# The RNA structural code underlying pathological regulation of RNA splicing in metastasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $353,057

## Abstract

PROJECT SUMMARY
 Widespread aberrant splicing is now considered a hallmark of cancer, and many of the resulting transcript
isoforms have been functionally implicated in tumorigenesis. However, the underlying regulatory pathways that
govern RNA splicing and the extent to which they play a role in cancer progression remain largely unknown.
Due to our limited knowledge of splicing regulation, we cannot solely rely on annotated pathways to study
changes in transcript isoforms. Moreover, bioinformatic strategies that are often used in discovering
transcriptional regulatory pathways often fail to capture the complexities of post-transcriptional regulation. For
example, common methodologies for cis-element discovery focus on sequence alone and largely ignore the
integral role of the RNA structural code in splicing. To address this challenge, we have developed a
computational framework that performs context-aware analysis of alternative splicing events to identify known
and novel regulators of RNA processing. Using this approach, we have discovered and partly characterized a
previously unknown RNA structural splicing enhancer (SSE) that drives aberrant splicing in highly metastatic
breast cancer. We have identified the associated RNA-binding protein that serves as the trans factor that
interacts with this novel SSE. We have shown that this pathway drives metastatic progression in xenograft
mouse models and that its activity is strongly associated with poor survival in patients. In this proposal, we will
build on this previous work to (i) perform a detailed dissection of this non-canonical regulatory pathway of
alternative splicing, its underlying molecular machinery, and its governing RNA structural code; (ii) evaluate the
contribution of this pathway to breast cancer progression; and (iii) establish the clinical relevance of this
pathway and its regulon to cancer.

## Key facts

- **NIH application ID:** 10654522
- **Project number:** 5R01CA244634-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Hani Goodarzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $353,057
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10654522

## Citation

> US National Institutes of Health, RePORTER application 10654522, The RNA structural code underlying pathological regulation of RNA splicing in metastasis (5R01CA244634-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10654522. Licensed CC0.

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