Research

Discoveries

By addressing fundamental scientific questions, CRI is improving our understanding of the biological basis of disease to cure people who would not be cured otherwise.

2024

December 2024

CRI scientists link hematopoietic cell transplant deaths to beta-blocker use

Previous Morrison Lab research discovered β2- and β3-adrenergic receptor signaling are needed for hematopoietic stem cells to regenerate after chemo or radiation therapy. CRI scientists discovered patients are at increased risk of death if they take certain previously prescribed beta-blockers in the weeks after an allogeneic hematopoietic cell transplant. Non-selective beta-blockers impaired hematopoietic regeneration, but b1-selective inhibitors did not. Cancer Discovery [online ahead of print]

October 2024

Morrison Lab discovers ancient viral DNA activates blood cell production during pregnancy, after bleeding

Scientists discovered retrotransposons, ancient viral remnants in the “junk DNA” of the mouse and human genomes, are activated during pregnancy and after significant bleeding in blood-forming stem cells to increase blood cell production. This is an important step toward defining the purpose of “junk DNA” in humans. Retrotransposon expression promotes stem cell division by activating the immune sensors, cGAS and STING, which induce an interferon response to stimulate blood cell production. Science 386:eado6836

August 2024

DeBerardinis Lab discovers kidney cancers rely on mitochondrial metabolism to metastasize

Discovered that contrary to how tumors operate while still in the kidney, metastatic kidney cancers rely heavily on mitochondrial metabolism. The mitochondrial electron transport chain is much more active in tumors that have metastasized than in tumors still growing in the kidney. Nature 633, 923-31

July 2024

Tumor growth fueled by nucleotide salvage

Cancer cells salvage purine nucleotides to fuel tumor growth, including purines in foods we eat, an important discovery with implications for cancer therapies. CRI researchers challenged the long-standing belief that tumors primarily acquire purine nucleotides – building blocks for DNA, which is required for cellular growth and function – by constructing them from scratch via de novo synthesis. Research also shows tumors significantly use the more efficient salvage, or recycling, pathway to acquire purines. Cell 187, 3602-18

June 2024

Metabolic inflexibility keeps damage at bay during liver regeneration

Researchers identified a type of metabolic inflexibility during liver regeneration that prevents cells with dysfunctional mitochondria from proliferating, which demonstrates one way regenerative cells root out damage. When their mitochondria are damaged, hepatocytes turn on PDK4, a metabolic enzyme that stops the cells from shifting to an alternative source of acetyl-CoA, so they can’t proliferate. Science 384:eadj4301

May 2024

Small cell lung cancer acquires cross-resistance due to extrachromosomal DNA amplification of MYC paralogs

Small cell lung cancer is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. CRI researchers & colleagues used a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. Cancer Discovery 14, 804-827

2023

April 2023

The presence of extrachromosomal DNA can accelerate cancer formation

Extrachromosomal DNA (ecDNA) found to harbor cancer-associated oncogenes and immunomodulatory genes that promote cancer development in pre-cancerous cells. These findings raise the possibility of earlier interventions and preventive measures for patients with tumors containing ecDNA and provide a new understanding of ecDNA’s role in cancer development. Nature 616, 798-805

April 2023

Mutant clones in the liver may fight fatty liver disease

Showed that clones of hepatocytes containing somatic mutations are selected for their ability to protect against the damaging effects of fatty liver disease. Through this elucidation of the biological basis for mutant clone expansion, the lab established a method by which adaptive pathways in metabolic disease can be identified. Cell 186, 1968-1984

January 2023

Lactate metabolism plays an important role in mitochondrial diseases

Discovered that muscles with mitochondrial defects use lactate as a key fuel source. This study suggests that there are unique nutrient requirements in mitochondrial disease that may be therapeutically targeted. Science Advances 9:eadd321

2022

October 2022

Researchers find that different stem cells are responsible for the repair of different kinds of bone injuries

Identified markers that distinguish skeletal stem cells in the bone marrow from skeletal stem cells on the outside surface of bones and compared their functions. The Leptin Receptor-expressing skeletal stem cells in the bone marrow are responsible for the steady-state production of new bone cells that maintain the adult skeleton and repair certain types of bone injuries. The Gli1-expressing skeletal stem cells on the outside surfaces of bones (in the periosteum) are responsible for fracture repair. Cell Stem Cell 29, 1547-1561

