Tuesday, April 23, 2024 4/23/2024

Exploring Interactions Between Retinoid and Vitamin D Signaling in Salivary Gland Homeostasis and Cancer

Award Number: F32DE027868
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Abstract: Basal cell derived salivary and breast cancers are correlated with poor patient prognosis, increased cancer reoccurrence and lack of definitive therapies1. In both branching organs, cytokeratin 5-positive (K5+) basal cells contribute to ductal cells during normal development2–4 and recent research has highlighted similarities in the K5+ basal cell origin of mammary and salivary squamous cells5,6. In mammary tumors of basal origin, irradiation- resistant cancer stem cells (CSCs) demonstrate K5 positivity1. Both Vitamin D and Vitamin A signaling pathways have been implicated in prevention of tumorigenesis7,8. In the developing9 salivary gland, we and others10 have recently demonstrated that retinoic acid receptor (RAR) signaling contributes to expansion of K5+ basal cells, a phenomena conserved in the adult salivary gland11. In both mammary12 and salivary glands13, CSCs display an upregulated level of ALDH, an aldehyde dehydrogenase that oxidizes Vitamin A to retinol, the precursor to retinoic acid and signaling through RARs. The relationship between RAR signaling and K5+ basal cells during tumorigenesis has yet to be explored. Work in the Welsh laboratory has shown that deletion of the Vitamin D receptor (VDR) in mice leads to increased cell proliferation and tumorigenesis in the breast7 where VDR activity is linked to K5+ cell fate transition4. In human population studies, low levels of Vitamin D are associated with increased cancer incidence and progression14–16. In the submandibular salivary gland (SMG), progenitor cell populations are highly positive for VDR17 and in humans, VDR localizes to epithelial cells18; yet, Vitamin D signaling has not been specifically explored in the salivary gland. We will test the hypothesis that co- activating VDR and RAR signaling will reduce K5+ basal cell expansion and tumorigenesis in the SMG. In this proposal we will address the following questions: 1) What is the role of VDR signaling in K5+ basal cell expansion and differentiation in the SMG? 2) Does VDR signaling synergize with RARa signaling to negatively regulate K5+ basal cell expansion in the SMG? 3) Will loss of VDR signaling synergize with inhibition of RARa signaling to enhance K5+ tumorigenesis in the SMG? 4) Will activation of VDR and RARa signaling in K5- TdTomato-positive tumor cells using directed delivery of vitamin derivatives and small molecules decrease tumorigenic cell properties? To determine if RARa and VDR signaling synergize in negatively regulating the K5+ population in the SMG, in Aim 1 we will inhibit RARa signaling in a VDR knockout K5 reporter mouse and trace K5+ basal cell fate. In Aim 2, we will determine if VDR and RARa pathways synergize to regulate K5+ cell expansion in basal salivary tumors. This aim will be achieved with targeted pharmacological inhibition of RARa signaling in a VDR knockout K5 reporter mouse induced for tumorigenesis with DMBA. Additionally, we will determine if activation of VDR and RARa signaling in K5-TdTomato-positive tumor cells using small molecules and vitamin derivatives in 3D culture will affect cell division and motility.


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: 2023 ( Subtotal = -$1,109 )
2023	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	000	3	11/23/2022	SUPPLEMENT FOR EXPANSION	-$1,109
														Subtotal = -$1,109

Issue Date FY: 2021 ( Subtotal = $23,122 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	001	3	4/9/2021	SUPPLEMENT FOR EXPANSION	$23,122
2021	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	000	3	4/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $23,122

Issue Date FY: 2020 ( Subtotal = $68,246 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	000	3	2/28/2020	NON-COMPETING CONTINUATION	$68,246
														Subtotal = $68,246

Issue Date FY: 2019 ( Subtotal = $62,410 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	000	2	4/9/2019	NON-COMPETING CONTINUATION	$62,410
														Subtotal = $62,410

Issue Date FY: 2018 ( Subtotal = $59,454 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	002	1	5/17/2018	NEW	$0
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	000	1	3/14/2018	NEW	$57,134
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Oral Diseases and Disorders Research	001	1	5/17/2018	NEW	$2,320
														Subtotal = $59,454

Grand Total All Awards = $212,123

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Exploring Interactions Between Retinoid and Vitamin D Signaling in Salivary Gland Homeostasis and Cancer

Award Number: F32DE027868

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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