Lawrence T. and Janet T. Dee Foundation - Center for Genomic Medicine
GENOMIC INNOVATION AWARDS
LAWRENCE T. & JANET T. DEE FOUNDATION
This publication was produced for the Lawrence T. & Janet T. Dee Foundation, whose Dee Family Genomics Innovation Awards and additional internal and philanthropic support helped fund the projects detailed within.
3 Exploring Genetic Underpinnings of Placental Insufficiency, Fetal Growth Restriction, and Stillbirth 4 Deconvolution of Polygenic Risk Scores Toward Molecular Consequences 4 Mapping Chronic Myelomonocytic Leukemia Clonal Architecture and Evolution at the Single-Cell Level 5 Molecular Phenotyping to Improve Discovery of Ovarian Cancer Risk Variants in the Utah Population Database
Molecular Determinants of Arteriovenous Malformations
The Utah Diabetes Database (UDDb): An Integrated Database to Accelerate Diabetes Gene Discovery
Segregation Distortion in Humans
Sperm Mutation Rates and Genomic Stability in Fertile and Infertile Men at Single-Cell Resolution
2021 GRANTS
11 Defining the Pharmacogenomic Landscape of G-Protein Coupled Receptors
12 Novel Gene Therapy for Human Phosphoglucomutase I Deficiency 2022 GRANTS
14 Towards Precision Genomics in Aortic Disease: Transcriptome Analysis of Bicuspid Aortopathy
15 Familial Multi-Cancer Configurations for Powerful Genomic Studies of ProgressiveRisk MGUS
16 A Pilot Project to Investigate De Novo and Inherited Genetic Variants Relevant for Recurrent Pregnancy Loss in Utah Families
2023 GRANTS
18 Genome Sequences Defining the Origins of Human Pancreatic Cancer 19 CRISPR/CAS9 Homology-Directed Repair in Primary Megakaryocytes for Rapid Screening of Platelet Gene Variant Functions
PROMISE
AND PROGRESS: THE DEE FAMILY
GENOMIC INNOVATION AWARDS
Dear Tim, David, and Foundation Board Members:
At the University of Utah, our donors share our deep commitment to advancing knowledge, driving innovation, and improving lives through groundbreaking research. This work wouldn’t be possible without your generosity. Your vision and support empower us to push the boundaries of human understanding, explore new frontiers of science and medicine, and make lifesaving discoveries.
Philanthropy has a profound ripple effect on the world. It enables our researchers to dream bigger, act bolder, and innovate faster. By supporting the Genomics Innovation Awards, you’re allowing new ideas to take root, leading to discoveries that have the potential to revolutionize health care and enhance the quality of life for future generations.
This publication celebrates the significant impact of philanthropy on our research mission. The updates shared here are a testament to the transformative power of research and the crucial role of philanthropy in creating a healthier, more vibrant world for all.
We invite you to learn more and see firsthand how, together, we are shaping a brighter future through discovery, innovation, and clinical care. Thank you for your commitment to making a meaningful impact and for sharing our unwavering belief that what we create today can improve lives for generations to come.
We are sincerely grateful for your partnership and continued support of genomic research.
Lynn Jorde, PhD
Co-Director,
Center for Genomic Medicine
Mark and Kathie Miller Presidential Endowed Chair in the Department of Human Genetics
Executive Director, Utah Genome Project Professor and Chair, Department of Human Genetics
Martin Tristani-Firouzi, MD
Co-Director, Center for Genomic Medicine
H. A. and Edna Benning Presidential Endowed Chair Professor, Department of Pediatrics, Division of Cardiology
GRANT UPDATES
2019 & 2020
The 2019-24 report contains updates for projects funded over the last three years and brief updates on the 2019 and 2020 projects. We encourage you to read this report in tandem with the report sent in spring 2021 (and re-printed and enclosed for your convenience).
