daley (@G_Q_Daley), an investigator and dean at Harvard Medical School and senior author of the other paper. His team was studying the Lin28/let-7 pathway, which regulates developmental timing and has been implicated in several types of cancer.

Mallo, on the other hand, was studying a gene called Gdf11, which was already known to be involved in triggering the development of the tail during embryonic development. In his lab, they found that mice with Gfd11 mutations had tails that were shorter and thicker than those of regular mice. “They also contained a fully grown neural tube inside, as opposed to a normal tail that is essentially made of vertebrae,” Mallo says. “We were able to pinpoint the Lin28 and Hox13 genes as key regulators of tail development downstream from Gdf11.”

Both pathways relate to the development of somites, which give rise to important structures associated with the vertebrate body plan. These blocks of cells eventually differentiate into dermis, skeletal muscle, cartilage, tendons, and vertebrae. As mammals develop, the somites are laid down sequentially along the body axis. Lin28 plays a role in regulating the timing of this repetitive process.

“From my perspective, one of the most important findings of our work is that a group of multipotent cells that build both the somites and the spinal cord are regulated by fundamentally different genetic networks and have different cell competences at two consecutive stages of development,” Mallo says. “This finding goes beyond the trunk to tail transition, possibly acquiring relevance in pathological processes like the initiation of metastasis.”

“There are also important implications in this research for understanding evolution,” says Daisy Robinton, a researcher at Harvard and first author of the study from Daley’s lab. “Anterior-posterior axis elongation is an important feature in bilateral animals, and natural selection has created a variety of tail lengths to suit different evolutionary pressures. Until now, little was known about how length is controlled and how the manipulation of genetics can impact morphogenesis.”

Robinton says the next steps for the Daley lab are to address the question of whether Lin28/let-7 acts similarly in other organ systems, as well as to explore more deeply how this pathway influences cell fate decisions during mammalian development.

For Mallo, future work will focus on uncovering further molecular details of how these players modulate the activity of tail bud progenitors and deepening the understanding of how these molecular interactions are mediated.

###

Developmental Cell, Robinton et al: “The Lin28/let-7 pathway regulates the mammalian caudal body axis elongation program.” https://www.cell.com/developmental-cell/fulltext/S1534-5807(18)31084-0 DOI: 10.1016/j.devcel.2018.12.016

Developmental Cell, Aires et al: “Tail bud progenitor activity relies on a network comprising Gdf11, Lin28 and Hox13 genes.” https://www.cell.com/developmental-cell/fulltext/S1534-5807(18)31072-4 DOI: 10.1016/j.devcel.2018.12.004

Posted on

Electrical signals kick off flatworm regeneration

Source: Cell Press
Date: 03/05/2019
Link to original
Image of article

Unlike most multicellular animals, planarian flatworms can regrow all their body parts after they are removed. This makes them a good model for studying the phenomenon of tissue regeneration. They are also useful for exploring fundamental questions in developmental biology about what underlies large-scale anatomical patterning.

In a study publishing March 5 in Biophysical Journal, scientists report that electrical activity is the first known step in the tissue-regeneration process, starting before the earliest known genetic machinery kicks in and setting off the downstream activities of gene transcription needed to construct new heads or tails.

“It’s incredibly important to understand how cells make decisions about what to build,” says senior author Michael Levin (@drmichaellevin), director of the Allen Discovery Center at Tufts University. “We’ve found that endogenous electrical signals enable cells to communicate and make decisions about their position and overall organ structure, so they know which genes to turn on.”

The species used in the study was Dugesia japonica. When parts of this flatworm are removed, the remaining tissues regrow the missing pieces at the correct ends–whether a head or a tail. Previous studies had shown that about six hours after amputation, the first genes associated with regrowing a missing part are turned on. But until now, it wasn’t known what happened before that or what mechanisms control which genes get turned on.

In the current experiments, led by Fallon Durant, who was a graduate student at the time, the heads and tails of the flatworms were removed. The researchers used voltage-sensitive fluorescent dyes that were able to indicate the various electrical potentials of the different regions. “You can literally see the electrical activity in the tissue,” Levin says. “Within a few hours of when this activity is seen, we can start to measure changes in gene expression.”

To show that a specific voltage pattern was responsible for turning on correct genes for each wound site, the team altered the resting potentials of cells at the different ends of the worms and observed the effects. By inducing ion flows that set each wound site to head- or tail-specific voltage patterns, they can create flatworms with two heads and no tail. They also studied the relationship between this electrical signal and the well-known Wnt protein signaling pathway, functioning downstream of the voltage-mediated decision machinery.

