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15Feb

CPRIT – TREC GRANT FUNDED: Gene – environment – lifestyle interactions in cancer

 

The Chapkin Lab is pleased to announce the award of a $6 million grant from Cancer Prevention and Research Institute of Texas – TREC funding to support research in “Gene – environment – lifestyle interactions in cancer”.   Dr. Robert Chapkin to serve as Deputy Director of the grant, Dr. Kenneth Ramos to serve as Director.  As part of this effort, we will establish a single-cell data science (SCDS) core at Texas A&M University in Bryan/College Station.  The SCDS core will serve as a Texas A&M Shared Resource Facility.  In terms of the complementary CPRIT grant and the SCDS core, Drs. James Cai and Yang Ni will serve as Director and co-Director, respectively.

https://www.cprit.texas.gov/grants-funded/grants/rp230204

 

8Feb

TEXAS A&M RESEARCHERS TO FURTHER DEVELOP UNIQUE CANCER DRUG WITH $2.3M NIH GRANT

Drs. Robert Chapkin, Gus Wright, James Cai, and Stephen Safe received a new NIH grant to perform a single cell multi-omic analysis of the colon tumor microenvironment to probe the mechanistic underpinnings of NR4A1-dependent modulation of T-cell exhaustion.

Story by Jennifer Gauntt, VMBS Communications

February 1, 2023

Preliminary data indicate that the compounds developed in the laboratory of Dr. Stephen Safe both kill tumors and rejuvenate the immune system, which becomes exhausted as it responds to cancer.

Dr. Stephen Safe in his lab
Dr. Stephen Safe is leading a team of researchers from Texas A&M University and Houston Methodist Hospital.

A team of Texas A&M University researchers has received a $2.3-millon grant from the National Institutes of Health to further explore a unique immunotherapy that could be the first of its kind to treat colon cancer and could hold the key to treating other forms of cancer as well.

The collaborative, four-year project will determine how to best utilize a new class of drugs developed in the laboratory of Dr. Stephen Safe, a Distinguished Professor in the Texas A&M School of Veterinary Medicine & Biomedical Sciences’ (VMBS) Department of Veterinary Physiology & Pharmacology. The project will also explore the effects of the new compounds on human and murine cancer cells.

Led by Safe, the team also includes VMBS researchers Gus Wright and James Cai, as well as College of Agriculture and Life Sciences researcher Robert Chapkin and Houston Methodist Hospital oncologist Maen Abdelrahim.

Safe’s compounds target two receptors—NR4A1 and NR4A2—that are normally responsible for helping humans and animals lower stress levels but are overexpressed in colon cancer and other solid tumors.

“In the case of solid tumors, these two receptors are bad; they regulate the growth of a cell, how it metastasizes, how it invades, and how it survives,” Safe said. “When we screened these receptors, we found out that our compounds that we’ve been working on over the years bind with high affinity (binding strongly). Binding can sometimes be bad, making the tumor worse, or binding can be good, by being an antagonist. In this case, the compounds are antagonists—they just wipe out the tumor.”

Not only does their preliminary data indicate that their compounds act as an immunotherapy and kill the tumor, but the compounds also rejuvenate the immune system, which becomes exhausted as it responds to cancer.

“Immune cells play a very important role in cancer treatment,” Safe said. “But what happens with tumor development is that eventually, the immune cells just get exhausted and become unable to mount a ‘tumor-killing’ response.

“Dr. Jim Allison and Dr. Tasuku Honjo’s Nobel Prize-winning work found that at least one of the reasons the immune cells don’t work is that they’re not only exhausted, but they don’t function because tumors can suppress immune cells, especially T-cells (which target specific foreign particles, such as cancer cells) and thereby avoid immune cell-dependent tumor surveillance (the tumors are misidentified as immune cells by the immune system),” Safe said.

Immunotherapies work by separating the T-cells from the tumor, allowing the immune system to destroy the tumor the way it would any other infection in your body.