GRANT UPDATES
Exploring Genetic Underpinnings of Placental Insufficiency, Fetal Growth Restriction, and Stillbirth
Nathan Blue, MD, Departments of Obstetrics & Gynecology and Population Health Sciences; Amelia Wallace, PhD, MPH, Department of Human Genetics; Aaron Quinlan, PhD, Departments of Biomedical Informatics and Human Genetics; Tsegaselassie Workalemahu, PhD, MSc, Departments of Internal Medicine and Obstetrics & Gynecology; Terry Morgan, MD, PhD, Oregon Health & Science University; Robert Silver, MD, Departments of Obstetrics & Gynecology and Population Health Sciences
As of June 2024, the analysis is complete. After reviewing preliminary data, the Society for Reproductive Investigation and the Society for Maternal-Fetal Medicine invited an oral presentation of this study to their national meetings. The study team also published a manuscript titled “Placental Somatic Mutation in Human Stillbirth and Live Birth: A Pilot Case-Control Study of Paired Placental, Fetal, and Maternal Whole Genomes.”
Though this study is complete, the data produced an unexpected and exciting new direction. The team used the data to complete a pilot test of a genome analysis tool based in artificial intelligence (AI) developed at the U in the Yandell Lab. The tool identified several key differences between stillbirths with placental disease, live births with fetal growth restriction and placental disease, and healthy live birth controls. The potential utility of the AI tool in these analyses is the basis for a recently established multiinstitutional collaboration that provided access to a new set of data to be analyzed.
N. Blue
A. Quinlan
A. Wallace
T. Workalemahu
T. Morgan
R. Silver
Deconvolution of Polygenic Risk Scores Toward Molecular Consequences
Nicola J. Camp, PhD, Departments of Internal Medicine, Biomedical Informatics, Family and Preventive Medicine, and Human Genetics; Anna R. Docherty, PhD, LP, Department of Psychiatry
Drs. Camp and Docherty published this work in Cancer Epidemiology, Biomarkers & Prevention. In the future, they plan to use their results to better understand how mammographic breast density influences breast cancer risk. They also plan to investigate how normal tissue surrounding breast tumors may hinder or support tumor growth. From this work, Dr. Camp received two Utah Grand Challenges Grants totaling $370,000.
Mapping Chronic Myelomonocytic Leukemia Clonal Architecture and Evolution at the Single-Cell Level
Michael Deininger, MD, PhD, Departments of Internal Medicine and Oncological Sciences; Xiaomeng Huang, MD, Department of Oncological Sciences; Gabor Marth, PhD, Department of Human Genetics
The wet lab portion of this project has been completed, and the mining of the complex data sets is still ongoing. Results have been published in Genome Research, and a manuscript describing this work has been submitted to the journal Blood Cancer
N. Camp
A. Docherty
M. Deininger
X. Huang
G. Marth
GRANT UPDATES
Molecular Phenotyping to Improve Discovery of Ovarian Cancer Risk Variants in the Utah Population Database
Jennifer A. Doherty, MS, PhD, Departments of Population Health Sciences and Obstetrics & Gynecology; Mollie Barnard, MS, ScD, Department of Population Health Sciences; Nicola J. Camp, PhD, Departments of Internal Medicine, Biomedical Informatics, Family and Preventive Medicine, and Human Genetics; Elke A. Jarboe, MD, Departments of Pathology and Obstetrics & Gynecology
Analyses were completed in summer 2022. Using germline genotyping data from 90 ovarian cancer cases spread across 15 ovarian cancer high-risk pedigrees, the investigators identified 11 regions of interest: two proof-of-principle regions (in BRCA2 and MSH2), three regions containing recent genome-wide association study hits, and six novel regions.
The investigators intend to publish the above findings as a stand-alone paper. Additionally, the above findings have provided preliminary data for several grant submissions–most recently, a Department of Defense Ovarian Cancer Academy application titled “Finding the Missing Heritability in Epithelial Ovarian Cancer: A Family-Based Approach.”
J. Doherty
M. Barnard
N. Camp
E. Jarboe
Molecular Determinants of Arteriovenous Malformations
Pinar Bayrak-Toydemir, MD, PhD, Departments of Pathology and Pediatrics; Kevin Whitehead, MD, Department of Cardiology
To investigate the genetic mechanism of arteriovenous malformation in hereditary hemorrhagic telangiectasia (HHT), the team evaluated multiple affected tissues from 14 individuals. DNA was extracted from fresh/frozen tissue from affected individuals and normal control tissue biopsies. A 736 vascular malformation and cancer gene next-generation sequencing panel was used to evaluate these tissues. Mutations were identified in 75% of biopsies of the affected individuals. This is the first report that nasal telangiectasias malformation in HHT is caused by non-inherited mutations that have affected two genes responsible for nasal health. Findings were submitted to the International Journal of Molecular Science The study results were also selected as an oral presentation at the International HHT meeting in France in October 2024.
