CLOSE
Tags Posts tagged with "Dave Tuveson"

Dave Tuveson

by -
0 1327
Dave Tuveson. Photo by Gina Motisi/CSHL

By Daniel Dunaief

While one bad apple might spoil the bunch, the same might be true of one bad cancer gene.

Cold Spring Harbor Laboratory’s Cancer Director Dave Tuveson and Derek Cheng, who earned his PhD from Stony Brook University while conducting research in Tuveson’s lab, recently explored how some mutant forms of genes in pancreatic cancer can involve other proteins that also promote cancer.

A gene well-researched in Tuveson’s lab, mutated KRAS promotes cell division. Mutant versions of this gene continue to produce copies of themselves, contributing to cancer.

Derek Cheng

Turning off or blocking this gene, however, doesn’t solve the problem, at least not in the laboratory models that track a cancer cell’s response.

In laboratory models of pancreatic cancer, a disease for which the prognosis is often challenging, other proteins play a role, creating what researchers call an “adaptive resistance” to chemotherapy.

In a paper published in the journal Proceedings of the National Academy of Sciences, Cheng, who is the first author and is currently in his final year of medical school at the Stony Brook Renaissance School of Medicine, and Tuveson showed that a protein called RSK1 interacts at the membrane with mutated KRAS. When KRAS is inhibited, the RSK1 protein, which normally keeps RAS proteins dormant, becomes more active.

“If you antagonize KRAS, you would get a rebound” as the cancer cells develop a resistance to the original drug, Tuveson said. “We found a feedback loop.”

The research “focused on identifying protein complexes with oncogenic KRAS that would potentially be relevant in pancreatic cancer,” Cheng explained in an email. “My work suggests that an RSK1/NF1 complex exists in the vicinity of oncogenic KRAS.”

While Cheng was able to show that the role of membrane-localized RSK1 provided negative regulation of wild-type RAS, it “remains to be studied what the role of the RSK1 at the membrane [is] in the context of oncogenic KRAS.”

KRAS is a molecular switch that turns on and off with the help of other proteins. With certain mutations, the switch doesn’t turn off, continuing to signal for copying and dividing, which are hallmarks of cancer cells. With specific activating mutations, the switch can lose its ability to turn off and constitutively signal for proliferation, metabolic reprogramming, and other behaviors characteristic of cancer cells, Cheng explained.

A cell with an oncogenic KRAS has the tendency to be more fit than a normal cell without one. Such cells will likely grow at a faster rate under stressful conditions, which, over time, can enable them to outcompete normal cells, Cheng continued.

When KRAS is in an oncogenic state, another protein, called RSK1 is hanging around the membrane. RSK1 has several functions and can participate in numerous cellular signaling pathways.

KRAS cytoplasm

While RSK1 is involved in protein translation by phosphorylating S6 kinase, it also has other functions at the plasma membrane, where it shuts down wild type RAS proteins.

Other researchers have suggested a negative feedback for RSK1 and NF1.

“Our contribution demonstrated some relevance of this interaction in pancreatic cancer cells,” Cheng explained in an email.

Cheng said RSK is known to have various effects, depending on the context. In the paper, the scientists showed that RSK has a “negative feedback properties, such as that, upon the removal of mutant KRAS, it has this negative regulatory role.”

Graduate student Sun Kim and post doctoral researchers Hsiu-Chi Ting and Jonathan Kastan are currently exploring whether RSK has a pro-oncogenic function on the membrane in the tumor cell.

So far, these studies suggest that while a direct inhibitor against oncogenic KRAS would likely be the greatest target for an effective therapy, cancer cells may still be able to use signals from other RAS isoforms.

“A combination of targeting KRAS and modulating regulators of RAS such as RSK1/NF1 and SOS1 may enhance therapeutic efficacy,” Cheng suggested.

Cheng is grateful for the opportunity to learn from numerous Tuveson lab members on ways cancer cells differ from healthy cells.

The discovery of the potential roles of RSK1 in cancer provides some possible explanation for the potential resistance mechanisms of mutant KRAS inhibitors.

While he was encouraged that a prestigious journal published the research, Tuveson said he hopes this type of observation “will lead to something that will be useful for a pancreatic cancer patient and not just” provide compelling ideas.