3d rendered medically accurate illustration of a cancer cell being attacked by leukocytes
Immunotherapies stimulate the body’s own immune system to kill cancer cells.

“One of the signals (the communication mechanism between T-cells and tumors), or checkpoints, is a gene called PD-L1, which is a checkpoint inhibitor; checkpoints bring the immune cell and the tumor cell together,” Safe said. “We found that in breast and colon cancer, NR4A1 regulates PD-L1 in the tumor, and treatment with our antagonist decreases PD-L1 expression and sensitizes the tumor to immune surveillance, killing it.”

By isolating the immune cells, Wright, an associate research scientist in the VMBS’ Department of Veterinary Pathobiology, was able to analyze the T-cells for markers of exhaustion and determined that with Safe’s compounds, those markers were “wiped out.”

“Previous studies showed that NR4A1 played a role in T-cell exhaustion, and our unique NR4A1 antagonists not only target NR4A1 in the tumor but also in T-cells; this dual targeting (the killing of the tumor and rejuvenating the immune system) is consistent with their high anticancer activity in mouse models.”

In the next phase of their research, the team will use the NIH grant to explore other areas of how the compounds work to, hopefully, prepare it for clinical trials.

While Safe works to “maximize” the compounds—that is, to select the most effective molecules for achieving their end goal—and to assess compound dosages, Abdelrahim, who is co-principal investigator on the project, will be examining the effects of the compound on human tissue; Wright will be working to further explore implications on the immune system; Cai, an associate professor in the VMBS’ Department of Integrative Biosciences, will be investigating how other individual cell types are affected by the compounds; and Chapkin, the Allen Endowed Chair in Nutrition & Chronic Disease Prevention and a University Distinguished Professor, will be further analyzing effects of NR4A1-targeting compounds on colonic epithelial stem cells in tumors.

Chapkin, Wright, and Cai will also perform a single cell multi-omic analysis of the colon tumor microenvironment to probe the mechanistic underpinnings of NR4A1-dependent modulation of T-cell exhaustion.

Ultimately, Safe believes their NR4A1-targeting drugs will also attenuate other types of cancer, including breast cancer, glioblastoma, and rhabdomyosarcoma, the most common soft tissue sarcoma in children.

“A lot of drugs that oncologists use now just target the specific genes/pathways in tumor cell—the drug kills it and the tumor usually regresses,” he said. “Those drugs are effective and inhibit some tumor growth, but they’re only targeting the tumor; they’re not targeting immune cells. I’m not sure how many drugs currently being used target both the tumor and the immune cells, but ours do, and this accounts for their potency in preclinical animal models.”

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For more information about the Texas A&M School of Veterinary Medicine & Biomedical Sciences, please visit our website at vetmed.tamu.edu or join us on Facebook, Instagram, and Twitter.

Contact Information: Jennifer Gauntt, Director of VMBS Communications, Texas A&M School of Veterinary Medicine & Biomedical Sciences; jgauntt@cvm.tamu.edu; 979-862-4216

 

2Feb

$1.19 million grant will leverage single-cell sequencing technology: National Institutes of Health-funded project will help with cancer diagnosis, treatment, prevention

 

$1.19 million grant will leverage single-cell sequencing technology

The Texas A&M University System has received a $1.19 million grant from the National Institutes of Health, NIH, for a multidisciplinary collaboration to study the intricate connections between genomics, nutrition and health. Understanding these connections will help in the diagnosis and treatment of cancer and other diseases.

Head and shoulder of an oriental man, Yang Ni, Ph.D., Department of Statistics in Texas A&M's College of Arts and Sciences
Yang Ni, Ph.D., associate professor in the Department of Statistics at Texas A&M’s College of Arts and Sciences, is the primary investigator for “Bayesian differential causal network and clustering methods for single-cell data.” (Courtesy photo)

Yang Ni, Ph.D., an assistant professor in the College of Arts and Sciences Department of Statistics, will be the principal investigator for the effort. The project, which aims to create a toolset for interpreting and correlating novel genetic information, is titled “Bayesian differential causal network and clustering methods for single-cell data.”

