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Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape

Award Number: R01CA249737
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape - Although the approval of novel targeted therapy drugs, such as BRAF inhibitors (BRAFi), MEK inhibitors (MEKi), and immune checkpoint inhibitors, has revolutionized melanoma treatment, long-term outcomes are still disappointing for many patients because of the development of drug resistance. A major contributing factor to tumor resilience and relapse is the presence of a “plastic” microenvironment, which is comprised of heterogeneous stromal cell populations embedded in a dense and stiff extracellular matrix (ECM). Particularly, the ECM not only functions as a barrier to drug penetration and distribution and also provides structural and adaptive signals, which can induce therapeutic escape pathways in melanoma cells. Genetically stable cancer- associated fibroblasts (CAFs) are known to be a notorious ECM-remodeling machine in the tumor stroma. We have discovered that the number of CAFs with nuclear β-catenin in the melanoma stroma increases significantly after the patients are treated with BRAFi/MEKi. We have established that increased nuclear β-catenin in CAFs is induced by BRAFi but not MEKi. Nevertheless, how BRAFi stimulates CAFs to reprogram their biological functions via hyperactivated nuclear β-catenin activity remains to be understood. We have obtained compelling data demonstrating that targeted depletion of β-catenin in CAFs ablates their ability to remodel the tumor microenvironment, downregulates abnormal BRAF/MAPK/ERK signaling in melanoma cells, and suppresses melanoma cell drug resistance in vitro and in vivo. RNA-Seq data show that β-catenin is essential for CAF to remodel the ECM by coining the CAF transcriptome. We have identified the β-catenin/TCF4 target gene periostin (POSTN) as an important matricellular protein secreted by CAFs to promote BRAFi resistance. The central hypothesis is that decoding and targeting the ECM-remodeling CAFs has the potential to create a drug-sensitive microenvironment that sensitizes melanoma cells to therapeutic agents and increase their response rate. In Aim 1, we will elucidate the pro-activation pathway(s) by which BRAFi stimulates CAFs to mediate melanoma drug resistance phenotypes. We will assess the role of hyperactivated nuclear β-catenin in the function of CAFs in melanoma. In Aim 2, we will determine whether the β-catenin-TCF4 transcriptional complex is the signaling hub that controls CAF-driven ECM remodeling and BRAFi/MEKi resistance. We will evaluate whether disrupting the β-catenin-TCF4 interaction in CAFs will sensitize BRAF-mutant melanoma cells to BRAFi/MEKi in vivo. In Aim 3, we will determine the roles of CAF-derived POSTN in melanoma cell growth and resistance to BRAFi/MEKi. We will investigate signaling pathways that are activated by POSTN in melanoma cells to promote their proliferation and resistance to BRAFi. The expected outcomes are to be an in-depth mechanistic characterization of the complex interactions among CAFs, BRAFi, and the ECM microenvironment that promote the growth and drug resistance in BRAF-mutant melanoma cells. The knowledge obtained will open the possibility of developing a “magic bullet” that could destroy the tumor niche to improve targeted therapy and optimize patient outcomes.


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: 2025 ( Subtotal = $363,124 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$36,312
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	5	4/17/2025	NON-COMPETING CONTINUATION	$326,812
														Subtotal = $363,124

Issue Date FY: 2024 ( Subtotal = $345,003 )
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	4	4/23/2024	NON-COMPETING CONTINUATION	$345,003
														Subtotal = $345,003

Issue Date FY: 2023 ( Subtotal = $355,954 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	3	5/3/2023	NON-COMPETING CONTINUATION	$355,954
														Subtotal = $355,954

Issue Date FY: 2022 ( Subtotal = $357,712 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	2	6/30/2022	NON-COMPETING CONTINUATION	$357,712
														Subtotal = $357,712

Issue Date FY: 2021 ( Subtotal = $375,431 )
2021	2021	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	1	6/15/2021	NEW	$375,431
														Subtotal = $375,431

Grand Total All Awards = $1,797,224

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Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape

Award Number: R01CA249737

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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