Cheng attended medical school for two years before joining Tuveon’s lab for the next six years.

Cheng defended his thesis in 2020 during the pandemic on a zoom call.

“I was one of the first people to defend with this format for both CSHL and SBU,” Cheng explained. “I was able to invite many friends and family that probably would not have been able to make the trip.”

Cheng’s family has battled cancer, which contributed to his research interests.

When he was an undergraduate, he had an uncle develop glioblastoma, while another uncle and his grandfather developed colon cancer.

“I knew I wasn’t going to be able to do much about their medical condition, but I wanted to work on something that people cared about,” Cheng explained.

Outside of the lab, Cheng enjoys working on his car and his motorcycles. He feels a sense of autonomy working on his own projects.

He’s most proud of a motorcycle for which he rebuilt the front end with parts from another model to outfit a larger brake system.

A native of St. Louis, Cheng is a fan of the hockey team, the Blues. He owns a game-worn jersey from almost every member of the 2019 cinderella team that won the Stanley cup, with some of those jerseys coming from Stanley Cup final games.

Cheng plans to apply to residency in internal medicine this year because he wants to continue applying what he learned in his scientific and medical training.

The clinical work reminds him to treat patients and not just the tumors, while scientific research trained him to loo at evidence and literature carefully to find clinical gaps, he explained.

by -
0 1994
Dennis Plenker Photo by Bob Giglione, 2020/ CSHL

By Daniel Dunaief

If the job is too easy, Dennis Plenker isn’t interested.

He’s found the right place, as the research investigator in Cold Spring Harbor Laboratory Cancer Center Director Dave Tuveson’s lab is tackling pancreatic cancer, one of the more intractable forms of cancer.

Plenker joined Tuveson’s lab in 2017 and is the technical manager of a new organoid facility.

Organoids offer hope for a type of cancer that often carries a poor prognosis. Researchers can use them to find better and more effective treatments or to develop molecular signatures that can be used as a biomarker towards a specific treatment.

Scientists can take cells from an organoid, put them in miniature dishes and treat them with a range of drugs to see how they respond.

The drugs that work on the organoids offer potential promise for patients. When some of these treatments don’t work, doctors and researchers can continue to search for other medical solutions without running the risk of making patients ill from potentially unnecessary side effects.

“Challenges are important and there is a sweet spot to step out of my comfort zone,” Plenker explained in an email.

Dennis Plenker Photo by Bob Giglione, 2020/ CSHL

In an email, Tuveson described Plenker as a “pioneer” who “likes seemingly impossible challenges and we are all counting on him to make breakthroughs.”

Specifically, Tuveson would like Plenker to develop a one-week organoid test, where tissue is processed into organoids and tested in this time frame.

Organoids present a cutting edge way to take the modern approach to personalized medicine into the realm of cancer treatments designed to offer specific guidance to doctors and researchers about the likely effectiveness of remedies before patients try them.

Plenker and others in Tuveson’s lab have trained researchers from more than 50 institutions worldwide on how to produce and use organoids.

“It’s complicated compared to conventional tissue culture,” said Plenker, who indicated that considerably more experience, resource and time is involved in organoid work. “We put a lot of effort into training people.”

Tuveson explained that the current focus with organoids is on cancer, but that they may be useful for other conditions including neurological and infectious diseases.

The way organoids are created, scientists such as Plenker receive a biopsy or a surgical specimen. These researchers digest the cells with enzymes into singular cells or clumps of single cells and are embedded. Once inside the matrix, they form organoids.

When they “have enough cells, we can break these down and put them into multi-well plates,” Plenker explained. In these plates, the scientists test different concentrations and types of drugs for the same patient.

It’s a version of trial and error, deploying a range of potential medical solutions against cells to see what weakens or kills cells.

“If you do that exercise 100 times, you can see how many times compound A scores vs. C, E and F. You get a sense of what the options are versus what is not working,” Plenker said.

While scientists like Plenker and Tuveson use targeted drugs to weaken, cripple or kill cancer, they recognize that cancer cells themselves represent something of a molecular moving target.

