# Context dependent tumor suppression

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $454,922

## Abstract

Project Summary
 We have identified a novel mode of autonomous programmed cell death that is controlled by p53 in
small cell lung cancer (SCLC) — the most deadly form of lung cancer. We capitalized on a genetically
engineered mouse model that we created to regulate endogenous p53 inactivation and its temporally
controlled reactivation in established mouse models of SCLC. We found that p53 controls a canonical
senescence program in approximately half of the tumors and a non-apoptotic cell death program in the rest.
The mechanism of cell death is distinct from known forms of programmed cell death but is dependent on
multiple members of the cyclophilin protein family of peptydyl-prolyl isomerases. We demonstrate that p53
regulates a distinct transcriptional program in dying SCLC tumors not active in senescing SCLC. Moreover, the
activation of this transcriptional program is abolished by small molecule inhibitors of cyclophilins. In aim 1 of
our project, we will interrogate the molecular underpinnings of this p53-cyclophilin interaction. At the cell
physiological level, p53-mediated SCLC cell death is associated with features of paraptosis; a poorly defined
mode of cell death not previously associated with p53 but characterized by excessive accumulation of
cytoplasmic vacuoles, cell swelling, and plasma membrane dysfunction. Additionally, we observed massive
induction of an endoplasmic reticulum-directed autophagy program (ER-phagy) during p53-mediated SCLC
death. In aim 2 of our project we will interrogate the molecular features and dissect the molecular determinants
of paraptosis and ER-phagy in this context. Finally, we present comparative genomics that implicates that the
`classical' molecular subtype of SCLC is represented by SCLC tumors that die after p53 restoration and that
the `variant' molecular subtype of SCLC is represented by SCLC tumors that senesce after p53 restoration. In
aim 3 of our project, we will determine if the effects of p53 restoration are distinct based on either the cell of
origin, or the collection of driver mutations as each of these impacts the molecular subtype that develops in
SCLC. Together, our project will elucidate an important molecular mechanism for controlling SCLC, shed light
on targetable vulnerabilities, and identify specific subsets of SCLC patients that may be susceptible to such
approaches.

## Key facts

- **NIH application ID:** 10801396
- **Project number:** 1R01CA279698-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David Feldser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $454,922
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801396

## Citation

> US National Institutes of Health, RePORTER application 10801396, Context dependent tumor suppression (1R01CA279698-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10801396. Licensed CC0.

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