NIMS Metabolite Imaging to ID Drug Resistant Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: A major challenge in the treatment of breast cancer is the effective application of chemotherapy. Selecting therapies based on the clinical and molecular characteristics of the tumor has the potential for an individualized, more effective, and less toxic treatment. Nearly 50% of breast cancer patients demonstrate primary and/or secondary resistance to doxorubicin, a drug used in four out of the six protocols defined by the American Cancer Society (CAF, AC, AC+, and A-CMF). The ability to subtype breast cancers based on doxorubicin sensitivity would therefore allow for improved treatment. Doxorubicin like many other chemotherapeutics activates enzymes that catalyze the production of ceramidea metabolite known to induce apoptosis. Many studies link ceramide (sphingolipid) expression to drug resistance: (1) Elevated levels of glucosylceramide synthase (GCS) and the corresponding elevation in glucospingosines suggest that apoptosis can be avoided through altered ceramide metabolism, (2) Overexpression of the ceramide transport protein (CERT) in resistant cancers suggest a role of ceramide transport in drug resistance, (3) Recent reports also link GCS, glycolipids, and over expression of p-glycoprotein (ABC transporter of the MDR/TAP subfamily) which is widely associated with drug resistance. Therefore, sphingolipids represent a promising class of molecular markers of doxorubicin resistant breast cancer. Recent advances in mass spectrometry make it possible to detect, identify and quantify spingolipids from tissues. However, existing approaches require tissue homogenization/extraction averaging out locally altered and clinical important levels within breast tumors, often associated with clusters of single tumor cells.
 
 
 
 
 
 
 
 Our novel approach is to utilize state-of-the-art nanotechnology (Nanostructure-Initiator Mass Spectrometry, NIMS) imaging to identify both the metabolic ‘fingerprint’ (i.e. metabolomics) of resistance as well as the heterogeneity within individual tumors. The aim is to utilize NIMS metabolite imaging technology to detect locally elevated levels of sphingolipids at the cellular level to define heterogeneity and identify drug resistant/sensitive breast cancers within individual tumors. For these studies we, first, plan to use drug resistant breast cancer cell lines to define a set of metabolic markers of resistance. The NIMS technique has a unique combination of high lateral resolution (10-75 γm), sensitivity (single cancer cells), and the ability to image metabolites at the cellular level within frozen tissue sections. The breast cancer samples include a diverse set of archival breast tumors (basal, luminal, ER+/-, PR+/-, and HER2+/-), and a 50+ cell line collection that has been well-characterized by our collaborator, Dr. Joe Gray at LBL and UCSF. 
 
 
 
 
 
 
 
 The successful development and implementation of the proposed metabolomics and imaging technologies for the detection and prognosis of drug resistant breast cancers will allow clinicians to distinguish between sensitive and drug sensitive cancers.