P57: Phosphorylation of IWS1 by AKT Maintains Liposarcoma Tumor Heterogeneity through Preservation of Cancer Stem Cell Phenotypes and Mesenchymal-Epithelial Plasticity

Thursday, March 23, 2023

2:46 PM – 2:51 PM

Location: SSO HUB: Melanoma & Sarcoma Zone

Author(s)

YW

Yu Wang, MD/PhD

Research Fellow
The Ohio State University, Tongji Hospital, Huazhong University of Science and Technology, United States

Disclosure information not submitted.
MG

Marina Goryunova, MD

Fulbright Visiting Scholar
The Ohio State University, United States

Disclosure information not submitted.
HZ

Hongji Zhang, MD/PhD

Assistant Professor
West Virginia University, United States

Disclosure information not submitted.
AL

Alessandro La Ferlita, PhD

Post Doctoral Scholar
The Ohio State University, United States

Disclosure information not submitted.
NS

Nipin Sp, PhD

Post Doctoral Scholar
The Ohio State University, United States

Disclosure information not submitted.
HH

Hai Huang, MD/PhD

Associate Professor
The Feinstein Institutes, United States

Disclosure information not submitted.
Timothy M. Pawlik, MD, PhD

Chair of Surgery
The Ohio State University Wexner Medical Center
Columbus, Ohio, United States

Disclosure(s): No financial relationships to disclose
Allan Tsung, MD

Chair Department of Surgery
University of Virginia, United States

Disclosure information not submitted.
RP

Raphael Pollock, MD PhD

Professor of Surgery, Director James Comprehensive Cancer Center
The Ohio State University Wexner Medical Center- Division of Surgical Oncology, United States

Disclosure information not submitted.
Alex C. Kim, MD, PhD

Assistant Professor of Surgery
The Ohio State University Wexner Medical Center, The James Cancer Hospital and Solove Research Institute
Columbus, Ohio, United States

Disclosure information not submitted.

Poster Presenter(s)

Joal D. Beane, MD

Assistant Professor
The Ohio State University Wexner Medical Center- Division of Surgical Oncology
Columbus, Ohio, United States

Disclosure information not submitted.

Disclosure(s):

Timothy M. Pawlik, MD, PhD: No financial relationships to disclose

Introduction: Chemotherapy remains the mainstay of treatment for patients with unresectable soft tissue sarcoma (STS), but response rates are only 25% and the overall survival is dismal. The aberrant activation of the PI3K/AKT pathway has been implicated in the aggressive clinical behavior of STS and in resistance to chemotherapy. However, the precise mechanism remains elusive and efforts to target AKT clinically have failed. IWS1 is a transcription elongation factor that is activated by AKT. Our aim was to determine if AKT-mediated phosphorylation of IWS1, is an important cellular event in the tumorigenesis of STS.

Methods: In vitro transwell and in vivo cell-derived xenograft experiments were performed using human SW872 and Lipo863 sarcoma cell lines following lentiviral transduction with shControl, shIWS1 (knockout), IWS1WT (wild type overexpression), shIWS1/WTR (knockout with wild type rescue), IWS1/MutR (knockout with IWS1-AKT phosphorylation site Ser720/Thr721 mutant rescue). Flow cytometry and Western blotting were used to assess the presence of cancer stem cells and the expression of EMT/MET transcription factors. Lastly, tumor specimens (n=33) and adjacent normal adipose tissue were examined by Western blotting to correlate expression of IWS1 with clinical outcomes in patients with STS.

Results: The expression of IWS1 promotes migration and invasion in vitro and tumor growth in vivo in an AKT-dependent manner (Fig 1A-B). Phosphorylation of IWS1 promotes the maintenance of cancer stem cells (CD133+) in both cell and xenograft models of STS and contributes to a “metastable” cell phenotype characterized by mesenchymal/epithelial plasticity that is AKT dependent (Fig 1C-D). In patients with STS, IWS1 expression is associated with reduced disease-specific survival (p=0.014), increased frequency of recurrence (SE 0.112, 95%CI 0.059-0.499, p=0.013), a shorter time to relapse after resection, and a shorter disease-free survival (HR=3.652, p=0.012).

Conclusions: These findings indicate that phosphorylation of IWS1 plays an important role in the pathobiology of human sarcomas by maintaining mesenchymal/epithelial plasticity and implicate IWS1 as an important molecular target to overcome chemotherapy resistance in STS.

Learning Objectives:

Describe one pathway important for soft tissue sarcoma tumorigenesis.
Describe one proposed mechanism by with the aberrant activation of the AKT pathway impacts sarcoma tumor biology.
Describe how inhibition of IWS1 may be used to help improve response to systemic therapy in patients with soft tissue sarcoma.