“There is a very dynamic shift that can happen between these subtypes” of cancer, Plenker said. “That can happen during treatment. If you start with what’s considered a good prognosis, you can end up with a higher fraction of basal cancer cells” which are more problematic and have a worse prognosis. “We and others have shown that you have a mixture of cell types in your tumor all the time.”

Part of what Plenker hopes to discover as the director of the organoid center is the best combination of ingredients to foster the growth of these versatile and useful out-of-body cancer models.

The gel that helps the cells grow is something Plenker can buy that is an extracellular matrix rich matter that is of murine, or rodent, origin. He hopes to develop a better understanding of some of these proprietary products so he can modify protocols to boost the efficiency of the experiments.

Plenker is “trying to innovate the organoids, and so he may need to adjust conditions and that would include inventing his own recipes,” Tuveson explained.

The facility, which received support from the Lustgarten Foundation, will engage in future clinical trials.

The type of treatments for pancreatic cancer patients typically fall into two arenas. In the first, a patient who is doing well would get an aggressive dose of chemotherapy. In the second, a patient who is already sick would get a milder dose. Determining which regimen is based on the current diagnostic techniques.

Plenker and his wife Juliane Dassler-Plenker, who works as a post-doctoral fellow in the lab of Mikala Egeblad at Cold Spring Harbor Laboratory, live in Huntington. The pair met in Germany and moved to the United States together.

Plenker calls himself a “foodie” and appreciates the hard work that goes into creating specific dishes.

In his career, Plenker always “wanted to help people.” He has appreciated the latest technology and has disassembled and put back together devices to understand how they work.

Prior to the pandemic, Plenker had gone on short trips to Germany to visit with friends and relatives. He is grateful for that time, especially now that he is much more limited in where he can go. He appreciates his landlord and a second American family which helps the couple feel welcomed and grateful.

In 2017, Plenker recalls attending a talk Tuveson gave in Washington, D.C. in which he invited anyone in the audience who wanted to improve a test to come and talk to him after the presentation.

“I was the only one in that regard who talked to him” after that lecture, Plenker said.

by -
0 1624
Tim Sommerville. Photo by Brian Stallard, 2018/ CSHL

By Daniel Dunaief

Many research efforts search for clues about the signals or processes that turn healthy cells into something far worse. Scientists look at everything from different genes that are active to signs of inflammation to the presence of proteins that aren’t typically found in a system or organ.

Tim Somerville, a postdoctoral researcher in Chris Vakoc’s laboratory at Cold Spring Harbor Laboratory, recently took a close look at a specific protein whose presence in a high concentration in pancreatic cancer typically worsens the expectations for a disease with an already grim prognosis.

This protein, called P63, has a normal, healthy function in skin cells for embryos and in maintaining normal skin for adults, but it doesn’t perform any important tasks in the pancreas.

Tim Somerville at Cold Spring Harbor Laboratory. Photo by Brian Stallard, 2018/ CSHL

Somerville wanted to know whether the protein appeared as a side effect of the developing cancer, like the appearance of skinny jeans someone wears after a diet starts working, or whether it might be a contributing cause of the cancer’s growth and development.

“What was unclear was whether [the higher amount of P63] was a correlation, which emerges as the disease progresses, or something more causal,” he said, adding that he wanted to find out whether “P63 was driving the more aggressive features” of pancreatic cancer.

Somerville increased and decreased the concentration of P63 in tissue cells and organoids, which are copies of human tumors, hoping to see whether the change had any effect on the cancer cells.

The postdoctoral researcher knocked out the amount of P63 through the use of CRISPR, a gene-editing technique. He also overexpressed P63, which is also a transcription factor.

“From those complementary experiments, we were able to show that P63 is driving a lot of the aggressive features of cancer cells,” Somerville concluded. “Rather than being a correlation that’s observed, it is functionally driving the cancer itself.”

Somerville recently published his research in the journal Cell Reports.

As a transcription factor, P63 recognizes specific DNA sequences and binds to them. With P63, Somerville observed that it can bind to DNA and switch on many genes that are active in the worse form of pancreatic cancer. He and his collaborators describe P63 as a master regulator of the gene program.

