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

Huisman, D. H.; Frodyma, D. E.; Svoboda, R. A.; Vieira, H. M.; Chatterjee, D.; Skupa, S.; Askew, J. A.; Fisher, K. W.; Kareta, M.; Oliver, T. G.; Lewis, R. E.

doi:10.1101/2022.02.11.480157

bioRxiv · 10.1101/2022.02.11.480157

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

Huisman, D. H.·Frodyma, D. E.·Svoboda, R. A.·Vieira, H. M.·Chatterjee, D.·Skupa, S.·Askew, J. A.·Fisher, K. W.·Kareta, M.·Oliver, T. G.·Lewis, R. E.

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Abstract

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.

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Huisman, D. H., Frodyma, D. E., Svoboda, R. A., Vieira, H. M., Chatterjee, D., Skupa, S., Askew, J. A., Fisher, K. W., Kareta, M., Oliver, T. G., Lewis, R. E.. 2022-02-12. Kinase Suppressor of Ras 2 regulates small-cell lung carcinoma tumor propagating cells. https://doi.org/10.1101/2022.02.11.480157

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