# The role of autophagy in the escape from replicative crisis and tumorigenesis

> **NIH NIH K99** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2021 · $163,080

## Abstract

Project Summary / Abstract
Tumorigenesis requires cells to bypass or escape two discrete and distinctive anti-proliferative barriers:
replicative senescence and crisis. Senescence is a permanent cell cycle arrest, activated as a primary response
to telomere deprotection and involves stimulation of the tumor suppressor pathways p53-p21WAF1 and/or p16INK4A-
Rb. Disruption of cell-cycle checkpoints renders cells capable of bypassing senescence and continuing
proliferation, while telomeres shorten further. Eventually such cells initiate a terminal response called replicative
crisis, during which critically short telomeres become subject to end-to-end fusions, resulting in massive cell
death. On rare occasion, a small group of cells will emerge spontaneously from crisis and evolve towards
malignancy, yet the mechanisms underlying cell death in crisis and crisis escape are not defined. Dr. Joe Nassour
has recently discovered an unrecognized function for macroautophagy (hereafter autophagy) in the elimination
of cells during crisis. Autophagy is therefore an essential component of the crisis response required for the
removal of cells at risk for malignant transformation. This suggests that autophagy defects can be the molecular
basis for tumorigenesis.
In his Pathway to Independence Award (K99/R00) proposal, Dr. Nassour, together with his Mentor Dr. Jan
Karlseder, and his Co-Mentors Dr. Reuben Shaw, Dr. Martin Hetzer, and Dr. Peter Adams, designed a dedicated
training plan and proposed a research project that sets out to dissect the molecular basis of mammalian
autophagy and its potential therapeutic role in the earliest stages of human cancer. In particular, Dr. Nassour will
focus on deciphering the mechanism of autophagy-dependent cell death in crisis (Aim 1), elucidating the
interplay between autophagy and genome stability (Aim 2), and evaluating the role of autophagy in neoplastic
transformation through crisis escape (Aim 3). The in vivo relevance of Aim 3 will be examined by employing
knockout and transgenic mouse models susceptible to telomere dysfunction-driven carcinogenesis. The
occurrence of cellular crisis in tissues and the impact of autophagy on tumor incidence will be examined. This
research will provide new insights into the function of autophagy in cancer biology, and should provide a rationale
for developing autophagy modulation approaches to ameliorate the efficacy of cancer therapy.
Dr. Nassour’s training plan will provide all the necessary professional development to direct an independent
laboratory using next-generation sequencing (NGS)-based ‘omics’ approaches and transgenic mouse models to
define the mechanisms and function of autophagy in cancer. Training modules in this award include:
Computational analysis and bioinformatics for NGS data, methods for handling and restraint in the mouse,
transgenic mouse technology, and mentorship skills such as teaching and grant writing; which will all be
necessary for the success following th...

## Key facts

- **NIH application ID:** 10200720
- **Project number:** 5K99CA252447-02
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Joe Nassour
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,080
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200720

## Citation

> US National Institutes of Health, RePORTER application 10200720, The role of autophagy in the escape from replicative crisis and tumorigenesis (5K99CA252447-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200720. Licensed CC0.

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