P. Bayrak-Toydemir K. Whitehead
GRANT UPDATES
M. Pezzolesi
The Utah Diabetes Database (UDDb): An Integrated Database to Accelerate Diabetes Gene Discovery
Marcus G. Pezzolesi, PhD, MPH, Departments of Internal Medicine, Human Genetics, and Nutrition and Integrative Physiology
As part of Dr. Pezzolesi’s work since receiving this seed grant, he and his team have identified a genetic variant associated with increased ceramide levels, diabetes, and advanced kidney disease that, importantly, is only seen in individuals of Pacific Islander ancestry. This work has led him and his team to establish the Utah Pacific Islander Diabetes Study, which currently includes more than 600 participants, and to begin studies to better understand genetic factors contributing to health and disease in this population.
Building on his genetic work with Utah’s Pacific Islander community, Dr. Pezzolesi co-founded the Haumana ‘O Pasifika Pacific Islander Research Internship program along with co-principal investigators Will Holland, PhD, and Kalani Raphael, MD. Drs. Pezzolesi, Holland, and Raphael were recently awarded a five-year $702,000 grant from the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases for continued support of this program. Additionally, Dr. Pezzolesi recently submitted a five-year $2.5 million grant application titled “Genetic Determinants of Cardiovascular-Kidney-Metabolic Syndrome in Native Hawaiians and Pacific Islanders” to continue building on the work supported by the Dee Family seed grant.
Segregation Distortion in Humans
Nitin Phadnis, PhD, Department of Biology; Jim Baldwin-Brown, PhD, Department of Biology; Kenneth I. Aston, PhD, Department of Surgery; Bruce Gale, PhD, Departments of Mechanical Engineering, Materials Science and Engineering, Electrical and Computer Engineering, and Biomedical Engineering
Dr. Phadnis was recently awarded a $1.9 million grant from the NIH’s National Institute of General Medical Science for a project titled “The Mechanisms of Segregation Distortion in Drosophila.” Building from the Dee Family seed grant, he will investigate the molecular mechanisms of distortion in two sex-ratio systems and test independent or shared origins and mechanisms of sex-ratio distortion in closely related species.
N. Phadnis
J. Baldwin-Brown
B. Gale
K. Aston
GRANT UPDATES
Sperm Mutation Rates and Genomic Stability in Fertile and Infertile Men at Single-Cell Resolution
Aaron Quinlan, PhD, Departments of Human Genetics and Biomedical Informatics; Kenneth I. Aston, PhD, Department of Surgery; Jingtao Guo, PhD, Department of Surgery; James M. Hotaling, MD, MS, FECSM, Departments of Surgery and Obstetrics & Gynecology
The research team plans to submit a publication showing that, as hypothesized, mutation rates are indeed higher in the sperm and blood of sub-fertile men. These findings suggest a possible connection to inherited deficiencies in DNA-damaged genes in sub-fertile men.
A. Quinlan
K. Aston
J. Hotaling
J. Guo
GRANTS
GRANTS
L. Albright
Defining the Pharmacogenomic Landscape of G-Protein Coupled Receptors
Justin English, PhD, Department of Biochemistry; Lisa Albright, PhD, Department of Internal Medicine
THE CHALLENGE
Variation in human genes leads to individual differences in responses to medications. G-protein coupled receptors (GPCRs) are targeted by more than 30% of all drugs approved by the Food and Drug Administration (FDA) and are the largest family of therapeutic targets in the human genome. Each person averages six missense mutations across the drug-targeted GPCR genes; less than 1% of these mutations have been pharmacologically characterized.
