# SWI/SNF chromatin remodelers in tumor-associated antigen-specific CD8+ cytotoxic T cells

> **NIH NIH K00** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $89,082

## Abstract

Project Summary/Abstract:
Transcriptional and chromatin dysregulation are hallmarks of cancer. In this project, we functionally characterize
alterations in the pioneer transcription factor, called FOXA1, that are highly recurrent in hormone-receptor driven
cancers and describe an innovative chromatin-based approach to identify and therapeutically target
transcriptional pathways that specify cellular identity in cancer. FOXA1 de-compacts chromatin to enable binding
of the androgen receptor (AR) to activate the PCa genes. By leveraging an aggregate PCa cohort with 1546
samples, we define three novel structural classes of FOXA1 alterations that notably diverge in clinical incidence,
genomic co-alterations, and pathogenic gain-of-functions. Notably, these three alteration classes collectively
recur in over 35% of the cases, making FOXA1 the third most-highly altered oncogene in metastatic PCa. Class1
mutations originate in primary PCa without ETS-fusions or SPOP mutations, alter the Wing2 secondary structure
within the DNA-binding domain, enable faster nuclear mobility, and strongly activate the AR program of prostate
oncogenesis. Contrastingly, class2 mutations are acquired in the metastatic disease, truncate the C-terminal
regulatory domain, enable dominant binding to the chromatin, and activate the WNT program of metastasis.
Finally, class3 structural variations are enriched in metastatic PCa, cluster within the FOXA1 topological domain,
and duplicate the highly conserved enhancer element that drives overexpression of FOXA1. In the F99 phase, I
propose to mechanistically elucidate the neomorphic activation of WNT-signaling by the FOXA1 class2 mutants.
I hypothesize the C-terminal domain of WT FOXA1 to recruit WNT-repressive cofactors to the chromatin, and
thus the C-terminal truncated class2 mutants that dominantly bind to the chromatin to transcriptionally de-repress
WNT-signaling. This hypothesis offers a unique opportunity to uncover a novel association between FOXA1 and
WNT transcriptional pathways. In the K00 phase, I aim to address the intriguing question of why driver oncogenes
are not universally shared across cancer types. As a likely explanation, I postulate the existence of requisite
interactions between oncogenic pathways and lineage-specific epigenetic/chromatin architecture in driving the
malignant phenotype, akin to FOXA1 or ERG (oncogenes) and AR (lineage-essential gene) in primary PCa. This
presents the opportunity of disrupting these essential, lineage-defining pathways in cancer as a promising
therapeutic strategy - a concept termed as “targeting the cancer cell identity.” Overall, our findings till date
substantiate FOXA1 as a principal oncogene and a viable therapeutic target in PCa. In the future, I propose to
delineate the molecular mechanism of aberrant WNT activation in FOXA1 class2-mutant tumors and propose a
novel therapeutic strategy of disrupting the cancer cell identity to improve patient survival. These findings will...

## Key facts

- **NIH application ID:** 10452046
- **Project number:** 4K00CA245825-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Abhijit Parolia
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $89,082
- **Award type:** 4N
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452046

## Citation

> US National Institutes of Health, RePORTER application 10452046, SWI/SNF chromatin remodelers in tumor-associated antigen-specific CD8+ cytotoxic T cells (4K00CA245825-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10452046. Licensed CC0.

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