34P - A novel gene family underlying cancer cell resilience

Background

Resilience to stress is a central phenotype underlying cancer cell biology. Cancer resilience empowers cell growth and survival in the face of harsh microenvironments, cytotoxic therapies, and loss of normal cellular regulatory processes. By understanding the mechanisms underlying cancer cell resilience, we may develop therapies which constrain tumors generally or synergize with existing drugs. Here, we sought to identify yet-unknown mechanisms by which cancer cells orchestrate resilience.

Methods

Using genome-scale CRISPR-Cas9 screening data from over 700 unique cancer cell lines (DepMap project), we developed a guilt-by-association “coessentiality” approach to identify genes involved cellular stress response signaling. We then used a combination of molecular biology, evolutionary biology, and computational biology approaches to validate predictions.

Results

Using an unbiased functional genomic approach and subsequent molecular validation, we identified HAPSTR1 (formerly: C16orf72) as a gene which becomes particularly important to cancer cells under stress conditions (e.g., DNA damage, protein aggregation, nutrient starvation). HAPSTR1, despite conservation through worms, yeast, and plants, had no known function. We found that HAPSTR1 encodes a dimeric protein which enables nuclear localization of HUWE1, an otherwise cytoplasmic ubiquitin ligase. Additionally, we show that mammals have a second HAPSTR gene, HAPSTR2 (formerly: RP11-364B14.3), which formed via an atypical evolutionary mechanism and functions to buffer the HAPSTR-HUWE1 pathway in specific cancer subsets.

Conclusions

Altogether, we present a new gene family and biochemical pathway leveraged by cancer cells to empower resilience. Disruption of this pathway broadly impairs stress response regulation and may thus be relevant to understanding and targeting resilience in human tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Institutes of Health (NIH-USA).

Disclosure

All authors have declared no conflicts of interest.