THE OPPORTUNITY
Drs. English and Albright proposed a high-throughput screening platform to pharmacologically profile all FDA-approved drugs targeting GPCRs and their known variants. As a proof of concept, the team initially profiled analgesic drugs against human opiate receptor variants, prioritizing mutations identified in the Utah genomics database. It was hypothesized that the successful implementation of this proposal would lay the groundwork for a precision medicine initiative at University of Utah Health aimed at providing individualized prescription and harm reduction guidelines for the $180 billion/year GPCR pharmaceutical market.
OUTCOMES
The study has concluded after additional work investigating the functional mechanisms of several mu-opioid receptor variants with observed pharmacogenomic defects. They have characterized seven variants common in humans with impacts on both endogenous and pharmaceutical ligands targeting the mu-opioid receptor, including fentanyl and morphine. Additionally, this work contributed to their recently submitted proposal to the Advanced Research Projects Agency for Health to study the complete pharmacogenomics of the human GPCRome.
NEXT STEPS
The paper disclosing the results of the team’s study and further elucidated mechanisms remains in preparation as the team finalizes a number of critical experiments to conclude their characterization of these common variants.
J. English
GRANTS
K. Lai
Novel Gene Therapy for Human Phosphoglucomutase I Deficiency
Kent Lai, PhD, Department of Pediatrics
THE CHALLENGE
Congenital disorders of glycosylation (CDG) are rare genetic disorders grouped by defective processes in which sugar is added to protein or fat molecules in the body, a process called glycosylation. Because this is a critical function, the effects of CDG can be seen throughout the body and its functions. Only 5% of patients in the rapidly growing group of more than 150 types of CDGs have a therapy, despite many of them having limited effectiveness. For patients with phosphoglucomutase 1 (PGM1) deficiency, also known as PGM1-CDG, an oral therapy has shown some efficacy in treating liver and endocrine disease. Still, it cannot rescue the myopathy (muscle disorders) and the lethal cardiomyopathy (disorders that affect the heart muscle) associated with the disorder.
THE OPPORTUNITY
This project aims to develop a new, safe, and more effective therapy to tackle the unmet medical needs of patients with CDGs using a mouse model that exhibits deteriorated cardiac functions and other phenotypes related to dilated cardiomyopathy. When completed, the proposed gene therapy approach will be among the first molecular therapeutics employed to treat a CDG.
OUTCOMES
The researchers developed a successful approach to deliver a new gene to replace the defective gene suspected to cause PMG1 directly into the hearts of the mice. This prevented and halted the progression of dilated cardiomyopathy, the most life-threatening complication in this type of CDG.
NEXT STEPS
It is possible that the same beneficial effects can be accomplished with a lower dose; thus, dosing studies in mice will be done to minimize any potential side effects. In addition, the viral vectors chosen to deliver the new gene can infect other organs affected by this disorder and could improve other disease phenotypes, such as myopathy or liver disease. Lastly, the researchers will be required to thoroughly assess the safety of the treatments in animal models before any clinical trials in humans can begin.
CONNECTED GRANT FUNDING
In December 2023, Dr. Lai received a $3.8 million (including indirect costs) NIH R01 titled “Pathobiological Mechanisms of Cardiac Disease in PGM1-CDG” to further study the effects of replacing the bad copy of PGM1 in mice using gene therapy.
GRANTS
GRANTS 2022
J. Glotzbach
M. Tristani-Firouzi
Towards Precision Genomics in Aortic Disease: Transcriptome Analysis of Bicuspid Aortopathy
Jason Glotzbach, MD, Division of Cardiothoracic Surgery; Aaron Quinlan, PhD, Departments of Human Genetics and Biomedical Informatics; Martin Tristani-Firouzi, MD, Department of Pediatrics; James M. Hotaling, MD, MS, FECSM, Departments of Surgery and Obstetrics & Gynecology
THE CHALLENGE
The aortic valve, which allows blood to exit the heart, is normally formed by three cusps. Bicuspid aortic valve (BAV) occurs when two of the three cusps are fused at birth. About half of patients with BAV also develop aortopathy, which is when the aorta enlarges to form an aneurysm or has a tear in the aortic wall, called a dissection. To prevent this, cardiovascular surgeons replace the aorta when it forms an aneurysm. The Achilles’ heel of this approach is that not all patients with BAV will develop an aneurysm, and not all patients with an aneurysm will develop dissection for unclear reasons.
