Graduation Date

Summer 8-15-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Robert E Lewis

Abstract

Kinase Suppressor of Ras 2 (KSR2) is a scaffold that facilitates Raf-MEK-ERK signaling and is expressed in the brain, pituitary, and adrenal gland. Here, we demonstrate that KSR2 functions in the adult brain to maintain organismal energy balance and in small-cell lung carcinoma (SCLC) to promote self-renewal and clonogenicity. Disruption of KSR2 in adult mice results in hyperphagia, obesity, reduced metabolic rate, and altered activity. Using spatial transcriptomics, we identify regions of the brain associated with regulation of feeding and energy expenditure with altered gene expression following KSR2 disruption. These findings reveal regions of interest in which targeted KSR2 disruption might disrupt feeding behavior and energy balance. These data also show that KSR2 regulates transcriptional programs in key regions of the brain via cell autonomous and non-cell autonomous mechanisms suggesting that KSR2 may affect organismal energy balance through its ability to remodel function in distal neurons, perhaps via projects from KSR2-expressing neuronal clusters.

Seeking an established cell line in which we could better study KSR2-dependent signaling in normal and malignant tissues, we discovered the expression of KSR2 in SCLC, which was previously unappreciated. SCLC tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors, which account for 70% of all SCLC, and is also expressed in pulmonary neuroendocrine cells (PNECs), a cell of origin for SCLC-A. 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.

Comments

2025 Copyright, the authors

Additional Files
Copyright Transfer and Article Reuse | American Association for Cancer Research.pdf (171 kB)
Electronic copies of copyright permissions
Download

Included in

Cell Biology Commons

Share

COinS