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Wang (Man-Tzu) Lab

Man-Tzu Wang, PhD

Ras proteins comprise a family of signal-transducing GTPases that are frequently mutated in human cancers. Oncogenic Ras mutations lock the protein in its GTP-bound form thus permitting its constitutive interaction with and activation of multiple effectors. The pathogenic mutations on KRAS, present in over 90% of pancreatic ductal adenocarcinomas (PDAC), 45% of colorectal cancers and 35% of lung adenocarcinomas, are the major driver of their poor outcomes and failure to respond to targeted therapies. However, unlike many other driver oncoproteins being successfully exploited as targets of therapeutic intervention, KRAS has not yielded to any types of therapeutic attacks and been considered as “undruggable” for many years. The goal of the Wang lab at the Hillman Cancer Center is to understand how KRAS drives malignancies in cells and to identify novel molecular targets of intervention to improve the clinical outcomes of KRAS-driven cancers.   
RAS mutations in human cancer
KRAS and stemness in cancers
The three closely related human RAS, H-Ras, N-Ras, and K-Ras genes, share a high degree of sequence homology as well as identical regulators and effectors. However, they also have unique roles in physiological and pathological processes. K-Ras mutations occur at high frequency in pancreatic and colorectal cancers and in lung adenocarcinomas, while N-Ras and H-Ras mutations are far less common. Furthermore, K-Ras deficiency results in embryonic lethality, whereas N- and H-Ras knockout mice develop normally. Our lab has defined that KRAS, but not HRAS, promotes cancer stem cell-like properties in the model of pancreatic cancer. We will continue to investigate 1) the roles of KRAS in cancer stemness/plasticity; and 2) the stemness-associated genetic, epigenetic, and transcriptomic signatures in KRAS-induced cancers.
 
Targeting novel regulatory mechanisms and effectors of KRAS
KRAS proteins does NOT appear to present suitable pockets to which drugs could bind, except for the GDP/GTP binding site: unfortunately, Ras proteins bind very tightly to these nucleotides (picomolar affinities and slow off-rates) making the prospect of identifying competitive nucleotide analogs seem virtually impossible. As a substitute for direct attack on the KRAS protein itself, our group has been and will be investigating the upstream and downstream pathways specific to KRAS, in the hope that blocking these pathways will provide clinical benefit for cancer patients suffering with Ras mutations.
 
Interruption of an autocrine circuit induced by oncogenic KRAS
RAS-induced inflammatory cytokine circuits promote cell transformation, tumor cell survival, angiogenesis, and metastasis in multiple types of cancers via activation of NF-kB, STAT3 or other pathways, but their relevance in KRAS-mutated solid tumors is not completely understood. Our group has found that expression of LIF, the most pleiotropic member of the IL-6 family that activates the STAT3 pathway, is stimulated by oncogenic KRAS in PDAC. Depletion of LIF by genetic means or neutralization of LIF by antibody reduces PDAC tumor engraftment in xenograft models. Moreover, LIF-neutralizing antibody synergizes with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven mouse model of PDAC. The data suggest a crucial role of LIF in KRAS-driven pancreatic cancer. Blockade of LIF may represent an attractive approach to improve the therapeutic outcome of traditional
chemotherapy of pancreatic cancer. In the future, we will use cell-based assays and multiple genetically engineered mouse models (GEMMs) to study 1) the functions of LIF in more KRAS-induced cancer models, including lung cancer; 2) how KRAS regulates LIF expression in cancers; 3) differential roles of LIF and other IL-6 family cytokines in KRAS-cancers; and 4) immune responses mediated by LIF in the tumor microenvironment of KRAS-induced cancers.

Link to lab website:  www.thewanglabpitt.org
 
Headshot of Man-Tzu Wang, PhD
Man-Tzu Wang, PhD
Assistant Professor

Man-Tzu Wang, PhD

Journal Articles

Wang MT, Fer N, Galeas J, Collisson EA, Kim SE, Sharib J, and McCormick F. Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS-driven pancreatic cancer. Nat Commun 10:3055, 2019. 
Wang MT, Holderfield M, Gales J, Delrosario R, To M, Balmain A, McCormick F. KRas promotes tumorigenicity through suppression of non-canonical Wnt signaling. Cell 163:1237-1251, 2015.
MT Wang, H Jiang, D Boral and D Nie. Cancer Stem Cells in Resistance to Cytotoxic Drugs: Implications in Chemotherapy. B. Bonavida (ed.), Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy, Resistance to Targeted Anti-Cancer Therapeutics 1, DOI: 10.1007/978-1-4614-7070-0_8, Springer Science+Business Media New York 2013.
Yang D*, Wang MT*, Tang Y, Chen Y, Jiang H, Jones TT, Rao K, Brewer GJ, Singh KK, Nie D. Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RAS(Q61L). Cancer Biol Ther 9:122-133, 2010. (*Shared first author).
Wang MT, Honn KV, Nie D. Cyclooxygenases, prostanoids, and tumor progression.  Cancer Metastasis Rev 26:525-534, 2007.