Kinase Suppressor of Ras 2 promotes small-cell lung carcinoma tumor initiation
Abstract Tumor propagating cells (TPCs) make up a small proportion of tumor cells responsible for self-renewal and long-term propagation of small-cell lung carcinoma (SCLC) tumors. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC TPCs. KSR2 is a molecular scaffold which promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC tumors as well as the pulmonary neuroendocrine cells from which the SCLC tumors arise. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells 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 significantly reduces the colony forming ability of TPCsin vitroand their tumor initiating capacityin vivo. 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.Impact Statement Manipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to the formation and maintenance of tumor propagating cells via ERK signaling..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 16. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huisman, Dianna H. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2022.02.11.480157 |
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XBI03523301X |
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| 520 | |a Abstract Tumor propagating cells (TPCs) make up a small proportion of tumor cells responsible for self-renewal and long-term propagation of small-cell lung carcinoma (SCLC) tumors. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC TPCs. KSR2 is a molecular scaffold which promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC tumors as well as the pulmonary neuroendocrine cells from which the SCLC tumors arise. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells 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 significantly reduces the colony forming ability of TPCsin vitroand their tumor initiating capacityin vivo. 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.Impact Statement Manipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to the formation and maintenance of tumor propagating cells via ERK signaling. | ||
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| 700 | 1 | |a Vieira, Heidi M. |e verfasserin |4 aut | |
| 700 | 1 | |a Skupa, Sydney |e verfasserin |4 aut | |
| 700 | 1 | |a Askew, James W. |e verfasserin |4 aut | |
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