Defining the metastasis-initiating cancer stem cells
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: Currently, there are no FDA-approved therapies to treat metastasis of triple-negative breast cancer. Development of therapeutics meets two major challenges: finding the protein target responsible for metastasis and development of tumor resistance to therapeutic drugs. Solid tumors are composed of genetically different cells (heterogeneous). This complexity contributes to drug resistance. We and others have recently found that the lipid consumption by cancer cells promotes metastasis. As lipids get consumed, triplenegative breast cancer cells look lipid-less. We have also identified a cell surface molecule—CD318—as a molecule responsible for lipid consumption, cancer invasion of surrounding normal tissues, and metastasis. This is significant since therapeutic drugs targeting proteins involved in lipid metabolism, as well as therapeutics specifically targeting CD318, are under development and expected to effectively block metastasis. Therefore, the first challenge is met. The second challenge—the tumor composition of genetically different cells (heterogeneity)—will be addressed in this grant. 
 Since the discovery that solid tumors are heterogeneous and rely on a small group of cancer cells—cancer stem cells—for growth and therapy resistance, there is considerable interest in targeting cancer stem cells and especially metastasis-initiating cells. Breast cancer stem cells were discovered by Dr. Clarke’s research group and are marked by a CD44 molecule on their cell surface. This group of cells is capable of sustained tumor growth and metastasis. Not surprisingly, the group of cancer stem cells shows further heterogeneity and contains a metastasis-initiating sub-group of cells, which still needs to be isolated, characterized and targeted. Since metastasis is the leading cause of breast cancer related deaths, our overarching goal is to shift the paradigm from targeting cancer stem cells towards targeting metastasis-initiating cells. Thus, in this proposal we aim to isolate the metastasis-initiating cells based on our findings that CD318 cell surface presence and lipid consumption are important features of triple-negative breast cancer cells promoting their metastasis. 
 The question(s) or central hypotheses of the research: We hypothesize that high lipid consumption can be used for identification, isolation, and subsequent targeting of metastasis-initiating cells. Specifically, we hypothesize that a group of triple-negative breast cancer cells with CD44 and CD318 on their cell surface will be lipid-less due to active lipid consumption making this group capable of metastasis. 
 The general methodology: This project will rely on the use of patient-derived xenografts of triple-negative breast cancer. These are the pieces of primary tumor and/or the pieces of metastatic lesions generously donated for research by breast cancer patients and grown as tumors in mice. These tumors represent an invaluable resource for studies of tumor heterogeneity, cancer stem cells, and metastasis-initiating cells, which cannot be investigated using established cell lines grown on plastic dishes. CD318 and CD44 are located at the cell surface of cancer cells and can be used as bait for cell isolation from the cell mixture in heterogeneous primary tumors. This process is called cell sorting. The dyes to stain lipids are also available to us and will be used to sort cancer cells into lipid-rich and lipid-less groups. Sorted cell groups will be assessed for their ability to invade and metastasize in a series of experiments in a test tube or in animals. We expect that the findings will shed light on breast cancer biology and will lead to pharmacological intervention to stop invasion and metastasis by therapeutically targeting metastasis-initiating cells. 
 Innovative elements of the project and potential impact: This project is innovative since it lies on the intersection of several expertise areas of my research group: including metastasis, tumor heterogeneity, targeted therapeutics, and lipid metabolism. The hypothesis that metastasis-initiating cells will have CD318 and CD44 on the cell surface and will actively consume lipids is innovative. Thus, my research group is uniquely positioned to lead this project, which will impact breast cancer treatment. This project will also rigorously investigate the metastatic potential of a cell population prospected to be targeted by drugs affecting lipid metabolism as well as CD318. Targeted therapeutics under development will either be fully justified for breast cancer treatment or the caveats will be identified and taken into consideration.