THE OPPORTUNITY
Surgical decisions have historically been based on the size of the aorta, but it is hypothesized that BAV and aortopathy also have a genetic cause. It is not understood how genetic risk plays a part in developing this lethal condition; this project aimed to address this knowledge gap by characterizing the changes in gene expression that occur in BAV patients’ aortas.
OUTCOMES
Specimen collection, RNA sequencing (RNASeq), and data analysis are complete. RNASeq data will be combined with single-cell transcriptional data in a future manuscript to report findings.
NEXT STEPS
Through these studies, the team learned that to understand the gene expression changes present in aortic aneurysms, single-cell RNA (transcription) analysis must be performed because there are many different types of cells within the aortic wall. The team has applied for additional seed grant funding to complete these studies. The results from this project represent an important first step towards understanding the genomic changes driving BAV aortopathy and will fit into the larger research goal to develop a clinically useful precision tool to stratify individual patient risk for aortic disease progression.
A. Quinlan
J. Hotaling
GRANTS
Familial Multi-Cancer Configurations for Powerful Genomic Studies of Progressive-Risk MGUS
Heidi A. Hanson, PhD, Department of Surgery; Afaf E. G. Osman, MD, Division of Hematology; Nicola J. Camp, PhD, Departments of Internal Medicine, Biomedical Informatics, Family and Preventive Medicine, and Human Genetics
THE CHALLENGE
A major challenge to genomic discoveries is that common diseases are extremely heterogeneous (meaning there are many routes to disease). Methods that allow researchers to group families with similar disease patterns provide opportunities to simplify that challenge and discover risk factors.
THE OPPORTUNITY
The investigators developed a novel method to classify families based on patterns of multiple diseases in relatives. This tool, PhenGenEE, is a machine-learning-inspired family clustering approach that mines the familial and medical data housed within the Utah Population Database (UPDB). This will be applied to MGUS families. MGUS is a common precursor to myeloma, a fatal plasma cell malignancy. Using longitudinal data in the UPDB, the investigators will identify MGUS that progresses to myeloma. Identifying family patterns consistent with progression provides critical information for early detection and prevention. Focusing on progressive-risk MGUS from homogeneous families will empower genomic studies to identify genetic factors and biomarkers to counsel families and advance precision medicine.
OUTCOMES
The team identified 11,700 individuals diagnosed with MGUS using electronic health records (EHRs) from U of U Health and Intermountain Health. Genealogy data in the UPDB was used to identify their 58,279 first-degree, 187,635 second-degree, and
511,098 third-degree relatives. To identify hematological malignancies or solid tumors in the relatives, the team used data from the Utah Cancer Registry, a statewide cancer surveillance registry active since 1966 that is linked to the UPDB. Autoimmune disease and bone health were also considered in the relatives and identified using U of U Health and Intermountain EHRs. Myeloma is a tumor of the plasma cells, which are mature B cells and part of the immune system. Thus, autoimmune disorders may be relevant. Some myeloma patients suffer bone pain due to the bone marrow being crowded by tumor cells, and bone health disorders may also be relevant. The team acquired diagnostic data for the 757,012 relatives and identified 6,498 hematological malignancies, 60,431 solid tumors, 216,156 autoimmune disorders, and 82,075 bone health disorders in the relatives. Many of these are elevated over expected levels.
NEXT STEPS
The team is performing final quality control on this vast amount of data for the machinelearning approach to identify familial patterns across these multiple diseases. The team will then identify family patterns unique to MGUS patients progressing to myeloma.
CONNECTED GRANT FUNDING
In 2023, Dr. Osman was awarded a $200,000 career development award from the American Society of Clinical Oncology to use the same strategy to understand familial clustering surrounding precursor disorders of chronic lymphocytic leukemia, another B-cell hematological malignancy.
