A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery

Year of Award:
Award Type:
Project Number:
RFA Number:
Technology Track:
Molecular & Cellular Analysis Technologies
PI/Project Leader:
Other PI or Project Leader:
Project SummaryTumor stroma, encompassing both extracellular matrix (ECM) and cells, regulates essentially all aspects oftumor growth and metastasis. Signaling among cancer cells, stromal cells, and ECM in tumors promotesproliferation of cancer cells and drug resistance among other key outcomes. Therefore, disrupting stroma-cancer cells signaling is essential to restoring drug sensitivity of cancer cells and improving outcomes forpatients. Despite this recognition, the lack of physiologic, high throughput human tumors models significantlyimpedes drug development and discovery efforts targeting tumor-stromal interactions.We will address this need by developing a high throughput tumor microtissue technology to recreate thecomplexity of native tumors and enable drug testing against tumor-stromal signaling. This facile technologyis based on two-step robotic micropatterning of user-defined cancer cells, stromal cells, and ECM using apolymeric aqueous two-phase system in 1536 microwell plates. A 3D mass of cancer cells is formed in anaqueous nanodrop settled at the bottom of a microwell and immiscible from the immersion aqueous phase.A second aqueous drop containing the stromal components is then dispensed to merge with the nanodropand surround the cancer cell mass to spontaneously generate a microtissue upon incubation. This approachuniquely offers the flexibility of incorporating tissue-specific matrix proteins and different stromal cells toreproduce physicochemical properties of tumors in vivo. We will validate this technology using triple negativebreast cancer (TNBC) as a disease model, demonstrating effects of carcinoma-associated fibroblasts (CAFs)and ECM on proliferation and drug responses of cancer cells. With this technology, we will test effects ofdisrupting tumor-stromal signaling on treatment efficacy against TNBC cells. These studies will useengineered tumor models of both TNBC cell lines and conditionally reprogrammed cells generated fromcancer cells of patients with metastatic TNBC to establish the feasibility of using our TMT model system forprecision oncology. We will perform combinatorial drug screening using standard chemotherapeutics andmolecular inhibitors against signaling pathways active in cells of specific TNBC patients to inhibit stroma-mediated proliferation and drug resistance of cancer cells, and validate the most effective treatments in mousexenograft models of human TNBC. Through this research, we expect to establish our TMT technology as atransformative advance that will be implemented broadly for drug discovery, mechanistic studies of breastcancer and other malignancies, and precision medicine.