# Building a spatial transcriptomics infrastructure for isoform profiling in aging pre-neoplastic tissues

> **NIH NIH R21** · JACKSON LABORATORY · 2024 · $191,765

## Abstract

PROJECT SUMMARY/ABSTRACT
Aging is the greatest risk factor for cancer, but it is not known which age-dependent cellular and molecular events
drive cancer initiation. Spatial transcriptomic approaches are revolutionizing our understanding of cancer
initiation, progression, and drug resistance by revealing expression patterns with tissue morphological context.
However, these approaches have not yet been applied to the interdisciplinary biology of aging-driven cancers,
despite the likelihood that intratissue and microenvironmental evolution mediate the aging phenotype. Moreover,
the majority of current single cell spatial projects are based on 3' short read RNA-sequencing (RNA-seq) and
therefore lack the ability to detect full-length spliced isoforms, which are frequently observed in tumors and are
known to impact tumor initiation and treatment response. Work from us and others has revealed widespread
alterations in alternative RNA splicing in human tumors, including in breast cancer, and that half of all spliced
isoforms detected in human breast tumors using long-read sequencing (LR-seq) are missed by RNA-seq and
absent from reference transcriptomes. In addition, we have causally linked the upregulation of specific splicing
factors with breast tumor initiation both in vitro and in vivo and identified age-dependent changes in spliced
isoforms in cancer-associated genes in mammary epithelial cells. Together, these results suggest that alternative
splicing is a critical mechanism underlying tumor initiation with age, and that spatial LR-seq approaches are
required to resolve these mechanisms. However, standardized approaches and resources to measure, quantify,
and visualize expression of full-length isoforms within tissues are lacking. This gap in infrastructure impedes the
field's ability to identify cell populations that express age-dependent isoforms, how such isoforms impact cancer
initiation for example through changes in receptor-ligand interactions. To address these infrastructure and
knowledge gaps, we will first develop approaches to map and analyze full-length RNA isoforms spatially
within tissue sections (R21 phase, Aim 1). These tools, which merge LR-seq and spatial transcriptomics, will
be applicable across sample types and will therefore be of broad, sustainable utility to the research community.
We will then apply these technologies to generate a spatial map of full-length RNA isoforms in healthy
breast tissues and tumors during aging (R33 phase, Aims 2 and 3). Finally, we will develop data sharing
and visualization tools for spatial isoform expression to enable others to mine our data via a web resource
(R33 phase, Aim 4). To achieve these goals, this project will leverage the complementary and interdisciplinary
expertise of the Anczukow lab in alternative splicing and breast cancer, and of the Chuang lab in systems biology
and spatial transcriptomics analysis. In response to NOT-CA-22-002, Notice of NCI's Participation in PAR-20-
070,...

## Key facts

- **NIH application ID:** 10911290
- **Project number:** 5R21AG080243-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** OLGA ANCZUKOW-CAMARDA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $191,765
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911290

## Citation

> US National Institutes of Health, RePORTER application 10911290, Building a spatial transcriptomics infrastructure for isoform profiling in aging pre-neoplastic tissues (5R21AG080243-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10911290. Licensed CC0.

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