A genome-wide CRISPR screen reveals cancer-specific regulators of hyaluronan binding and cellular invasion
Kim, J.; Kovacs, H.; Parthasarathy, A.; Chen, S.; Krishnamoorthy, V.; Al-Seragi, M.; Zhao, M.; Huang, Y.-H.; Austin Dean, P.; Johnson, P.; Roskelley, C.; Wisnovsky, S.
Show abstract
Metastatic spread of cancer cells is driven by binding between the cell-surface receptor CD44 and hyaluronan (HA) in the extracellular matrix. The specific oncogenes that drive increased CD44-HA binding in cancer remain poorly defined. Using a fluorescently labeled hyaluronan probe, we performed a genome-wide CRISPR screen to identify genes whose knockdown disrupts HA binding in breast cancer cells. We subsequently developed a bioinformatic analysis pipeline that enabled stratification and prioritization of cancer-specific regulators. This work provides a first-in-class resource for the identification of druggable targets to inhibit HA binding. We further validate RAB4A, a top hit from our screen, as a novel regulator of this process. Mechanistically, RAB4A KO dramatically reduces CD44 expression and inhibits the invasion of breast cancer cells through HA-rich matrices. This study validates a novel strategy for identifying regulators of cancer cell invasion and identifies immediate actionable targets for anti-metastatic therapy.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- EZH2 Engages TGFβ Signaling to Promote Breast Cancer Bone Metastasis via Integrin β1-FAK Activation 95%
- A recurrent pathogenic BRCA2 truncating variant reveals a role for BRCA2-PCAF complex in modulating NF-κB-driven transcription 95%
- EFA6B regulates a stop signal for collective invasion in breast cancer 95%
Similar papers in this journal
- Evolution of chromosome arm aberrations in breast cancer through genetic network rewiring 96%
- Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate 94%
- PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape 94%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.