Wednesday, May 2, 2018

Lung tumors "talk" to bone cells to promote tumor growth and spread!

And I'm back!  My apologies for the long wait between posts; I've been working on a few other projects in the interim (more on this another time) and haven't had much time to write lately.

Anyway, let's dive right into the interesting science I have for you today!  I'm jumping the gun a bit and posting this write-up of an upcoming episode of Audiommunity for two reasons, 1.) because we actually recorded the episode many months ago but had to painstakingly reconstruct the audio because of technical issues with our recording software, and therefore I have been sitting on this write-up for quite some time, and 2.) I just think this work is so darn cool! 

In the general field of cancer research, the tissues, cells and organs directly surrounding tumors are referred to as the tumor "microenvironment", and understandably is a hot area of study.  Having a good grasp on what the non-tumor "bystander" cells are doing near the tumor helps researchers develop better-targeted therapies (ie turning the immune system against the tumor, à la immunotherapy).  But what is less well understood is whether or not tumors have any systemic effects on organs and tissues more distant from the primary cancer site, and whether those distant tissues may in turn influence the tumors growth and behavior.  

To get at this question, Audiommunity's very own Camilla Engblom, along with coauthor Christine Pfirschke, and a large team directed by Mikael Pittet at Mass General Hospital in Boston, investigated a specific type of lung cancer called lung adenocarcinoma and discovered that, remarkably, the tumors "talk" to cells in the bone marrow (in mice).  The result of this cross-talk is the trafficking of cells to the lungs that promote tumor growth and spread.  This work was published in the journal Science last December as a paper entitled "Osteoblasts remotely supply lung tumors with cancer-promoting  SiglecFhigh neutrophils".  

So how did they make this important discovery?  It began with a simple observation that mice with lung tumors had increased bone density and bone formation activity.  They pinned that activity down to cells called osteoblasts, the cells in the bone marrow responsible for building new bone.  To test the connection between the lung tumors and osteoblasts, they created a mouse model in which the osteoblasts were fluorescently labeled (so they could be tracked) and were able to be depleted in the mouse upon injection of diphtheria toxin.  When they knocked down the osteoblasts in mice with lung tumors, they found that over time the tumors were reduced in size and number.  

How were these bone marrow-resident osteoblasts having an impact on tumors all the way in the lung?  The researchers hypothesized that the osteoblasts must be supplying the tumor microenvironment with tumor-promoting cells.  When they looked at the type and amount of immune cell infiltrates in the lung, they found that knocking out osteoblasts resulted in a two-fold decrease of neutrophils.  Coming at it another way, if they knocked down neutrophils using an antibody without knocking down osteoblasts, they saw a large reduction in tumor volume.

These results weren't associated with all neutrophils, but specifically a population of tumor-promoting neutrophils with high levels of a lectin called SiglecF on their surface.  These SiglecF(high) neutrophils were pretty rare in normal, healthy lung tissue, but were increased 70-fold in mice with lung tumors!  Differential gene expression comparing SiglecF(high) neutrophils to SiglecF(low) neutrophils showed the SiglecF(high) cells expressed genes associated with tumor-promoting functions, such as angiogenesis, myeloid cell differentiation and recruitment, extracellular matrix remodeling, suppression of T cell responses, and tumor cell proliferations and growth, among other things (yikes!).  Additionally, when SiglecF(high) and (low) neutrophils were isolated from mice, mixed with lung tumor cells ex vivo, and then injected into new mice, tumor growth was accelerated in the mice that were injected with the SiglecF(high) neutrophil tumor preparations.  So, clearly, SiglecF(high) neutrophils= bad news.

The final piece of the puzzle is figuring out how the tumor cells are communicating with osteoblasts in the bone marrow.  A look at the serum from mice with and without tumors identified a candidate factor called RAGE (receptor for advanced glycation end products) that was upregulated about two-fold in the tumor-bearing mice. RAGE, as well as the circulating form of this receptor called sRAGE, have previously been shown to be connected with bone activity and regulation.  In good agreement with this, when they added sRAGE to the serum of tumor-free mice, they saw increased osteoblast activity and increased bone marrow neutrophil maturation.  While this part of the study will require more work to pin down, it all hangs together very nicely so far.

To summarize, lung tumor cells "talk" to bone marrow osteoblasts (possibly through a circulating factor called sRAGE), which then send tumor-promoting neutrophils to the sites of lung tumors.  So what is the takeaway from this work?  First, that osteoblast cell activity and SiglecF(high) neutrophils may be useful biomarkers in human patients, and possibly even good targets for cancer therapies.  And second, and perhaps more importantly, that it is critical to consider the entire body when studying cancer because cancer is a systemic disease!

Nice work Camilla et al!  Now please enjoy this cartoon!

Hmm, this call seems legit...


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