# Oncogenic mechanism of Sox2 in Rb-deficient tumors

> **NIH NIH R01** · SANFORD RESEARCH/USD · 2021 · $377,438

## Abstract

PROJECT SUMMARY
The retinoblastoma tumor suppressor (Rb) is a central gene that has been implicated in the formation of
multiple solid tumors. It does so by both the regulation of cellular proliferation and driving cellular differentiation
to establish cellular identity. Lack of Rb then leads to cancer, yet the mechanisms which underlie the pro-
oncogenic consequences of Rb-loss are still not fully understood. A novel role for Rb in the repression of
essential pluripotency genes has been identified and this repression of pluripotency serves to restrict cellular
plasticity and tumor formation. One of the Rb-regulated pluripotency genes identified was Sox2 which can
indeed be oncogenic in some cellular contexts. However, the mechanisms of Sox2 oncogenic activity in tumors
formed by Rb-loss are currently unclear. This proposal is based upon the hypothesis that upregulation of Sox2
after Rb-loss is a crucial oncogenic driver in the Rb-loss initiated tumors, and is due in part to the ability of
Sox2 to enhance cellular plasticity and upregulate progenitor-state pathways. To investigate this hypothesis,
this project will aim to establish the role of Sox2 in cancer initiation upon loss of Rb. This will be achieved by
the utilization of genetically engineered mouse models which will test if Sox2 is required for the initiation and
growth of multiple Rb-loss initiated tumors. The role for Sox2 in the maintenance and propagation of these
tumors will be studied by standard growth and transplantation assays using established mouse and human cell
lines. Finally, this project will aim to elucidate the oncogenic mechanisms of Sox2 in cancer. Genomic-scale
investigations into the gene network regulated by Sox2 will be examined by ChIP-seq of Sox2 in tumor cell
lines in conjunction with RNA-seq, ChIP-seq of modified histones, and ATAC-seq to identify the means of
regulation of the greater Sox2 network. Downstream targets will be validated by their overexpression or
knockdown in tumor cell lines or GEMMs. This investigation will identify the extent that Rb-loss initiated tumors
are dependent upon Sox2 and the mechanisms by which Sox2 participates in tumor development by the
elucidation of the broader Sox2 network in cancer. This will serve to build a cohesive gene expression network
to describe the oncogenic effects that follow Rb-loss and describe how these tumors are formed.
Understanding this downstream Sox2 network may provide novel targets for the treatment of these tumors and
will provide a groundwork for future investigations into the development of cancer therapeutics.

## Key facts

- **NIH application ID:** 10194418
- **Project number:** 5R01CA233661-03
- **Recipient organization:** SANFORD RESEARCH/USD
- **Principal Investigator:** Michael S. Kareta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,438
- **Award type:** 5
- **Project period:** 2019-07-23 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194418

## Citation

> US National Institutes of Health, RePORTER application 10194418, Oncogenic mechanism of Sox2 in Rb-deficient tumors (5R01CA233661-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10194418. Licensed CC0.

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