# Understanding the role of autophagy-regulated cell death in the escape from replicative crisis

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2022 · $625,994

## Abstract

Abstract
Tumor cells arise upon escape from two distinct and critical barriers that limit proliferation of human cells,
replicative senescence and crisis. Cells in replicative senescence arrest permanently while continuing to
metabolize, triggered by short telomeres. Senescence entry however, is avoided by impairment of the main cell
cycle checkpoints controlled by the p53 and Rb tumor suppressive pathways. Following senescence bypass and
continued proliferation, cells undergo crisis, which is a phase highlighted by substantial telomere deprotection
and widespread cell death. Crisis is a stringent tumor-suppressive barrier, as it removes the vast majority of cells
that avoid senescence. However, rarely cells overcome this barrier and become neoplastic. The molecular
mechanisms and pathways underlying cell death in crisis and spontaneous crisis evasion are not understood.
Here, it is proposed to investigate the molecular mechanisms underlying the escape from crisis and crisis bypass,
with the expectation that the resulting discoveries will have a strong impact on our understanding of the early
steps in cancer development. The preliminary data presented here suggest a novel concept for replicative crisis
that implicates autophagy as a major regulator of cell death. Autophagy suppression allowed cells to bypass
crisis and continue to proliferate, while accumulating multiple genomic aberrations. This discovery is of profound
significance for understanding how genome instability evolves during the early steps of cancer development.
Furthermore, the finding suggests that autophagy inhibitors might have counterproductive effects and promote
the establishment of neoplastic cells instead of eliminating them. In three specific aims it is proposed to decipher
the exact signaling pathways that lead from dysfunctional telomeres to the activation of autophagy-controlled
cell death (Aim 1), to determine the consequences of telomere-driven autophagy and of autophagy inhibition
during crisis (Aim 2), and to understand the role of autophagy-driven cell death in crisis on tumor development
in vivo (Aim 3). In summary, this grant proposal focuses on the mechanisms underlying cell death during
replicative crisis, the mechanism of how autophagy is activated and regulated in response to replicative crisis,
and how inhibition of autophagy during crisis enables cells with an unstable genome to escape this final barrier
against tumor cell establishment and drive malignancy. We will thereby explore our novel hypothesis, in which
temporary or permanent resistance to autophagic cell death is the initial event required for the emergence of
post-crisis cells and an abrupt rise in genome instability, leading to the establishment of neoplastic cells.

## Key facts

- **NIH application ID:** 10296665
- **Project number:** 5R01CA234047-03
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Jan Karlseder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $625,994
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296665

## Citation

> US National Institutes of Health, RePORTER application 10296665, Understanding the role of autophagy-regulated cell death in the escape from replicative crisis (5R01CA234047-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10296665. Licensed CC0.

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