H. Hanson
N. Camp
A. Osman
A Pilot Project to Investigate De Novo and Inherited Genetic Variants Relevant for Recurrent Pregnancy Loss in Utah Families
Tsegaselassie Workalemahu, PhD, MSc, Departments of Internal Medicine and Obstetrics & Gynecology; Robert Silver, MD, Department of Obstetrics & Gynecology; Hilary Coon, PhD, Department of Psychiatry; Aaron Quinlan, PhD, Departments of Human Genetics and Biomedical Informatics
THE CHALLENGE
About 3% of pregnancies result in pregnancy loss, contributing to a significant economic and emotional burden. A prior history of pregnancy loss increases recurrence risk in subsequent pregnancies. Unfortunately, the causes of ~50% of recurrent pregnancy loss (RPL) are unknown. Though there are diagnostic tests and treatments for RPL, they increase cost and anxiety, and they may cause harm without clear efficacy.
THE OPPORTUNITY
While some cases of RPL have genetic causes, newer genetic technology, such as whole genome sequencing, allows for identifying previously unrecognized genetic causes of RPL. The power of this technology can be further amplified by examining paternal DNA so that inherited and newly occurring genetic variations that are likely causal can be identified. The team proposed identifying genetic variants relevant to RPL in families. The resulting data will support the discovery of RPLcausal genes for translation into improved diagnostic and clinical management and, importantly, closure to grieving families.
OUTCOMES
Dr. Workalemahu and his colleagues published their findings that inherited and newly occurring mutations may be relevant to fetal death. Specifically, they linked 29 mutations to impacts on known genes involved in embryonic/fetal development and congenital abnormalities.
NEXT STEPS
The researchers plan to expand the analysis to prospectively (after the study began) collected samples from additional families. The team will also link cases of stillbirth to the Utah Population Database where they are working to identify other inherited genes for targeted sequencing for stillbirth.
CONNECTED GRANT FUNDING
In 2023, Dr. Workalemahu was awarded a grant from the NIH for $3,398,481 to expand the number of families sequenced (including parent-offspring DNA from affected and unaffected pregnancies) to help identify lethal genes contributing to sporadic and recurrent pregnancy loss. Elucidating pregnancy loss-causing genes may lead to biomarkers useful for risk stratification, identifying genes relevant to normal and abnormal pregnancy, and novel therapeutic targets.
T. Workalemahu
H. Coon
R. Silver
A. Quinlan
GRANTS 2023
GRANTS
J. Rowley
CRISPR/CAS9 Homology-Directed Repair in Primary Megakaryocytes for Rapid Screening of Platelet Gene Variant Functions
Jesse Rowley, PhD, Department of Internal Medicine
THE CHALLENGE
Platelets are blood cells that form blood clots and prevent bleeding, and individuals with inherited platelet disorders have frequent and sometimes lethal episodes of uncontrolled bleeding or clotting. Identifying a mutation known to cause disease in the DNA of patients with a suspected inherited clotting disease can inform decision-making, clinical management, and treatments. However, many DNA mutations identified in genetic tests lack the functional information to decide if the mutation causes disease. Mutations affecting blood platelets are missing this information because they don’t have a nucleus or DNA, which makes mutation studies challenging.
THE OPPORTUNITY
This project developed a new, fast, and disease-relevant approach to test DNA mutations identified in individuals with inherited platelet disease. The approach used CRISPR/CAS9 to directly make DNA mutations in cells isolated from the body, which allows for studies across diverse genetic backgrounds that may extend to other diseases.
OUTCOMES
This project developed a new, fast, and disease-relevant approach to test DNA mutations identified in individuals with inherited platelet disease. CRISPR/CAS9 was used to directly make these DNA mutations in cells isolated from the body, and the cells were tested to determine whether they could cause disease.
NEXT STEPS
With expanded funding, the researchers aim to functionally define all possible disease variants for this disease in terms of their function and clinical classification. They will extend this approach to other genes and diseases.
CONNECTED GRANT FUNDING
The lead investigator received two external grants: an R01 from the NIH for $2,684,960 and an American Society of Hematology grant for $149,531.80.
