# Mapping p53 dynamics to cell-fate outcomes in reprogramming and oncogenesis

> **NIH NIH F99** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $48,974

## Abstract

Project Summary
 Cell fates are decided as an organism develops. In human development, pluripotent stem cells
differentiate into the three layers of ectoderm, mesoderm, and endoderm. These classes of tissue further
differentiate into specific cell types with specific functions including neurons, immune cells, and skin cells. These
identities are stable; once a cell differentiates into its final state, it will not revert back to a stem cell state, nor will
it transform into another cell type. A skin cell will not spontaneously become a neuron, even if the neuron is
damaged. However, Takahashi and Yamanaka demonstrated that cells have the potential to revert back to a
stem cell fate when they reprogrammed mouse fibroblasts into induced pluripotent stem cells (iPSCs) by forced
overexpression of stem cell-specifying transcription factors. In 2010, Vierbuchen and colleagues demonstrated
that fibroblasts could be reprogrammed directly to neurons using neuron-specific transcription factors, bypassing
the need for an iPSC-intermediate. However, reprogramming efficiencies in each of these systems was low; very
few cells are actually capable of changing their cellular identity.
 In 2019, Babos and Galloway greatly improve reprogramming efficiencies in direct motor neuron
reprogramming, demonstrating improved reprogramming yields 100 times greater than the original process.
They drew upon factors that enhanced another cell fate transition: cancer. Genes that promote a healthy cell’s
transition to cancer also improved the ability of a cell to change its cell type. Thus, reprogramming can serve as
a model of cancer initiation. By understanding the molecular mechanisms by which these oncogenes promote
reprogramming, we can understand how oncogenes evade cellular barriers to cancer and establish tumors.
In the F99-phase of the proposed research, I will investigate the role of the tumor suppressor protein p53 in
oncogene-mediated reprogramming. p53 is the most frequently mutated gene in cancer. Rather than p53
expression being lost in cancer, it is most often mutated to create a protein unable to perform its designated
functions and accumulates to abnormally high levels. As a synthetic biologist, I will design synthetic gene circuits
that track and report p53 levels during reprogramming. I will isolate cells that accumulate p53 and investigate
their ability to reprogram.
 In the K00-phase of the proposed research, I will extend my investigations of p53 to three-dimensional
models of ovarian cancer. Ovarian cancer is often diagnosed at late stages, after the cancer has metastasized,
leading to poor patient outcomes. 3D models of tumor initiation can shed light on the early stages of ovarian
cancer and enable clinicians to catch the cancer early, when the disease is most easily treated. By inducing
cancer initiation in 3D models of ovarian cancer and tracking cancer progression using p53-sensors, I will identify
the drivers of tumor establishment and factors assoc...

## Key facts

- **NIH application ID:** 10906234
- **Project number:** 5F99CA284280-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Adam Matthew Beitz
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-08-11 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906234

## Citation

> US National Institutes of Health, RePORTER application 10906234, Mapping p53 dynamics to cell-fate outcomes in reprogramming and oncogenesis (5F99CA284280-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10906234. Licensed CC0.

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