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Protein which characterises and regulates the spread of aggressive cancer cells identified.

It is known that the cells inside a malignant cancer tumour differ a lot. While some cancer cells do not cause trouble, others become aggressive and start to spread, or metastasize, to other organ sites. However, it is extremely difficult to predict which cells become aggressive or not.  Now, a study from researchers at The Rockefeller University and the University of Bergen (UiB) have identified a protein, namely PITPNC1, which acts as a biomarker for aggressive cancer cells and regulates a process where these cancer cells can ‘cut’ into healthy cells to metastasize.  The team state that their findings show aggressive cancer cells that are spreading in colon, breast, and skin cancer contained a much higher portion of the protein PITPNC1, than the non-aggressive cancer cells; which means the global medical community can predict which of the cancer cells will spread at a much earlier stage.  The opensource study is published in the journal Cancer Cell.

Previous studies show that the steps of the cancer metastatic cascade requires precise regulation of multiple cellular phenotypes and extracellular interactions.  Understanding the molecular and cell-biological mechanisms by which genes execute these metastatic processes is a prerequisite for the development of effective therapies for treating and potentially preventing metastatic disease. A key feature of metastatic cells is their ability to affect various cell types within the tumour microenvironment through the release of secreted factors.  PITPNC1 was previously identified as a gene targeted by miR-126, a metastasis-suppressor microRNA.  The cell-biological function of PITPNC1, however, was not defined.  The current study shows that PITPNC1 is genetically amplified in a large fraction of human breast cancers and that its overexpression causes metastatic progression of breast, melanoma, and colon cancers.

The current study utilised biochemical and in vitro methods to show that PITPNC1 binds PI4P which in turn localizes PITPNC1 to the Golgi compartment within the cell.  Results show that PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. Data findings show that RAB1B localization to the Golgi allows for the recruitment of GOLPH3, which facilitates Golgi extension and enhanced vesicular release; PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10.

The lab also observed that the PITPNC1 protein has also got a very specific function in the process of spreading cancer once it has characterized aggressive cancer cells.  The group explain the cancer cells metastasize through the body’s blood vessels, and to get into the blood vessels the cell needs to penetrate tissue, both when it leaves the tumour and when attaching to a new organ.  Results show that PITPNC1 regulates a process whereby the cancer cells can secrete molecules which cut through a network of proteins outside the cells, like scissors. Data findings show that the cancer cell is then able to penetrate the tissue and set up a colonies at new organ sites.

The team surmise that their findings show PITPNC1, a protein that correlates in expression with tumour progression in breast cancer, colon cancer, and melanoma, regulates metastatic secretion.  For the future, the researchers state that they hope to reach the point where they can offer a custom-made therapy that targets the function of this protein, to stop cancer metastasis before it begins.

Source: University of Bergen (UiB)

PITPNC1 Promotes Golgi Extension, a Phenotype Associated with Metastasis.   Golgi structure was analyzed in TEM images of LM2 cells transfected with siRNAs targeting PITPNC1 or a control siRNA. n = 50/group.  PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion.  Halberg et al 2016.
PITPNC1 Promotes Golgi Extension, a Phenotype Associated with Metastasis. Golgi structure was analyzed in TEM images of LM2 cells transfected with siRNAs targeting PITPNC1 or a control siRNA. n = 50/group. PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion. Halberg et al 2016.

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