Tumorigenesis in the Metabolically Aged Tissue Microenvironment
The accumulation of mutations is not the only connection between aging and cancer. Mounting evidence indicates that the aging tissue microenvironment actively selects and promotes the progression of mutant cells towards malignancies. We hypothesize that age-related metabolic changes play a key role in this process. Building on our recent findings (Maus et al. Nature Metabolism, 2023), we investigate how disrupted iron metabolism in the aged tissue microenvironment promotes inflammation, and micronutrient shortages, subsequently diverting the differentiation trajectory and fitness landscape of precancerous cells in the bone marrow and colon towards malignancy. Our goal is to develop methods that can non-invasively locate high-risk sites for cancer development, and therapeutics that can rejuvenate the tissue microenvironment thereby combating cancer.
Research projects
Colon Metabolism and Cancer Promotion: developing early detection strategies for young adults
About the project
There is a worldwide increase in the incidence of colorectal cancer in people under 50 years of age, who are not subject to routine colonoscopy programs. Due to this, young individuals with colorectal cancer are often diagnosed at an advanced and difficult-to-treat stage of cancer. There is an urgent need for affordable, easy-to-use, and non-invasive early detection methods for young patients with colorectal cancer. To meet this need, we propose to study how colon aging promotes cancer and to develop novel early detection methods for young individuals with colorectal cancer.
Our preliminary findings suggest that iron homeostasis becomes disrupted with aging in the colon, which is associated with a microenvironment that has differential effects on the wild-type epithelium when compared to precancerous clones. We hypothesize that age-associated iron dyshomeostasis in the colonic microenvironment promotes tumorigenesis by providing a competitive advantage to precancerous clones. By identifying key mechanisms and biomarkers of age-assocaited iron dyshomoestasis in the colon, we aim to enhance early detection in colorectal cancer patients, specialy in young individuals with colorectal cancer.
In the lab
Marc Guasch Piqueras is heading up this research project in the lab.
Marc Guasch Piqueras
PhD student
Aging and Cancer lab
Collaborators
Understanding and translating the role of age- and chemotherapy-induced iron dyshomeostasis
in MDS and AML
About the project
Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder involving peripheral blood cytopenia, with a high risk of conversion to acute myeloid leukemia (AML). Risk factors for MDS include older age and chemotherapy, which have been suggested to put selective pressures on hematopoietic clones, favoring the expansion of precancerous and cancerous clones. We found that iron accumulates while iron availability decreases with aging in the bone marrow. The limited iron availability correlated with the decline of lymphopoiesis and expansion of immature myeloid blasts. Thus, we hypothesize that iron dyshomeostasis caused by aging and chemotherapy could be selective forces promoting MDS and AML. In this project, we will investigate how aging, and chemotherapy disrupt iron homeostasis in the bone marrow and the impact of iron dyshomeostasis on clonal diversity, DNA methylation profile, and progression to AML. Finally, we will explore therapeutic strategies that restore iron homeostasis in bone marrow as potential treatments for MDS and the prevention of conversion to AML.
In the lab
Ning Huang is heading up this research project in the lab.
Ning Huang
PhD student
Aging and Cancer lab
