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(PQ1) Molecular circuit of multi-ciliogenesis regulates choroid plexus differentiation and tumor development

Award Number: R01CA220551
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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(PQ1) Molecular circuit of multi-ciliogenesis regulates choroid plexus differentiation and tumor development - Project Abstract Neoplasms of the choroid plexus (CP) are rare primary brain tumors predominantly found in childhood. CP tumors range from the more common and benign CP papilloma (CPP), to the rare CP carcinoma (CPC) that is poorly understood but highly lethal. Treatments for CPC include surgery, radiation, and chemotherapy that cause severe long term side effects in survivors. Development of more effective and less debilitating therapies for CPC has been hampered by limited knowledge of the role of specific molecular defects, including abnormal NOTCH signaling and recurrent genomic alterations, in CPC. Insights into how these genes and pathways affect proliferation and growth of CPC will lead to targets for new therapies that can specifically suppress tumor growth without deleterious effects on the developing brain. By inducing sustained NOTCH1 expression, we developed mouse models of CP tumor that recapitulate CPP in humans. Lineage studies revealed that NOTCH-induced CPP originates from roof plate progenitors, both of which exhibit active NOTCH signaling and undergo proliferation driven by Sonic Hedgehog (SHH) from CP epithelium. In contrast, CP epithelial cells with clustered multiple primary cilia on the apical surface fail to respond to SHH, suggesting that the NOTCH pathway suppresses multi-ciliogenesis to preserve the singular primary cilium critical for the SHH signaling. Though key genes of the multi-ciliation network driven by Geminin coiled-coil domain-containing protein 1 (GEMC1) are expressed in CP epithelium, the transcriptional program is suppressed in NOTCH-activated CPP that lacks multi-ciliated cells. Conversely, GEMC1 loss results in the lack of multi-ciliation in the CP. In Aim 1, we will investigate GEMC1-directed multi-ciliate differentiation during CP development and tumorigenesis. We will determine whether activation of GEMC1 transcriptional cascade is sufficient to overcome constitutive NOTCH signaling to induce multi-ciliogenesis, and attenuate SHH signaling in CP tumor. Functional studies of GEMC1 and identification of its transcriptional targets will establish the molecular mechanisms of multi-ciliation in the CP, and uncover potential therapeutic venues for CP tumor. Consistent with abnormal SHH and NOTCH signaling in CP tumor in humans, simultaneous activation of both pathways in mice leads to malignant CP tumors that exhibit solitary primary cilium. Similarly, CPCs in humans are characterized by singular primary cilium and recurrent genomic alterations affecting crucial regulators of multi-ciliate differentiation. In Aim 2, we will utilize novel mouse models to investigate the molecular mechanisms of the genetic interaction between the NOTCH and SHH pathways and evaluate potential targeted therapeutics. We will determine whether the loss of GEMC1 drives CPC in collaboration with constitutive SHH signaling. The proposed studies will significantly advance our understanding of CPC and identify potential therapeutic targets.


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 = -$52,955 )
2024	2021	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Cancer Biology Research	000	6	2/6/2024	NON-COMPETING CONTINUATION	-$52,955
														Subtotal = -$52,955

Issue Date FY: 2021 ( Subtotal = $350,889 )
2021	2021	NEW YORK INSTITUTE OF TECHNOLOGY	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Cancer Biology Research	000	6	8/24/2021	NON-COMPETING CONTINUATION	$350,889
														Subtotal = $350,889

Issue Date FY: 2020 ( Subtotal = $350,038 )
2020	2020	NEW YORK INSTITUTE OF TECHNOLOGY INC	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Cancer Biology Research	000	5	8/4/2020	NON-COMPETING CONTINUATION	$350,038
														Subtotal = $350,038

Issue Date FY: 2019 ( Subtotal = $338,739 )
2019	2019	NEW YORK INSTITUTE OF TECHNOLOGY INC	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Cancer Biology Research	000	4	8/12/2019	NON-COMPETING CONTINUATION	$338,739
														Subtotal = $338,739

Issue Date FY: 2018 ( Subtotal = $315,193 )
2018	2018	NEW YORK INSTITUTE OF TECHNOLOGY INC	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Cancer Biology Research	004	3	8/2/2018	NON-COMPETING CONTINUATION	$315,193
2018	2017	NEW YORK INSTITUTE OF TECHNOLOGY INC	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Cancer Biology Research	003	2	4/30/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$37,057
2018	2017	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Cancer Biology Research	000	1	1/19/2018	NEW	-$283,894
2018	2017	NEW YORK INSTITUTE OF TECHNOLOGY INC	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Cancer Biology Research	001	2	1/19/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$283,894
2018	2017	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Cancer Biology Research	002	1	4/30/2018	NEW	-$37,057
														Subtotal = $315,193

Issue Date FY: 2017 ( Subtotal = $383,749 )
2017	2017	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Cancer Biology Research	001	1	8/15/2017	NEW	$5,256
2017	2017	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Cancer Biology Research	000	1	8/9/2017	NEW	$378,493
														Subtotal = $383,749

Grand Total All Awards = $1,685,653

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(PQ1) Molecular circuit of multi-ciliogenesis regulates choroid plexus differentiation and tumor development

Award Number: R01CA220551

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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