Co-investigators for the project will be Robert Chapkin, Ph.D, Distinguished Professor and Allen Endowed Chair in the College of Agriculture and Life Sciences Department of Nutrition and Department of Biochemistry and Biophysics, and James Cai, Ph.D., associate professor in the School of Veterinary Medicine and Biomedical Sciences Department of Veterinary Integrative Biosciences.

The project aims to advance single-cell data science, the study of how genes and gene expression differ among individual cells in one organism. Because cancer arises from genetic abnormalities in individual cells, scientists believe that single-cell data science will reveal medically important information.

This NIH award is tied to a pending grant to the Cancer Prevention and Research Institute of Texas, CPRIT, to assess gene-environment-lifestyle interactions in cancer. Chapkin is spearheading that effort in collaboration with Ken Ramos, M.D., Ph.D., executive director at Texas A&M’s Institute of Biosciences and Technology.

Ramos and Chapkin have also submitted a $6 million grant titled “Gene-environment-lifestyle interactions in cancer” to the CPRIT to create a new regional center of excellence in cancer research.

Chapkin said the NIH grant’s goals and personnel will complement the establishment of a single-cell data science core at Texas A&M that will serve as a shared-resource facility.

Purpose and goals of single-cell technology

The emergence of new technologies such as single-cell RNA sequencing and spatial profiling has brought about many methods to study gene regulation and cell differentiation in the single cells of multicellular organisms.

Ni will lead the effort, along with students and postdocs, to develop and implement new statistical methods for discovering causal gene regulation and molecular cell types with single-cell RNA-sequencing data.

“We will also work closely with Drs. Chapkin and Cai to solve real-world biological and biomedical problems,” he said.

“New methods are required to compare molecular differences at the single-cell level, so we can translate the knowledge advanced by single-cell RNA sequencing and spatial mapping to improve disease diagnosis, treatment and prevention,” Ni said.

 A balding man, Dr. Robert Chapkin , sitting in his laboratory looking through a microscope
Robert Chapkin, Ph.D., is one of the co-principal investigators for the single-cell technology and high-throughput genomic sequencing project. (Texas A&M AgriLife photo by Laura McKenzie)

Single-cell technology and high-throughput sequencing have enabled entirely new realms of biology, such as “deep phenotyping” and personalized medicine.

“In these applications, big data provide insights into cures for various diseases, including cancer,” Chapkin said.

Single-cell data allows for the detection of cell-to-cell interactions, gene networks and the spatial organization of gene expression in tissue samples.

“There is a consensus that single-cell multiomics data, in which data sets of different groups are combined during analysis, and spatial information will be driving next-generation solutions in oncology,” Chapkin said.

He said this type of single-cell multiomic research, is highly innovative.

“It will enable the characterization of previously unapproachable clinical phenomena, such as ’deep landscapes’ of cancer heterogeneity that will reveal more about the dynamics of the tumor microenvironment,” Chapkin said.

Ni said a long-term goal of the project is to develop novel statistical methods for generating and evaluating new hypotheses about complex cellular processes across disparate sample groups, such as disease subtypes and treatment groups.

Specifically, Ni said the team will work to design and validate Bayesian network and clustering models. The novel statistical models and related analytical tools will help accurately describe changes in gene regulation and cell differentiation in response to experimental interventions at the single-cell level under different experimental conditions.

“Without such tools, mechanistically understanding gene regulatory activities and cell differentiation will likely remain difficult,” he said. “And the proposed methods would be widely applicable to a range of data generated under different experimental conditions, disease subtypes and treatment groups.”