“Most of the people working on this problem study genetic and biochemical signals like transcription factors or growth factors,” Levin says. “We’ve decided to focus on electrical signals, which are a very important part of cell-to-cell communication.” He compares the electrical signals his group studies to those that occur in the brain. “A stimulus comes in and an electrical event triggers biochemical second-messenger events in the cells and downstream activity of the electrical network, such as decision making or forming a memory,” he notes. “This electrical system is super ancient and very highly conserved.”

Future research will focus on breaking down these signals in much more detail. For example, researchers would like to know how regenerated tissues make decisions about the size, shape, and scale of the new parts that they grow and how the bioelectric circuits store changes in body patterning, as is seen in two-headed worms that continue to make two-headed animals in subsequent rounds of regeneration.

“With perhaps the exception of infectious disease, the majority of problems in health and biomedicine hinge on understanding how cells get together to build a specific organ or other structure,” Levin concludes. “If we can figure out how to manipulate these processes, we can start to develop ways to correct birth defects and address everything from traumatic injury to degenerative diseases, aging, and cancer.”

###

This research was funded by an Allen Discovery Center Award from the Paul G. Allen Frontiers Group, the G. Harold and Leila Y. Foundation, the Templeton Foundation, and the National Science Foundation.

Biophysical Journal, Durant et al.: “The role of early bioelectric signals in the regeneration of planarian anterior/posterior polarity” https://www.cell.com/biophysj/fulltext/S0006-3495(19)30065-7

Posted on

In mice, single population of stem cells contributes to lifelong hippocampal neurogenesis

Source: Cell Press
Date: 03/28/2019
Link to original
Image of article

Scientists once thought that mammals entered adulthood with all of the neurons they would ever have, but studies from the 60s found that new neurons are generated in certain parts of the adult brain and pioneering studies from the 90s helped identify their origins and function. In the latest update, a team of researchers has shown in mice that a single lineage of neural progenitors contributes to embryonic, early postnatal, and adult neurogenesis in the hippocampus, and that these cells are continuously generated throughout a lifetime. The study appears March 28 in the journal Cell.

“Conceptually, this suggests that our brains have the capacity for continuous improvement, adaptation, and incorporation of new cells into the circuitry,” says senior author Hongjun Song of the Perelman School of Medicine at the University of Pennsylvania. “This turns out to be very important, because the hippocampus is well known to be important for learning, memory, and mood regulation.”

Neurogenesis was originally believed to have two phases: the developmental phase, which occurred mostly in embryos and immediately after birth and in which neurons are generated from a stem cell that build up circuitries of the full nervous system. Adult neurogenesis was thought to originate from a specialized population of neural stem cells that were “set aside” and distinct from the precursors generating neurons during embryogenesis. But it turns out it’s not so straightforward.

In the current study, the researchers labelled precursor neural stem cells in mice at a very early stage of brain development. They then followed the lineage of cells throughout development and into adulthood. Their findings revealed that new neural stem cells with the precursor cells’ label were continuously generated throughout the animals’ lifetimes.

RNA-seq and ATAC-seq analyses were used to confirm that all the cells in the lineage had a common molecular signature and the same developmental dynamics.

“Earlier studies have suggested that specific parts of the brain, such as the olfactory bulb and the hippocampus, can generate neurons,” Song says. “Until this study, it wasn’t clear how this happens. We’ve shown for the first time in a mammalian brain that development is ongoing from the beginning, and that this one process happens over a continuum that lasts a lifetime.”

The prevalence of adult neurogenesis in humans and primates is an area of active discussion in the field and more research is needed to determine whether the process of stem cell generation observed in the mouse pertains to other mammals too. The investigators plan to study the processes of neurogenesis in more detail, to look for ways to potentially increase or preserve it, as well as to determine how it’s regulated at the molecular level.

“This paper has implications for understanding how the brain maintains a ‘young’ state for learning and memory,” says co-senior author Guo-li Ming, also of the Perelman School of Medicine. Additionally, “if we could harness this capacity and this mechanism, we may be able to repair and regenerate parts of the brain,” she concludes.

###

This research was supported by the National Institutes of Health, an EMBO postdoctoral fellowship, and the Swedish Research Council.

Cell, Berg et al.: “A Common Embryonic Origin of Stem Cells for Continuous Developmental and Adult Neurogenesis” https://www.cell.com/cell/fulltext/S0092-8674(19)30159-X