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Role of Bone in Primary and Metastatic Cancer

Award Number: R01CA235096
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Role of Bone in Primary and Metastatic Cancer - Program Director/Principal Investigator (Last, First, Middle): Faccio, Roberta, PhD ABSTRACT Recent evidence from our lab and others indicates that the insurgence of a primary tumor leads to changes in the bone microenvironment that affect the residing hematopoietic and mesenchymal populations. These changes in the bone microenvironment occur during the early stages of tumor development, prior to any evidence of metastatic dissemination, and become more pronounced while the primary tumor progresses, even in tumors that do not metastasize to the bone. We find increased numbers of immature myeloid cells that can actively suppress T cell proliferation in bone marrow of mice bearing primary breast tumors and in newly diagnosed stage II-III breast cancer patients compared with controls. In addition to changes in immune populations, bone residing osteoblasts and osteocytes, normally involved in bone formation and regulation of bone homeostasis, respond to distal tumors by upregulating various inflammatory cytokines as well as inhibitors of the Wnt signaling pathway, such as Dkk1. Several of these bone-produced factors act locally to change the basal bone homeostasis, but can also have systemic effects that can impact, either directly or indirectly, primary tumor growth and future tumor dissemination to various sites. Wnt signaling plays important roles in bone development, hematopoiesis and cancer. Dkk1 is a Wnt/β-catenin inhibitor, known to suppress bone formation and promote bone resorption. Increased levels of Dkk1 are often observed in cancer patients and correlate with poor prognosis. We recently reported that Dkk1 is upregulatated by osteoblasts and osteocytes in the bone of mice with primary breast tumors and in cancer associated fibroblasts (CAFs) in the primary site, but at a level much lower than in the bone. Intriguingly, we found that Dkk1 exerts immune suppressive effects and its neutralization decreases primary tumor growth by reducing immature myeloid populations and enhancing T cell immune surveillance. Based on these exciting findings, our central hypothesis is that bone residing osteoblasts and osteocytes modulate primary breast cancer growth and metastatic dissemination to multiple sites by creating a systemic immune suppressive environment via production of Dkk1. Aim1. Exploring the role of the bone microenvironment during tumor progression. The goal of this aim is to determine the anti-tumor effects of Dkk1 deletion in bone versus its deletion at tumor site. Aim2. Determine the mechanism by which Dkk1 modulates immune suppression. The goal of this aim is to determine the cellular mechanism by which Dkk1 induces immune suppression. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page 1 Continuation Format Page


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	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	5	11/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $342,268 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Biology Research	000	5	6/28/2024	NON-COMPETING CONTINUATION	$342,268
														Subtotal = $342,268

Issue Date FY: 2023 ( Subtotal = $353,076 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	4	6/30/2023	NON-COMPETING CONTINUATION	$353,076
														Subtotal = $353,076

Issue Date FY: 2022 ( Subtotal = $353,076 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	3	7/25/2022	NON-COMPETING CONTINUATION	$353,076
														Subtotal = $353,076

Issue Date FY: 2021 ( Subtotal = $360,281 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	2	7/1/2021	NON-COMPETING CONTINUATION	$360,281
														Subtotal = $360,281

Issue Date FY: 2020 ( Subtotal = $360,281 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	1	3/10/2020	NEW	$360,281
														Subtotal = $360,281

Grand Total All Awards = $1,768,982

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Role of Bone in Primary and Metastatic Cancer

Award Number: R01CA235096

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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