October 2022

Scientists discover a new mechanism for therapy resistance in acute leukemias

Developed new preclinical cell models that helped identify a previously unknown class of mutations responsible for resistance to targeted therapies in IDH mutant acute myeloid leukemia patients. These findings could lead to new strategies for monitoring disease progression and for helping prevent or overcome resistance to targeted cancer therapies. Cancer Discovery 13, 170-193

August 2022

Researchers identify new druggable therapeutic pathway in a deadly form of brain cancer

Discovered that mutations in IDH genes, which are common in adult and adolescent brain tumors, cause cells to become addicted to a metabolic process called de novo pyrimidine nucleotide synthesis. This addiction stems from the ability of IDH mutations to increase susceptibility to DNA damage, which provides new insights into the ways that these mutations reprogram brain cell biology. Cancer Cell 40, 939-956

May 2022

Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation

Discovered that the niche for blood-forming stem cells in the bone marrow promotes the maintenance of blood-forming stem cells by producing an anti-inflammatory growth factor, adiponectin, that helps to protect blood-forming stem cells from inflammation, which increases in response to infection and aging. Nature Cell Biology 24, 697-707

April 2022

Researchers uncover unique metabolic needs during pregnancy

Developed a new technique to assess metabolism in developing mouse organs in utero, making it possible to learn how metabolic defects like inborn errors of metabolism impact fetal development. Nature 604, 349-353

2021

April 2021

Scientists discover “jumping” genes that can protect against blood cancers

Found that transposons protect against certain blood cancers. Also identified a new biomarker that could help predict how patients will respond to cancer therapies and lead to new therapeutic targets for acute myeloid leukemia. Nature Genetics 53, 672-682

February 2021

Scientists identify cells responsible for liver tissue maintenance and regeneration

Identified the cells responsible for liver maintenance and regeneration and pinpointed their location within the liver. These midlobular hepatocytes in zone 2 give rise to new hepatocytes during growth, homeostasis, and regeneration. Science 371:eabb1625

February 2021

Researchers identify mechanism by which exercise strengthens bones and immunity

Identified a specialized environment in the bone marrow where new bone and immune cells are produced around arterioles and found that maintenance of this niche, as well as the bone- and immune-forming cells that it contains, requires load-bearing exercise. Together, these findings identify a new way that exercise strengthens bones and immune function. Nature 591, 438-444

2020

August 2020

Lymph protects metastasizing melanoma cells from ferroptosis

Discovered that melanoma cells tend to metastasize through lymphatics because the lymphatics protect melanoma cells from oxidative stress, which kills most melanoma cells that attempt to metastasize through the blood by inducing ferroptosis, a form of cell death marked by lipid oxidation. Nature 585, 113-118

2019

December 2019

CRI scientists discover metabolic feature that allows melanoma cells to spread

Found certain melanoma cells are more likely to spread through the body. Efficiently metastasizing melanoma cells take up more lactate because they have higher levels of a lactate transporter, called monocarboxylate transporter 1 (MCT1), on their cell surface as compared with inefficient metastasizers. This demonstrates that metabolic differences among melanoma cells confer differences in metastatic potential. Nature 577, 115-120

April 2019

New screening approach helps identify sources of rare genetic diseases in children

Used the integration of genomic and metabolomic data to identify inborn errors of metabolism, potentially opening a new approach to diagnose metabolic diseases in children. Cell Reports 27, 1376-1386

April 2019

Researchers show that mutations in human livers can promote tissue regeneration

Found that genetic mutations accumulate in the adult liver as a result of chronic liver damage. A subset of these mutant clones promote tissue regeneration without promoting liver cancer, demonstrating that somatic mutations are sometimes selected for their ability to promote tissue regeneration. Cell 177, 608-621

2018

June 2018

Researchers discover new vulnerability in small cell lung cancer

Identified a subset of small cell lung cancers that depend on de novo purine synthesis for growth and can be treated with drugs that block this pathway. Cell Metabolism 28, 369-382

2017

October 2017

CRI study challenges long-standing concept in cancer metabolism

Discovered that lactate, long considered a waste product of cancer cells, fuels lung cancer metabolism in some patients. Cell 171, 358-371

August 2017

CRI scientists develop an innovative system to characterize regulatory DNA sequences responsible for human diseases

Developed a new high-throughput method to study regions of DNA that control which genes are turned on and off in cells. This method allows researchers to better understand how genes become dysregulated in cancer and other diseases. Cell 170, 1028-1043

August 2017

CRI scientists discover vitamin C regulates stem cell function and suppresses leukemia development

Discovered that blood-forming stem cells take up unusually high levels of vitamin C, which regulates their function and suppresses the development of leukemia. Good vitamin C nutrition could be important to suppress the development of leukemia in people with clonal hematopoiesis, a common pre-leukemic condition. Nature 549, 476-481

