Faculty
Kian-Huat Lim.jpg

Kian-Huat Lim, MD, PhD

Assistant Professor
Department of Medicine
Oncology Division
Molecular Oncology

Clinical Interests

  • Pancreatic cancer
  • Colon cancer
  • Biliary cancer
  • Neuroendocrine tumor

Research Interests

  • Inflammation
  • Innate immunity
  • Gastrointestinal cancer
  • Tumor-stroma interaction
  • KRas
  • TLR

Contact

  • 314-362-5740 (tel)
  • 314-362-7086 (fax)
  • Room 502 McDonnell Medical Sciences Building (lab)
  • Division of Oncology
    Campus Box 8069
    Washington University Medical School
    660 South Euclid Avenue
    St. Louis, MO 63110

Research

 

The two ongoing research directions in our lab are:

 

1) Understanding the role of the innate immune inflammatory pathway in pancreatic and colon cancer

Both intrinsic and extrinsic factors underlie the aggressive behavior and hence poor prognosis of PDAC. Intrinsically, PDAC cells are driven by strong oncogenic events including KRas mutants and hyperactivation of the NF-κB transcription factors which render PDAC cells highly metastatic and resistant to chemotherapy. Extrinsically, the PDAC tumor microenvironment is highly fibrotic and rife with immune-suppressive myeloid cells. We recently found that PDAC cells "armored" themselves by activating the innate immune pathway, a self-defense mechanism that is normally summoned when cells are injured or invaded by microorganisms. PDAC cells frequently activate Interleukin-Receptor Associated Kinase 4 (IRAK4), the master switch that controls the innate immune signaling, to drive NF-κB activity and resist killing by chemotherapeutic agents (Fig. 1A). Supporting these findings, patients whose tumors show upregulated IRAK4 activity have a much poorer survival (Fig 1B). Capitalizing on these observations, our lab is interested in (1) identifying how IRAK4 is activated in PDAC, relating specifically to the TLRs; (2) understanding the role of IRAK4, in immune and stromal fibroblasts in PDAC; and (3) devising novel therapeutic strategies that can be advanced into clinical trials. Our lab employs genetically-engineered mouse models (KPC and IRAK4 KO mice), patient-derived cancer cell lines and human PDAC cell lines to answer these questions. We are currently testing novel IRAK4 inhibitors in combination with chemotherapy and immunotherapy in genetic PDAC mouse models. In the future, we plan to extend our studies to colon cancer. (also see http://pancreatic-cancer.wustl.edu/Research-Opportunities/Career-Enhancement-Program)

 

FigAB
FigC

Fig. 1. Hyperactivated Innate Immunity in PDAC. A) IHC images showing constitutive phospho-IRAK4 staining in PDAC tissue but not in normal adjacent pancreas in human and KPC mouse, a genetically-engineered murine model. (Bar=50μm). B) Kaplan-Meier survival analysis showing poor survival of patients with phospho-IRAK4 + PDAC. C) Schematics showing research questions in the lab.

 

2) Using proteomic approach to identify novel “Achilles Heel” of oncogenic KRas in PDAC

Activating mutations of KRas are the most common oncogenic event in PDAC. The KRas mutant protein exerts it oncogenic might by driving multiple signaling cascades (Figure). Using a proteomic array analysis, we identified a few new candidate proteins that could have significant role in KRas oncogenesis. Using genetically-defined human cell lines with expression of KRas, we sought to determine whether these candidates have critical role in KRas-induced transformation and growth, and could be targeted. In collaboration with Dr. Andrea Wang-Gillam, we are testing a novel potent ERK1/2 inhibitor (BVD-523) in pancreatic cancer cell lines and mouse models. To this end, we have identified a few resistance mechanisms that could be simultaneously targeted to render ERK inhibition more effective in curbing KRas-driven cancer cell growth.

 

KRas