GRANTS
C. Murtaugh
Genome Sequences Defining the Origins of Human Pancreatic Cancer
Charles Murtaugh, PhD, Department of Human Genetics
THE CHALLENGE
Pancreatic cancer is notoriously untreatable. New approaches are needed to find effective therapeutic targets. In studying the origins of pancreatic cancer, Dr. Murtaugh discovered that it begins when normal, well-behaved cells lose the stable “cell identity” that allows them to function correctly. He found that in mouse models, early alterations of cell identity appear to determine later tumor aggressiveness, but it remains unknown if this applies to humans. In addition, it is unclear if human pancreatic cancer cells can be “domesticated” and returned to a non-growing state by reversing the molecular changes observed in mouse models. Funds are being used to pursue two projects: (1) can we infer the cell of origin of human pancreatic cancer and relate this to disease outcomes; and (2) can we arrest or kill human pancreatic cancer cells by reversing their loss of cell identity?
THE OPPORTUNITY
An inroad into the question of the cell of origin (project one) came from recent findings that cell identity in normal human tissue can leave an indelible “footprint” in the genome caused by mutations affecting specific genes linked to the cell’s identity. Dr. Murtaugh hypothesized that, by analyzing the genomes of human pancreatic tumors, the cellular source from which they arose could be inferred, and the process by which normal cell identity was disrupted could be reconstructed. The tools developed relate tumor origins to patient outcomes and may be applied to pancreatic and other human cancers.
Regarding the reversion of cell identity in pancreatic cancer (project two), previous investigations in mouse models identified a specific molecular pathway that is disrupted early in pancreatic cancer development. Dr. Murtaugh has reactivated this pathway in human cells and found a surprising heterogeneity in response. Some cells are killed or their growth arrested if the cell identity regulators are activated, while others are resistant. The mechanisms underlying both outcomes are being investigated: How do cell identity genes suppress tumor cell growth in some contexts, and why are they unable to do so in all contexts?
OUTCOMES
The research team observed that nonrandom mutations in genes of normal pancreatic cells create a “lineage mark” in tumor cells, serving as permanent traces of the cell of origin. Similar cell-of-origin marking occurs in human liver, prostate, and esophageal cancer. A manuscript describing these findings, relating to project one, is being finalized, and an NIH grant was awarded to support further work in this area. The team is therefore focusing Dee-funded efforts on project two, where a key signaling pathway has been identified that appears to act as an “executioner” of human pancreatic cancer cells when they are forced to revert to a normal cell state. Experiments are being finalized, and a manuscript reporting these results is being prepared.
NEXT STEPS
With NIH funding, project one will be extended by investigating human biospecimens at the University of Utah to relate cell of origin-specific genome mutations to clinical outcomes in pancreatic cancer. The team is also interested in determining if these mutations also arise in mouse models; if so, these models can be used to understand how and when these mutations appear. In project two, the problem of heterogeneity, i.e., why some cancer cells resist the effects of cell identity regulators, is still being investigated. A drug screening study is being prepared to search for clinically applicable
compounds that can be used to induce the re-expression of cell identity regulators in pancreatic cancers to leverage their ability to suppress cell growth.
CONNECTED GRANT FUNDING
Dr. Murtaugh was awarded an NIH grant in spring 2024 (1R21CA288671-01, $257,000 total direct costs over two years) to pursue and extend project one, developing methods to determine the “cells of origin” of pancreatic and liver cancers and relate this finding to clinical outcomes.
OUTCOMES
A MESSAGE OF GRATITUDE
Philanthropy provides critical support for health sciences research. Generous donor support continues to aid in advancing our understanding of human health, including genomics. As evidenced by the Lawrence T. and Janet T. Dee Foundation’s Innovation Awards, seed grants can propel emerging innovations and allow researchers to explore novel concepts. You have generously given emerging and growing research programs the support they need to thrive.
We are proud and grateful to partner with you on a collective mission of accelerating research, ultimately unlocking the potential for brighter, healthier futures. With your support, genomic medicine will continue to improve human health through faster diagnoses, better disease prevention, and personalized, value-driven care. Our integrated team of scientists, clinicians, and educators share a vision: harnessing the
Rachel Hess, MD, MS Associate Vice President for Research, Health Sciences Professor, Departments of Population Health Sciences and Internal Medicine Co-Director, Utah Clinical and Translational Science Institute H. A. and Edna Benning Presidential Endowed Chair