June 2017

DeBerardinis lab discovered an aggressive subset of lung cancer that relies on an unusual metabolic pathway to survive

Found that an aggressive form of lung cancer relies on a previously unknown mechanism to make DNA. Inhibiting this pathway selectively blocks growth of these cancers by causing DNA damage. Nature 546, 168-172

2016

December 2016

CRI scientists discover new bone-forming growth factor that reverses osteoporosis in mice

Discovered a new bone-forming growth factor, Osteolectin (Clec11a), which is necessary for the maintenance of adult skeletal bone mass and which can systemically promote bone formation when injected into mice, including mice with osteoporosis. eLife 5:e18782

April 2016

Scientists find metabolic twist that drives cancer survival

Discovered a metabolic pathway that allows cancer cells to grow in a free-floating state, a necessary step during metastasis. The new pathway allows cells to counteract the oxidative stress that accompanies loss of attachment. Nature 532, 255-8

March 2016

CRI researchers link absence of protein to liver tissue regeneration

Found that inactivating Arid1a, a gene associated with some human cancers, promotes liver regeneration after injury. Several normal tissues accumulate Arid1a mutant clones prior to cancer development, likely because these clones possess increased regenerative capacity. Cell Stem Cell 18, 456-66

February 2016

CRI pioneers method for in-depth research on malignant tumors

Developed a new method to study tumor metabolism in cancer patients, overturning long-standing perceptions that were based on studies of cancer cells in laboratory dishes and identifying the nutrients tumors use to make energy and grow. Cell 164, 681-94

2015

November 2015

CRI identifies emergency response system for blood formation

Identified a specialized microenvironment in the spleen that supports emergency blood-cell formation (extramedullary hematopoiesis) when blood cell production in the bone marrow is inadequate. Nature 527, 466-471

October 2015

Antioxidant use may promote spread of cancer

Found that antioxidants promote the survival of cancer cells during metastasis. These results raised the possibility that cancer should be treated with pro-oxidants rather than antioxidants and explained why administration of antioxidants to patients led to worse outcomes in clinical trials. Nature 527, 186-91

September 2015

CRI scientists see through bones to uncover blood-forming stem cell details

Was first to use a tissue-clearing technique to identify the location of blood-forming stem cells in the bone marrow, improving our understanding of the microenvironment in which they reside. Nature 526, 126-30

2014

June 2014

CRI finds key to identifying, enriching mesenchymal stem cells

Found that Leptin Receptor-expressing stromal cells that are a key source of growth factors in the niche for blood-forming stem cells in the bone marrow also include the skeletal stem cells that form the adipocytes and osteoblasts that arise in adult bone marrow. These cells maintain and repair the adult skeleton. Cell Stem Cell 15, 154-68

March 2014

Researchers discover a method of measuring protein synthesis in adult stem cells

Discovered a method of measuring protein synthesis in adult stem cells. This demonstrated that stem cells synthesize protein more slowly than other progenitors, likely to maintain the quality of their proteome. Nature 509, 49-54

January 2014

Scientists find estrogen promotes blood-forming stem cell function

Found that estrogen activates the division of blood-forming stem cells. Increased estrogen levels during pregnancy activate blood-forming stem cells and increase the production of red blood cells, which is necessary to maintain blood cell counts during pregnancy. Nature 505, 555–8

2013

June 2013

CRI scientists identify distinct subsets of hematopoietic stem cells and multipotent progenitors

Found new markers to distinguish biologically distinct subpopulations of stem cells and multipotent progenitors in the blood-forming system. This study also demonstrated that all blood-forming stem cells reside in niches associated with blood vessels in the bone marrow. Cell Stem Cell 13, 102-16

February 2013

Scientists identify bone-marrow environment that helps fight infection

Identified a microenvironment, or niche, in which specialized blood-forming cells produce infection-fighting white blood cells (T cells and B cells) in the bone marrow. This demonstrated that there are distinct locations in the bone marrow that maintain stem cells and restricted blood-forming progenitors in the bone marrow. Nature 495, 231–5

2012

January 2012

Blood-forming stem cells’ growth identified in first CRI breakthrough

Identified the microenvironment, or niche, in which blood-forming stem cells are maintained within the bone marrow, a long-standing goal in the field of stem cell biology. This study also reported the discovery of Leptin Receptor-expressing stromal cells in the bone marrow that are the main source of growth factors required for the maintenance of blood-forming stem cells. Nature 481, 457–62

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