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Investigating the molecular mechanisms of MYC-driven transcriptional reprogramming of the tumor microenvironment in prostate cancer

Award Number: F31CA310286
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Investigating the molecular mechanisms of MYC-driven transcriptional reprogramming of the tumor microenvironment in prostate cancer - Project Summary Prostate cancer is the second leading cause of cancer-related death in men and remains largely resistant to immunotherapy due to its immunologically cold tumor microenvironment (TME). However, benign prostate lesions, such as proliferative inflammatory atrophy (PIA), are characterized by active immune infiltration. Prior work has established that MYC acts as a molecular switch, initially promoting immune activation in early lesions before driving immune suppression in invasive disease. While MYC’s oncogenic role is well known, the transcriptional and chromatin remodeling mechanisms underlying this immune switch remain poorly understood. We hypothesize that MYC-driven reprogramming is mediated through SMARCD2, a critical subunit of the BAF chromatin remodeling complex, orchestrating differential binding of key transcription factors (AR, ERα, ERβ, MYC) to modulate the immune response within the prostate TME. Our long-term objectives are to understand the molecular dynamics underpinning prostate cancer progression from immune activation to immune escape and leverage this knowledge to inform the development of novel therapeutic strategies aimed at reversing immunosuppression and increasing available treatment options for advanced prostate cancer. To achieve this, Aim 1 will define transcription factors driving immunogenic vs. Immunosuppressive programs in prostate cancer by comparing benign proliferative atrophy (PIA) lesions to invasive carcinoma. We propose a model where early MYC activation fosters immune activation, whereas sustained MYC activation drives immunosuppression. Using coupled single nucleus ATAC- and RNA- seq on human prostatectomy samples, we will profile transcriptomic and chromatin landscapes to identify candidate regulators and networks associated with distinct immune states. Furthermore, Aim 2 will determine the tumor cell-intrinsic mechanisms by which MYC-driven chromatin remodeling initiated immunosuppression, focusing on the BAF complex subunit SMARCD2’s role in reprogramming both androgen and estrogen receptor activity. Hi-Plex CUT&Tag assays will reveal genome-wide binding patterns of AR, ERα, ERβ, and MYC in later stage prostate cancer cells. Additionally, functional studies using CRISPR/Cas9 mediated knockout and lentiviral-inducible overexpression of SMARCD2 followed by bulk RNA-seq and CUT&Tag assays in prostate cancer cell lines, will investigate SMARCD2’s regulatory role in altered transcription factor occupancy and immunosuppression. Collectively, this proposal integrates cutting-edge genomic techniques with robust molecular characterization to define novel transcriptional and epigenetic mechanisms underlying immune modulation in prostate cancer. This innovative approach will significantly advance our understanding of prostate cancer biology and identify novel therapeutic targets to improve clinical outcomes for prostate cancer patients.


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 = $50,114 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	1	4/13/2026	NEW	$50,114
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	001	1	4/13/2026	NEW	$0
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Investigating the molecular mechanisms of MYC-driven transcriptional reprogramming of the tumor microenvironment in prostate cancer

Award Number: F31CA310286

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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