Description

Cells undergoing senescence present a characteristic stable cell cycle arrest; thus, senescence is considered to be an intrinsic tumour suppressor mechanism in vivo and in vitro. However, senescent cells display also what has been named as a "Senescence-Associated Secretory Phenotype" or SASP, which mediates both anti- and pro-tumourigenic properties in neighbouring cells.

During this last decade, the development of prosenescence therapies has become an attractive strategy as cellular senescence acts as a barrier against tumour progression. In this context, CDK4/6 inhibitors induce senescence and reduce tumour growth in breast cancer patients. However, even though cancer cells are arrested after CDK4/6 inhibitor treatment, genes regulating senescence in this context are still unknown limiting their antitumour activity. For this reason, we have performed a functional genome-wide CRISPR/Cas9 genetic screen to identify genes preventing the activation of senescence induced by CDK4/6 inhibitors ().

Following this approach, our lab has identified two genes implicated in the coagulation pathway - the coagulation factor IX (F9) and Protein Z Vitamin K Dependent Plasma Glycoprotein (PROZ) - whose loss prevent the induction of senescence. We believe these markers could be used to predict patient response to CDK4/6 inhibitors improving the efficacy of cancer treatments and overall disease outcome (Cell Death Dis 2022).

Figure 2. CRISPR/Cas9 screening identifies candidate genes whose loss are implicated in Palbociclib cell cycle arrest. (A) Schematic representation of the proof-of-concept genome-wide screen performed using the GeCKOv2 pooled sgRNA library. Cells were infected with the library (CRISPR/Cas9) or the control (control) and treated with Palbociclib (Palbo) for 14 days. (B) MCF7 cells expressing either the control (C) or the GeCKO library after 14 days Palbo treatment were stained with crystal violet.

 

 

 

 

 

 

 

 

Figure 2. CRISPR/Cas9 screening identifies candidate genes whose loss are implicated in Palbociclib cell cycle arrest. (A) Schematic representation of the proof-of-concept genome-wide screen performed using the GeCKOv2 pooled sgRNA library. Cells were infected with the library (CRISPR/Cas9) or the control (control) and treated with Palbociclib (Palbo) for 14 days. (B) MCF7 cells expressing either the control (C) or the GeCKO library after 14 days Palbo treatment were stained with crystal violet.