University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Breast Oncology Program Seminar

December 12, 2018, 8:30 am – 10:00 am

Mount Zion
2340 Sutter Street
Lurie Seminar Room
San Francisco, CA 94143

Ruth Muschel, MD, PhD, University of Oxford   >view speaker profile

"Modulation of Liver Metastasis and the Cancer Immune Response by the Extracellular Matrix"

Abstract: Metastasis is well known clinically to be associated with cancer treatment failure. The liver and lungs are the most frequent sites for distant metastases overall. In colon cancer in particular the liver is the major site of metastatic disease. In murine models we found that liver metastases were infiltrated by myeloid cells. Similarly in human colorectal carcinoma liver metastases, there was also a notable influx of myeloid cells, the neutrophils.  These tumor neutrophils expressed FGF2 unlike their naïve counterparts.  Depletion of neutrophils or blockade of FGF2 with antibodies greatly reduced metastatic growth suggesting potential therapeutic targets. 

FGF2 is sequestered by the extracellular matrix (ECM). This led us to characterize the ECM in liver metastases.  After isolation of ECM and mass spectrometry we identified and quantitated the protein constituents in ECM from human colorectal cancer liver metastases.  Many of the proteins identified as overexpressed were well-known extracellular matrix proteins that interestingly formed a signature indicating poor prognosis for many cancers.
A protein not previously known to be in the ECM, protein arginine deiminase 4, PAD4 was overexpressed in liver metastasis ECM compared to that of normal liver, colon or primary colorectal cancers. PAD4 is an enzyme that converts arginine in proteins to citrulline.  As a result we searched for citrullination in the ECM of liver metastases and found much higher levels than in adjacent liver, normal colon or primary colorectal cancers.  While citrullination of the ECM is well described in arthritis, it has not previously been identified in cancer ECM. Downregulation of PAD4 in cancer cells or pharmacological inhibition led to greatly decreased liver metastasis development as well as altered EMT, which could be phenocopied by plating cancer cells on biochemically citrullinated collagen in tissue culture.  Overall these studies demonstrate the capacity of cancer cells to modulate the behavior of the cancer through alteration of the ECM. 

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