Huisman, D. H. | Search bioRxiv

bioRxiv2022

Post-transcriptional control of SRSF9 promotes the epithelial-to-mesenchymal transition (EMT) in colorectal cancer cells

In human colorectal cancer (CRC) cells the Raf/MEK/ERK scaffold Kinase Suppressor of Ras 1 (KSR1)-dependent signaling is required for the epithelial-to-mesenchymal transition (EMT)-like phenotype. Here we show that KSR1 promotes the association of differentially spliced mRNA bearing recognition sites for the Serine/Arginine-Rich (SR) splicing factor SRSF9. CRISPR/Cas9 disruption of KSR1 destabilizes SRSF9 protein, which interacts preferentially with mRNA encoding Epithelial Stromal Interaction 1 (EPSTI1). EPSTI1 protein mediates Ras and KSR1-dependent induction of EMT. Analysis of EPSTI1 splice variants reveals that inclusion of exon 8 is critical to the ability of EPSTI1 to promote the E-to N-cadherin switch and CRC cell motile and invasive behavior. These data reveal a mechanism in CRC cells in which Ras-induced and KSR1-dependent signaling affects pre-mRNA splicing to control behaviors critical to cancer cell dissemination and metastasis.

cell biology↗

bioRxiv2022

Kinase Suppressor of Ras 2 regulates small-cell lung carcinoma tumor propagating cells

Small-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs) in vitro and their tumor initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target. ImplicationsManipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.

cancer biology↗