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Multiscale hydrogel biomaterials-enabled 3D modeling of cancer drug resistance

Award Number: R01CA279815
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Multiscale hydrogel biomaterials-enabled 3D modeling of cancer drug resistance - Project Summary/Abstract Developing new anticancer drugs has been very slow and costly. A major reason is that the commonly used 2D cancer cells and animal models for drug discovery today are very different from the 3D tumors in human patients. Lately, 3D tumor models have been made by suspending tumor cells in medium to form multicellular spheroids/organoids, growing the cells in hydrogels/scaffolds, and incorporating blood vessels. However, little has been done to build 3D vascularized tumor models for recapitulating the drug resistance in patient tumors. We recently developed a novel multiscale hydrogel biomaterials-based bottom-up strategy to control the formation of the two distinct tissue domains in tumors - a 3D vascular network and an avascular/intervascular tumor cell-containing region, for studying cancer drug resistance. This is achieved by producing 3D avascular micro-tumors (µtumors) first and using them as the building blocks for assembling with endothelial cells (ECs) under dynamic perfusion culture, to form 3D vascularized tumors with a complex 3D vascular network that mimics the vascular-intervascular organization of in vivo tumors. Importantly, our data show quantitatively for the first time that, the 3D vascularized tumors are much more drug resistant than 3D avascular µtumors, indicating tumor blood vessels not only transport nutrients/oxygen but also enhance cancer drug resistance. However, no 3D vascularized tumor was built in vitro with cells differentiated from cancer stem cells (CSCs) for drug discovery, although the rare CSCs have been posited to possess the exclusive ability of tumorigenesis and be responsible for the many failures of cancer chemotherapy due to their high drug resistance. Moreover, no CSCs isolated with contemporary methods are shown to differentiate into a type of cells that are not in tumors. This cross-tissue multilineage differentiation is a key property of stem cells (e.g., adipose-derived stem cells can differentiate into osteoblasts that are absent in fat). Thus, a method for isolating true CSCs is in need. We recently developed a novel core-shell hydrogel biomaterials-based approach for isolating CSCs by culturing one (1) single cancer cell (from a cell line) in the nanoliter hydrogel core of microcapsules that mimic pre-hatching embryos, where totipotent-pluripotent stem cells are cultured in human body. Importantly, the isolated CSCs are capable of endothelial, cardiac, neural, and osteogenic differentiations and highly tumorigenic, metastatic, and drug resistant, indicating the cells isolated with our bioinspired 1-cell culture are truly CSCs. In this project, we propose to further develop the novel bioinspired approach for isolating CSCs from breast tumors of human patients. In view of the highly drug resistant nature of the CSCs isolated with our bioinspired 1-cell culture and their ability of differentiating into ECs in vivo that may reduce patient survival, we further propose to use the CSC-derived ECs and cancer cells for building 3D vascularized tumors, to better model the drug resistance in patient tumors than existing 3D vascularized tumors made using non-CSC cancer cells and non-CSC (and often non-cancer-related) ECs (e.g., human umbilical vein endothelial cells known as HUVECs).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $416,785 )
2026	2026	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	001	4	4/10/2026	NON-COMPETING CONTINUATION	$416,785
2026	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	000	3	12/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,785

Issue Date FY: 2025 ( Subtotal = $416,785 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$41,677
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	000	3	3/7/2025	NON-COMPETING CONTINUATION	$375,108
														Subtotal = $416,785

Issue Date FY: 2024 ( Subtotal = $399,272 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	000	2	3/14/2024	NON-COMPETING CONTINUATION	$378,257
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$21,015
														Subtotal = $399,272

Issue Date FY: 2023 ( Subtotal = $440,347 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	000	1	3/28/2023	NEW	$438,118
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Biology Research	001	1	3/30/2023	NEW	$2,229
														Subtotal = $440,347

Grand Total All Awards = $1,673,189

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Multiscale hydrogel biomaterials-enabled 3D modeling of cancer drug resistance

Award Number: R01CA279815

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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