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Defining and characterizing microenvironmental drivers of disseminated tumor cell dormancy in brain

Award Number: R01CA252874
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Defining and characterizing microenvironmental drivers of disseminated tumor cell dormancy in brain - Project Summary Brain metastases arise later than metastases at other sites. Once they do, they are rapidly debilitating and lethal. The time it takes for brain metastases to emerge suggests that a dormancy phase is involved. This notion is supported by clinical and experimental data. Indeed, our own preliminary data show that breast cancer cells become dormant upon entering the brain, and that emerging from this state is the rate-limiting step of metastasis. These data indicate that targeting dormant disseminated tumor cells (DTCs) is a logical approach to brain metastasis prevention. However, despite a growing understanding of dormancy mechanisms in common metastatic sites like lung and bone marrow, a parallel understanding of how DTCs are driven into a dormant state in brain has not developed. The overarching goal of this proposal is to address this issue. We will formulate a basic framework for how the brain microenvironment drives DTCs into a dormant state, with support from clinical specimens, so that we can leverage this understanding for therapies that keep DTCs dormant indefinitely. Our recent investigations have revealed that dormant DTCs occupy the brain’s vascular niche, where perivascular astrocytes suppress their outgrowth. We suspect that astrocytic contributions to the parenchymal basement membrane are responsible for DTC suppression, and that these contributions converge on a common receptor: dystroglycan. Therefore, our hypotheses are that: (i) astrocytic basement membrane is a key driver of DTC dormancy, and (ii) dystroglycan function must remain intact for DTCs to interpret these signals. We will test these hypotheses through two specific aims: Aim 1. Determine whether astrocytic basement membrane promotes and sustains DTC dormancy. Aim 2. Elucidate the dystroglycan-mediated signaling axis that effects DTC quiescence in brain. We have brought every relevant resource to bear in order to address these aims. These resources span: (i) long-term intravital imaging to determine the fate of DTCs following ablation of DTC-associated astrocytes; (ii) transgenic mice to measure the outcome of ablating astrocyte derived basement membrane molecules on DTC fate; (iii) rare clinical specimens to establish whether astrocytes and astrocytic basement membrane are asso- ciated with dormant DTCs in humans; and (iv) a host of mutant, over- and under- expression constructs to solve how dystroglycan functions from the outside-in to drive DTC quiescence. The significance and innovation of this work lie in the identification of the first dormancy drivers in brain, ultimately to unravel dystroglycan-driven signaling that effects disseminated breast tumor cell quiescence. This work will set the stage for agonists of dystroglycan function that serve as prophylactics for brain metastasis prevention.


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: 2024 ( Subtotal = $460,702 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	6	4/4/2024	NON-COMPETING CONTINUATION	$460,702
														Subtotal = $460,702

Issue Date FY: 2023 ( Subtotal = $475,250 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	5	4/5/2023	NON-COMPETING CONTINUATION	$475,250
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	4	11/30/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $475,250

Issue Date FY: 2022 ( Subtotal = $475,249 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	004	4	8/18/2022	NON-COMPETING CONTINUATION	$475,250
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	002	2	7/27/2022	NON-COMPETING CONTINUATION	-$21,864
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	003	3	7/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$21,864
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	2	6/9/2022	NON-COMPETING CONTINUATION	-$161,634
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	3	6/9/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$161,633
														Subtotal = $475,249

Issue Date FY: 2021 ( Subtotal = $484,949 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	2	4/30/2021	NON-COMPETING CONTINUATION	$484,949
														Subtotal = $484,949

Issue Date FY: 2020 ( Subtotal = $483,488 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	1	5/4/2020	NEW	$483,488
														Subtotal = $483,488

Grand Total All Awards = $2,379,638

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Defining and characterizing microenvironmental drivers of disseminated tumor cell dormancy in brain

Award Number: R01CA252874

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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