Single-cell modeling and connecting

Graphic of how single-cell RNA sequencing and spatial mapping can be used to develop "deep phenotyping" - keywords on the graphic are Cancer, Therapeutics, Tumor, Microenvironment, T cell exhaustion, Cancer stem cells, Single cells, Metabolomics (small molecultes), Trancsriptomics (mRNA), Epigenomics (DNA) and Proteomics (proteins)
The project will identify variables and probable relationships using single-cell RNA sequencing data to develop an interface between human genetics, computational statistics and data science. (Graphic courtesy of Robert Chapkin)

A Bayesian network model governs the probability and causal rules of a set of variables. An example would be a Bayesian network representing the probable relationships between diseases and their symptoms.

“In a Bayesian network model, first you identify main variables in the problem you want to solve,” explained Ni. “Then you specify or learn the structure of the network, which is the causal relationships between all the variables identified. After that, you determine the probability rules governing the relationships between those variables.”

Cai is also an affiliated faculty member in the College of Engineering Department of Electrical and Computer Engineering, and the Cai lab members develop analytical frameworks to study single-cell genomics data gathered from various types of cells.

In this project, he will play a bridging and coordinating role by connecting statisticians with molecular biologists to create an interface between human genetics, computational statistics and data science.

Sharing the results

Ni will lead the effort to disseminate the project’s results more broadly through open-source software, conference presentation, graduate and undergraduate education and mentoring, and hosting interdisciplinary workshops and symposia.

“We’re arranging for these workshops to provide travel stipends to help underrepresented students in STEM and encourage their participation,” he noted.

To help prepare next-generation researchers, statisticians and data scientists and improve public statistical literacy and engagement, Ni will also host data science competitions designed to engage undergraduate students.

“I also plan to develop a new graduate course on causal networks, and supervise the research of postdoctoral, graduate and undergraduate researchers,” he said.

Link to AgriLife Today:  https://agrilifetoday.tamu.edu/2022/11/30/1-19-million-grant-will-leverage-single-cell-sequencing-technology/

23Apr

Chapkin Lab Members Compete in Student Research Week

Student Research Week (SRW) is the largest student run research symposium in the nation. This four day competition highlights student research occurring on the Texas A&M campus. Students who participate are provided a venue to present their work through either oral presentations or poster sessions. This event allows students, faculty, and the community to see the depth and breadth of research conducted at Texas A&M. For the past 20 years, SRW has been a valuable tool in meeting the university’s mission of academic, research, and service excellence. SRW is a premier program of the Graduate and Professional Student Council and is supported by several academic and nonacademic departments on campus.

Huajun Han, Destiny Mullens, Michael Salinas and Gabriella Webster of Chapkin Lab all competed.

Destiny Mullens took home 1st in the Veterinary Medicine & Biomedical Sciences Category in Graduate Oral with her presentation titled:  “Host exfoliome responses to a dietary lignan intervention in the context of enterolactone excretion phenotype” Click Here to view her Abstract.

Gabriella Webster placed 1st in the Agriculture and Life Sciences Category in Undergraduate Oral with her presentation titled: “Illuminating molecular mechanisms by which dietary DHA aids in colon cancer prevention” Click Here to view her Abstract. Click Here to view her presentation.

6Feb

Untimely immune cell clocks may contribute to obesity and diabetes in shift workers

Texas A&M reclocksearchers discover the effects of shift work on immune cell clocks may lead to metabolic disorders

About 15 million Americans don’t have a typical nine-to-five workday, and many of these—nurses, firefighters and flight attendants, among many other professions—may see their schedule change drastically one week to the next. As a result, these shift workers’ biological clocks, which keep track of the time of day, cannot keep accurate time, potentially making the negative effects of a high fat diet on metabolic disorders even more pronounced, according to new research published in The FASEB Journal. Continue Reading…..

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Chapkin Laboratory
Lab Phone: 979-845-0448
Office Phone: 979-845-2142
E-mail: r-chapkin@tamu.edu

 

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2253 TAMU, 112 Cater-Mattil
College Station, TX 77843-2253

 

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College Station, TX 77843-2253

 

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