Thursday, March 13, 2025
3/13/2025
Abstract Fat is one of the three main nutrients, along with carbohydrate and protein. Fats are important sources of fatty acids (FAs), which are lipids that play a pivotal role in metabolism and cell survival, especially for cancer cells. Saturated FAs (SFAs) and monounsaturated FAs (MUFAs) can be synthesized in cells, while polyunsaturated FAs (PUFAs) are only ingested from diet. In general, cells acquire FAs from exogenous sources via a FA transporter, such as CD36, and/or endogenously through de novo lipogenesis involving an enzyme, fatty acid synthase (FASN). Importantly, FASN is normally expressed at low levels in normal healthy tissues (except liver and adipose tissues). However, FASN is highly expressed in many cancer cells and high levels of FASN expression are associated with poor prognosis in various cancers, including breast cancer. Consequently, much of the work on lipid metabolism in cancer has been focused on FASN. However, the capacity of cancer cells to utilize lipids of exogenous origin (e.g., SFAs, MUFAs, and PUFAs) is poorly understood. Recently, we have shown that when HER2+ breast cancer cells acquire resistance to FDA-approved drugs, lapatinib and trastuzumab, there is a metabolic shift in cells toward a reliance on CD36-mediated FA uptake over de novo fatty acid synthesis for maintaining the cellular fatty acid pool (Feng et al., Cell Reports, 2019). Accordingly, resistant cells become “addicted” to the CD36 pathway so that genetic or pharmacological inhibition of CD36 kills resistant cells, but not drug-sensitive cells or normal healthy cells in vitro and in vivo. Moreover, deletion of Cd36 in mice significantly attenuated MMTV-neu-driven tumorigenesis. Additionally, we also validated in multiple breast cancer cohorts that CD36 expression increased following anti-HER2 therapy in breast cancer patients, which was associated with poor prognosis. Based on these results, we hypothesize that CD36-mediated FA uptake is required for HER2+ breast tumor cells to acquire resistance to HER2 inhibitors. In this grant proposal, we aim to determine the signaling pathway downstream of CD36, especially focusing on the metabolic fate of exogenous FAs that are taken up into a cancer cell by CD36. We will also determine the efficacy of a rational diet-based strategy to target CD36-mediated metabolic rewiring in mouse breast cancer models. Results from our studies will establish the significance of CD36-mediated FA uptake as a key event for breast cancer cells to acquire resistance to anti-HER2 therapy. This outcome will have a durable impact in cancer research since our findings will uncover the underappreciated role of dietary fats in drug resistance. The experiments in the current proposal are designed to involve undergraduate researchers in every aspect. We have built specific research training plans for undergraduate students at all levels to provide them with not only a high-quality research experience, but also the tools necessary to successfully complete the project at hand and in their future endeavors.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).