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Ceramides as drivers of metabolic dysfunction and colorectal cancer risk

Principal Investigator
Name
Mary Playdon
Degrees
M.P.H., Ph.D.
Institution
University of Utah and Huntsman Cancer Institute
Position Title
Assistant Professor
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2023-0050
Initial CDAS Request Approval
Jun 12, 2023
Title
Ceramides as drivers of metabolic dysfunction and colorectal cancer risk
Summary
At least a quarter of colorectal cancers (CRC) are attributable to obesity,(GBD 2017 Colorectal Cancer Collaborators) a condition characterized by insulin resistance, dyslipidemia, and type 2 diabetes (T2D). These metabolic perturbations—which are independently associated with colorectal malignancies (Murphy, 2018)—likely result from the ectopic deposition of lipids in tissues not suited for fat storage.(McGarry 2001) Ceramides are especially deleterious lipids, as they induce insulin resistance and hepatic steatosis (Chaurasia 2015, Summers 2018) while showing strong associations with type 2 diabetes and heart disease.(Cheng 2015, Havulinna 2016, Boon 2013) Because of numerous preclinical studies showing that ceramide-lowering interventions prevent diabetes and heart failure, ceramide synthesis inhibitors are being explored as novel therapeutics (Chaurasia 2019).

In addition to contributing to the metabolic dysfunction that increases cancer risk, our preliminary data implicate ceramides in the formation of the hyperproliferative cell clusters that precede colorectal tumors.(Beyaz 2016) In humans, ceramides and/or ceramide-synthesizing enzymes were upregulated in serum or tissues from patients with adenomas or CRC. In preclinical models (mice, mammalian organoids, and flies), ceramides altered metabolism and accelerated proliferation of intestinal stem cells (ISCs), the site of origin of most CRCs. These data support our central hypothesis that ceramides operate through multiple mechanisms to accelerate formation of hyperproliferative lesions and increase CRC risk.
Aims

Aim 1. Develop and characterize a ceramide-based score that signals risk of CRC in (a) epidemiologic
and (b) bariatric surgery cohorts. (1a) Quantify 60 ceramides and derive a “ceramide risk score” that
predicts CRC, employing a rigorous discovery-replication design. We will leverage data and banked blood from
well-characterized epidemiologic cohorts—(1) the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer
cohort (~912 case control pairs), (2) the European Prospective Investigation into Cancer and Nutrition (EPIC)
(~900 case control pairs), and (3) the Southern Community Cohort Study (SCCS) (~712 case control pairs)—to
identify ceramides robustly associated with CRC. We will interrogate molecular interactions of the ceramide
risk score with other obesity and cancer-related pathways (e.g., inflammation, hyperinsulinemia), and identify
potential dietary patterns associated with ceramides. Aims 1b and 1c do not leverage PLCO samples or data
and will not be discussed in this PLCO EEMS application.
Aim 2. Determine whether ceramide reduction strategies prevent formation of colorectal tumors in
experimental models. Aim 2, a pre-clinical aim, is not discussed in detail in this PLCO EEMS application.

Collaborators

Mary Playdon (University of Utah)
Neli Ulrich (University of Utah)
Scott Summers (University of Utah)