Laboratory of Robert Lewis, PhD

The Lewis Lab performs research on tumor initiation and dissemination, and tumor drug resistance.

Only a select subset of tumor cells can give rise to another tumor. These tumor initiating cells – also referred to as cancer stem cells – often arise through the conversion of neoplastic epithelial cells into motile and invasive mesenchymal cells via a process termed the epithelial-to-mesenchymal transition. That process provides tumor cells the potential to migrate to distal organs and form metastases, which are often lethal to the patient. Tumor initiating cells are, or overlap with, therapy resistant tumor cells.

The Lewis laboratory's goal is to understand the cellular mechanisms essential to the formation and maintenance of tumor initiating cells, their potential to invade other tissues, and their ability to resist cancer therapy. Where possible, the laboratory seeks to validate components of these cellular mechanisms and devise strategies for their manipulation that might be converted into new cancer therapies.

Using patient-derived tumor organoids, tumor cell lines, genetically engineered mouse models, single cell RNA sequencing, and spatial transcriptomics, the Lewis Lab is identifying downstream effectors of the molecular scaffolds KSR1 and KSR2 that affect EMT, TIC formation, and drug resistance in colorectal and lung cancers. Studies manipulating KSR proteins demonstrate their critical role in these processes (e.g., Rao et al. eLife 2021 and Daley, Vieira et al. PNAS 2023).

Selected Publications

1. Daley BR, Vieira HM, Rao C, Hughes JM, Beckley ZM, Huisman DM, Chatterjee D, Sealover NE, Cox K, Askew JW, Svoboda RA, Fisher KW, Lewis RE*, Kortum RL*. SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status. Proc Natl Acad Sci. 2023, in press. *Corresponding author

2. Rao C, Frodyma DE, Southekal S, Svoboda RA, Black AR, Guda C, Mizutani T, Clevers H, Johnson KR, Fisher KW, Lewis RE. KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition. eLife. 2021 May 10;10:e66608. doi: 10.7554/eLife.66608. PMID: 33970103. PMCID: PMC8195604.
3. McMillian EA, Kwon G, Clemenceau JR, Fisher KW, Vaden RM, Shaikh AF, Neilsen BK, Kelly D, Potts MB, Sung YJ, Mendiratta S, Hight SK, Lee Y, MacMillian JB, Lewis RE*, Kim HS*, White MA*. Cell Chem Biol. 2019 Oct 17;26(10):1380-1392.e6. doi: 10.1016/j.chembiol.2019.07.008. Epub 2019 Aug 1. PMID: 31378711. PMCID: PMC9161285. *Corresponding author
4. Neilsen BK, Frodyma DE, McCall JL, Fisher KW, Lewis RE. ERK-mediated TIMELESS expression suppresses G2/M arrest in colon cancer cells. PLoS One. 2019 Jan 10;14(1):e0209224. doi: 10.1371/journal.pone.0209224. eCollection 2019. PMID: 30629587. PMCID: PMC6328106.
5. Das B, Neilsen BK, Fisher KW, Gehring D, Hu Y, Volle DJ, Kim HS, McCall JL, Kelly DL, MacMillian JB, White MA, Lewis RE. A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells. Sci Rep. 2018 Feb 28;8(1):3770. doi: 10.1038/s41598-018-22090-6. PMID: 29491475. PMCID: PMC5830883.
6. McCall JL, Gehring D, Clymer BK, Fisher KW, Das B, Kelly DL, Kim H, White MA, Lewis RE. KSR1 and EPHB4 regulate Myc and PGC1β to promote survival of human colon tumors. Mol Cell Biol. 2016 Aug 12;36(17):2246-61. Print 2016 Sep 1. doi: 10.1128/MCB.00087-16. PMID: 27273865. PMCID: PMC4985931.
7. Guo L, Costanzo-Garvey DL, Smith DR, Neilsen BK, MacDonald RG, Lewis RE. Kinase suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis. Mol Metab. 2016 Dec 18;6(2):194-205. doi: 10.1016/j.molmet.2016.12.004. eCollection 2017 Feb. PMID: 28180061. PMCID: PMC5279912.
8. Guo L, Costanzo-Garvey DL, Smith DR, Zavorka ME, Venable-Kang M, MacDonald RG, Lewis RE. Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2). Sci Rep. 2016 Aug 26;6:32093. doi: 10.1038/srep32093. PMID: 27561547. PMCID: PMC4999994.
9. Fisher KW, Das B, Kim HS, Clymer BK, Gehring D, Smith DR, Costanzo-Garvey DL, Fernandez MR, Brattain MG, Kelly DL, MacMillan J, White MA, Lewis RE. AMPK promotes aberrant PGC1β expression to support human colon tumor cell survival. Mol Cell Biol. 2015 Nov;35(22):3866-79. doi: 10.1128/MCB.00528-15. Epub 2015 Sep 8. PMID: 26351140. PMCID: PMC4609747.
10. Henry MD, Costanzo-Garvey DL, Klutho PK, Lewis RE. Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of Ras 2^-/- Physiol Rep. 2014 Jul 1;2(7):e12053. doi: 10.14814/phy2.12053. Print 2014 Jul 1. PMID: 24997067. PMCID: PMC4187555.
11. Potts MB, Kim HS, Fisher KW, Hu Y, Carrasco YP, Bulut GB, Ou YH, Herrera-Herrera ML, Cubillos F, Mendiratta S, Xiao G, Hofree M, Ideker T, Xie Y, Huang LJ, Lewis RE, MacMillian JB*, White MA*. Using functional signature ontology (FUSION) to identify mechanisms of action for natural products. Sci Signal. 2013 Oct 15;6(297):ra90. doi: 10.1126/scisignal.2004657. PMID: 24129700. PMCID: PMC4075427. *Corresponding author
12. Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, Fernandez MR, Fisher K, Kortum RL, Hong EG, Jun JY, Ko HJ, Schreiner A, Volle DJ, Treece T, Swift AL, Winer M, Chen D, Wu M, Leon LR, Shaw AS, McNeish J, Kim JK, Morrison DK, Tschöp MH, Lewis RE. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab. 2009 Nov;10(5):366-78. doi: 10.1016/j.cmet.2009.09.010. PMID: 19883615. PMCID: PMC2773684.