Pancreatic cancer is often discovered after the irreversible conversion of normal, functional cells into a cancerous tumor that can spread to other organs. It also resists chemotherapy. Research teams in the labs of Vakoc and Dave Tuveson, the director of the Cancer Center at CSHL, and other principal investigators at CSHL and elsewhere are seeking to understand it better so they can develop more effective treatments.

Tim Somerville. Photo by Yali Xu

Vakoc was impressed with the work his postdoctoral researcher performed in his lab. Somerville is “one of the most scholarly young scientists I have ever met,” Vakoc explained in an email. “He is simply brilliant and thinks deeply about his project and is also driven to find cures for this deadly disease.”

At this point, Somerville is pursuing why P63 is activated in the pancreas. If he can figure out what triggers it in the first place, he might be able to interfere with that process in a targeted way. He also might be able to think about ways to slow it down or stop the disease.

The form of P63 that is active in the pancreas is not a mutated version of the protein that functions in the skin. If scientists tried to reduce P63, they would need to develop ways to suppress the cancer promoting functions of P63 without suppressing its normal function in the skin.

Many of the genes and proteins P63 activates are secreted factors and some of them contribute to inflammation. Indeed, researchers are exploring numerous ways inflammation might be exacerbating the progression of cancer.

P63 is also active in other types of cancer, including lung, head and neck cancers. Frequently, elevated levels of P63 in these other forms of cancer also lead to a worse prognosis.

Somerville explained that the changes P63 makes in a pancreatic cancer cell may expose new weaknesses. By studying cells in which he has overexpressed the protein, he hopes to see what other addictions the cells may have, which could include a reliance on other proteins that he could make compounds to target.

A resident of Huntington, Somerville has worked in Vakoc’s lab for three years. While he has spent considerable time studying P63, he is also looking at other transcription factors that are involved in pancreatic cancer.

Somerville wants to contribute to the discovery of why one form of pancreatic cancer is so much worse than the other. “If we can understand it, we can find new ways to stop it,” he said.

Originally from Manchester, England, Somerville is working in the United States on a five-year visa and plans to continue contributing to Vakoc’s lab for the next couple of years. At that point, he will consider his options, including a potential return to the United Kingdom.

Tim Somerville. Photo by Gina Motisi, 2018/CSHL

Somerville appreciates the opportunity to work on pancreatic cancer with Vakoc and with Tuveson, whose lab is next door. The researcher is enjoying his time on Long Island, where he takes walks, enjoys local restaurants and, until recently, had been playing on a Long Island soccer team, which played its matches in Glen Cove.

For Somerville, Cold Spring Harbor Laboratory has exceeded his high expectations. “The research that goes on here and the interactions you can have at meetings” have all contributed to a “great experience,” he said.

Somerville is excited to be a part of the pancreatic cancer team.

“With the work from [Tuveson’s] lab and ours, we’re finding new things we didn’t know,” he said. “It’s only when you understand those different things and the complexity that you can start thinking about how to tackle this in a more successful way. If the research carries on, we’ll make improvements in this disease.”

by -
0 2818
Photo by Ela Elyada

By Daniel Dunaief

What if, instead of defeating or removing enemy soldiers from the battlefield, a leader could convince them to join the fight, sending them back out to defeat the side they previously supported? That’s the question Giulia Biffi, a postdoctoral researcher at Cold Spring Harbor Laboratory, is asking about a particular type of cells, called fibroblasts, that are involved in pancreatic cancer.

Fibroblasts activated by cancer cells secrete a matrix that surrounds cancer cells and makes up about 90 percent of pancreatic tumors.

Giulia Biffi. Photo by ©Gina Motisi, 2018/CSHL

Responding to a molecule called IL-1, an inflammatory potential tumor-promoting fibroblast may enhance the opportunity for cancer to grow and spread. Another type of fibroblast responds to TGF-beta, which potentially enables them to restrain tumors.

Researchers had suggested that the inflammatory fibroblasts are tumor promoting, while the myofibroblasts are tumor defeating, although at this point, that still hasn’t been confirmed experimentally.

Researchers knew TGF-beta was important in biology, but they didn’t know that it was involved in preventing the activation of an inflammatory tumor-promoting version.

