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Endothelial-to-osteoblast transition in prostate cancer bone metastasis

Award Number: R01CA174798
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2013
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Endothelial-to-osteoblast transition in prostate cancer bone metastasis - Project Abstract/Summary Bone metastases are the major contributing factors to prostate cancer (PCa) morbidity and mortality. PCa bone metastases are uniquely osteoblastic and characterized by new bone formation, which promotes tumor growth in bone. Thus, bi-directional interaction between the PCa cells and their mis-induced bone plays a critical role in PCa progression in bone. It has been assumed that metastatic PCa induces new bone formation by stimulating the proliferation of osteoblasts in the bone marrow. However, we recently demonstrated that tumor-associated endothelial cells could give rise to osteoblasts through a little-appreciated process known as endothelial cell-to- osteoblast (EC-to-OSB) conversion, generating in the process EC-OSB hybrid cells with unique properties. Our studies showed that tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa. This new insight into the surprising bone-forming role of EC-OSB hybrid cells in PCa bone metastasis provides a novel rationale to target these cells in the tumor microenvironment. We hypothesize that tumor-induced EC-to-OSB conversion generates EC-OSB hybrid cells, which provide paracrine factors to support metastatic PCa growth in bone. Our objective is to target EC-OSB hybrid cells for improving therapy for bone metastasis. We will: Aim 1. Determine the mechanisms underlying endothelial cell-to-osteoblast (EC-to-OSB) transition. EC-to-OSB conversion requires both the inhibition of angiogenesis and activation of osteoblastogenesis pathways in endothelial cells. Our preliminary results indicate that BMP4 activates the Notch-Hey1 pathway to inhibit angiogenesis and the p38MAPK-β-catenin-OSX pathway to stimulate osteogenesis. We will examine how BMP4 integrates these two pathways to reprogram the endothelial cells. Aim 2. Identify EC-OSB hybrid cell secreted factors (EC-OSB factors) that promote PCa progression. EC-OSB hybrid cell secretome was examined by both iTRAQ (protein) and RNAseq (gene) analyses. Tenascin C was identified along with CTGF and versican, which together may constitute an “EC-to-OSB signature”. We will investigate the effects of these EC-OSB factors on PCa cell activity in vitro and in vivo. The “EC-OSB signature” will also be tested as biomarkers for osteoblastic bone metastasis using clinical samples. Aim 3. Develop strategies that target EC-OSB hybrid cells to improve therapy outcomes for PCa bone metastasis. The EC- OSB hybrid cells may contribute to de novo therapy resistance described previously. We will examine whether we can improve therapy outcomes for PCa bone metastasis by combining cabozantinib or cabazitaxel (targets PCa tumor) with Rad-223 (targets EC-OSB hybrid cells). Aim 4. Determine whether EC-to-OSB transition occurs in normal bone and the fraction of EC-OSB hybrid cells in tumor-induced bone. We generated a new Double Reporter Mice (col11-GFP/Tie2-cre/Rosa-tdTomato), in which EC are RFP+, OSB are GFP+, and EC-OSB are RFP+/GFP+, to examine whether EC-OSB hybrid cells are involved in normal bone development and their fraction in tumor-induced bone.


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 = $0 )
2026	2023	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	10	12/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	10	11/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $312,130 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	10	11/4/2022	NON-COMPETING CONTINUATION	$286,650
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	10	3/14/2023	NON-COMPETING CONTINUATION	$25,480
														Subtotal = $312,130

Issue Date FY: 2022 ( Subtotal = $312,130 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	9	5/20/2022	NON-COMPETING CONTINUATION	$25,480
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	9	11/30/2021	NON-COMPETING CONTINUATION	$286,650
														Subtotal = $312,130

Issue Date FY: 2021 ( Subtotal = $318,500 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	8	1/22/2021	NON-COMPETING CONTINUATION	$15,925
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	8	11/16/2020	NON-COMPETING CONTINUATION	$302,575
														Subtotal = $318,500

Issue Date FY: 2020 ( Subtotal = $318,500 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	7	1/16/2020	NON-COMPETING CONTINUATION	$31,850
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	7	11/18/2019	NON-COMPETING CONTINUATION	$286,650
														Subtotal = $318,500

Issue Date FY: 2019 ( Subtotal = $333,500 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	003	6	5/8/2019	COMPETING CONTINUATION	$15,770
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	6	11/1/2018	COMPETING CONTINUATION	$333,500
2019	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	10/25/2018	NON-COMPETING CONTINUATION	$0
2019	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	5	5/8/2019	NON-COMPETING CONTINUATION	-$15,770
														Subtotal = $333,500

Issue Date FY: 2017 ( Subtotal = $88,988 )
2017	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	3/31/2017	NON-COMPETING CONTINUATION	$55,788
2017	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	5	6/7/2017	NON-COMPETING CONTINUATION	$33,200
														Subtotal = $88,988

Issue Date FY: 2016 ( Subtotal = $332,000 )
2016	2016	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	2/26/2016	EXTENSION WITH OR WITHOUT FUNDS	$332,000
														Subtotal = $332,000

Issue Date FY: 2015 ( Subtotal = $332,000 )
2015	2015	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	3/10/2015	NON-COMPETING CONTINUATION	$332,000
														Subtotal = $332,000

Issue Date FY: 2014 ( Subtotal = $322,040 )
2014	2014	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	4/16/2014	NON-COMPETING CONTINUATION	$322,040
														Subtotal = $322,040

Issue Date FY: 2013 ( Subtotal = $332,000 )
2013	2013	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	3/26/2013	NEW	$249,000
2013	2013	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	7/1/2013	NEW	$83,000
														Subtotal = $332,000

Grand Total All Awards = $3,001,788

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Endothelial-to-osteoblast transition in prostate cancer bone metastasis

Award Number: R01CA174798

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2013

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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