New Signal Transduction Targets for Cancer Therapy

Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with few treatment options. We have identified leukemia inhibitory factor (LIF), a stem cell factor, as a key paracrine factor, secreted mainly by activated cancer-associated-fibroblasts (CAFs) in the tumor micro-environment (TME), that acts on pancreatic tumor cells to maintain a stem cell-like population. Blockade of LIF with a neutralizing monoclonal antibody (mAb) slows tumor progression in the KPC mouse model of PDAC and augments efficacy of gemcitabine chemotherapy treatment to prolong survival. LIF levels are strongly elevated in both mouse and human pancreatic tumor tissue, and LIF is also is detected in serum from tumor-bearing mice and human PDAC patients, suggesting its use as both as a biomarker and as a therapeutic target. In addition its action on tumor cells, we have found that LIF acts on myeloid cells in the immune microenvironment to sustain a protumorigenic population of tumor-associated macrophages.

Histidine phosphorylation, the so-called “hidden phosphoproteome”, is poorly characterized. To study histidine phosphorylation we generated mAbs that selectively recognize the 1-pHis and 3-pHis-isoforms, and have determined the structural basis of antibody recognition of pHis. We have used these mAbs for immunoblotting and immunofluorescence staining to detect increased levels of pHis proteins in human cell lines, and also to survey the pHis proteome and identify new sites of histidine phosphorylation. Using these mAbs, we collaborated with Michael Hall (Biozentrum, Basel) to show that pHis levels are elevated in liver tumors in a mouse model, and in human hepatocellular carcinoma (HCC) tumor tissue, as a result of reduced levels of the LHPP pHis phosphatase in tumor tissue. On this basis, we propose that LHPP serves as a tumor suppressor in HCC, and that histidine phosphorylation can act as a cancer driver. Consistently, we have recently observed elevated levels of pHis proteins in PDAC stromal cells.

cell biologygeneticsmolecular biology

Audience: researchers in the discipline

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Colloquium zooming Molecular & Cellular Biology LUMS

Series comments: Zooming Molecular & Cellular Biology Colloquium was initiated on July 28th, 2020 by the Biology department at Syed Babar Ali School of Science & Engineering (SBASSE), Lahore University of Management Sciences (LUMS). The series follows through various topics which come under the ambit of Molecular and Cellular Biology and we’ve had the pleasure and honor of hosting some of the most knowledgeable scientists from around the globe. Organizers can be reached out at 24100162@lums.edu.pk or 24100001@lums.edu.pk for the Zoom link of individual talks. All lectures are LIVE streamed on SBASSE's official Facebook page.

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