Biffi, however, recently found that IL-1 promotes the formation of inflammatory fibroblasts. She believes these fibroblast promote tumor growth and create an immunosuppressive environment.

In an article published in the journal Cancer Discovery, Biffi showed that it’s “not only possible to delete the population, but it’s also possible to convert [the fibroblasts] into the other type, which could be more beneficial than just getting rid of the tumor-promoting cells,” she said.

Biffi works in Director Dave Tuveson’s CSHL Cancer Center laboratory, which is approaching pancreatic cancer from numerous perspectives.

Her doctoral adviser, Sir Shankar Balasubramanian, the Herchel Smith Professor of Medicinal Chemistry at the University of Cambridge, suggested that the work she did in Tuveson’s lab is an extension of her successful research in England.

“It is evident that [Biffi] is continuing to make penetrating and important advances with a deep and sophisticated approach to research,” Balasubramanian explained in an email. “She is without a doubt a scientist to watch out for in the future.”

To be sure, at this stage, Biffi has performed her studies on a mouse model of the disease and she and others studying fibroblasts and the tumor microenvironment that dictates specific molecular pathways have considerable work to do to extend this research to human treatment.

She doesn’t have similar information from human patients, but the mouse models show that targeting some subsets of fibroblasts impairs cancer growth.

“One of the goals we have is trying to be able to better classify the stroma from pancreatic cancer in humans,” Biffi said. The stroma is mixed in with the cancer cells, all around and in between clusters of cells.

The results with mice, however, suggest that approaching cancer by understanding the molecular signals from fibroblasts could offer a promising additional resource to a future treatment. In a 10-day study of mice using a specific inhibitor involved in the pathway of inflammatory fibroblasts, Biffi saw a reduction in tumor growth.

If Biffi can figure out a way to affect the signals produced by fibroblasts, she might be able to make the stroma and the cancer cells more accessible to drugs. One potential reason other drugs failed in mouse models is that there’s increased collagen, which is a barrier to drug delivery. Drugs that might have failed in earlier clinical efforts could be reevaluated in combination with other treatments, Biffi suggested, adding if scientists can manage to target the inflammatory path, they might mitigate some of this effect.

A native of Bergamo, Italy, which is near Milan, Biffi earned her doctorate at the Cancer Research UK Cambridge Institute. Biffi lives on a Cold Spring Harbor property which is five minutes from the lab.

When she was young, Biffi wanted to be a vet. In high school, she was fascinated by the study of animal behavior and considered Dian Fossey from “Gorillas in the Mist” an inspiration. When she’s not working in the lab, she enjoys the opportunity to see Broadway shows and to hike around a trail on the Cold Spring Harbor campus.

Biffi started working on fibroblasts three years ago in Tuveson’s lab. “I really wanted to understand how fibroblasts become one population or the other when they were starting from the same cell type,” she said. “If they have different functions, I wanted to target them selectively to understand their role in pancreatic cancer to see if one might have a tumor restraining role.”

A postdoctoral researcher for over four years, Biffi is starting to look for the next step in her career and hopes to have her own lab by the end of 2019 or the beginning of 2020.

When she was transitioning from her doctoral to a postdoctoral job, she was looking for someone who shared her idealistic view about curing cancer. Several other researchers in Cambridge suggested that she’d find a welcome research setting in Tuveson’s lab. Tuveson was “popular” among principal investigators in her institute, Biffi said. “I wanted to work on a hard cancer to treat and I wanted to work with [Tuveson].”

Biffi hopes that targeting the inflammatory pro-tumorigenic fibroblasts and reprogramming them to the potentially tumor-restraining population may become a part of a pancreatic cancer treatment.

She remains optimistic that she and others will make a difference. “This can be a frustrating job,” she said. “If you didn’t have hope you can change things, you wouldn’t do it. “I’m optimistic.”

Biffi points to the hard work that led to treatments for the flu and for AIDS. “Years back, both diseases were lethal and now therapeutic advances made them manageable,” she explained in an email. “That is where I want to go with pancreatic cancer.”

TBR News Media is your local news and entertainment website.
We provide you with the latest breaking news and information for your community.
Contact us: [email protected]

Most Viewed

©