A vascular-restricted, tumor-induced neutrophil population drives vascular occlusion, pleomorphic necrosis and metastasis

Jose Adrover Montemayor, PhD
Postdoctoral fellow
Cold Spring Harbor Laboratory
Cold Spring Harbor, NY, USA

This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS3), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

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In person : 
IRCM Auditorium
110, avenue des Pins O, H2W 1R7 Montreal

Online :
Zoom link : https://zoom.us/j/95269762104
ID : 952 6976 2104
Code : 476372

IRCM conferences are set to occur under a hybrid format. However, please note that last-minute changes to online-only lectures may occur due to unforeseen circumstances. We invite you to visit this webpage again a few days before attending.

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About this conference : 
The presence of necrosis in the primary tumor is associated with poor prognosis in cancer, but is considered a passive process, occurring when tumor growth outpaces nutrient supply. Here we report that it can be actively driven by a neutrophil subpopulation present in tumor-bearing mice and patients with cancer. Using tissue clearing to evaluate the three-dimensional architecture of tumors, we identified mouse models of cancer with either 1) a classical central necrotic core or 2) a novel pleomorphic necrotic architecture. Since the pleomorphic necrotic structures were reminiscent of the tumor vascular bed, we hypothesized that they could be actively caused by vascular occlusion. Indeed, we found that blood flow was interrupted by intravascular neutrophil aggregates associated with neutrophil extracellular traps (NETs) in the models showing pleomorphic necrosis. Genetic and pharmacological inhibition of NET-formation reduced neutrophil intravascular aggregation and necrosis in the primary tumors, and reduced metastasis to the lungs. We found that the tumors showing pleomorphic necrosis elicited changes in the hematopoietic compartment, inducing a myeloid skew in hematopoietic stem and progenitor cells. This led, in mice bearing tumors with pleomorphic necrosis, to the appearance of a novel Ly6Ghigh Ly6Clow neutrophil subpopulation. Compared to Ly6Chigh, the Ly6Clow neutrophils exhibited increased NET formation and, interestingly, the inability to extravasate in response to inflammatory challenges. Here, we show that pleomorphic tumor necrosis is caused by a vascular-restricted, tumor-induced neutrophil subpopulation, and that it can be targeted to reduce metastatic spread.

About Jose M. Adrover : 
Dr. Jose M. Adrover earned his PhD in Biochemistry, Molecular Biology and Biomedicine at the Spanish National Cardiovascular Research Centre (CNIC) in Madrid, under the supervision of Dr. Andrés Hidalgo. He then pursued his postdoctoral training in the lab of Dr. Mikala Egeblad, at Cold Spring Harbor Laboratory (CSHL). He investigates the vascular-immune interplay in the tumor microenvironment and the role of spontaneous tumor necrosis in metastatic spread. His work has been published in some of the most several prestigious journals, such as Nature, Cancer Cell, Immunity, and Journal of Experimental Medicine, and even features on the cover of certain editions.

Interview with Dr. Jose M. Adrover

Question

Please tell us about your career path, leading up to your application to the Early-Career Scientist Seminar Series

Réponse | Answer 

“I did my PhD in the Hidalgo lab at the Spanish National Centre for Cardiovascular Research (CNIC) in Madrid. My work revolved around the circadian control of neutrophil biology. In two main publications, we described that the neutrophil transcriptomic and proteomic profile, phenotype and effector functions are controlled by the core clock machinery in a circadian fashion. We defined the process of "neutrophil aging" that neutrophils undergo in the short course of their lifespan in circulation. This process synchronizes the periods of activity (when pathogen encounter is more likely) with the maximum immune-readiness of fresh neutrophils. During the resting periods, this process ensures the clearance of aged neutrophils out of the bloodstream while reducing their pro-inflammatory properties. We found that these circadian changes in neutrophils underlie diurnal variation in disease outcome in several disease models, including sepsis, acute lung injury, myocardial infarction, or stroke. 

I then moved to the Egeblad lab at Cold Spring Harbor Laboratory (CSHL) in New York to continue my postdoctoral training and study the role of the innate immune system in cancer biology, with the basic underlying idea that cancer is a systemic disease, and that the presence of the tumor has systemic effects. I’m focusing on tumor necrosis, as it known in the clinical practice that patients with necrotic tumors have much worse prognosis and increased metastasis. So, we are working on understanding how tumor necrosis is initiated. We found that the primary tumor – bone marrow hematopoietic interplay is critical for the appearance of a novel neutrophil population that has the unexpected property of being unable to extravasate in response to inflammatory stimuli, while having increased ability to form neutrophil extracellular traps (NETs). We found this population aggregates and form NETs in the tumor microvasculature, causing blood flow blockade, downstream hypoxia and necrosis of the vascular bed. This, in turn, establishes a high selective pressure in tumor cells in peri-necrotic regions which drives the grain of pro-metastatic traits. Finally, against the common belief that necrosis is a passive phenomenon stemming from the quick growth rate of tumors, we found that inhibiting NETs can completely abrogate the presence of necrosis in tumors, secondarily reducing their metastatic spread.”

Question

Please tell us about your passion for research. What motivates you most about your work? What do you hope to accomplish as a scientist?

Réponse | Answer 

“I'm broadly interested in the role of the innate immune system in the steady state and in inflammatory conditions. In particular, I'm interested by the interplay between neutrophils and the vascular compartment, as many highly prevalent diseases, including cardiovascular diseases and cancer, have a clear vascular involvement. From the basic biology perspective, I’m very intrigued by the properties and functions of neutrophils, especially their short half-life, which forces the organism to devote a huge amount of resources to continuously produce neutrophils (2/3rds of the whole hematopoietic effort are devoted to produce neutrophils), just to dispose of them after 12h in circulation. I also focus on the innate immune system as I believe that it will help us find commonalities in several disease models, and cancer types. For instance, NETs play a prominent role in cardiovascular disease (myocardial infarction, stroke, atherosclerosis) but also on acute lung injuries (such as TRALI or ARDS), and cancer (to name a few). In cancer, the huge success of immunotherapy is still limited by the very precise nature of its effector cells. On the other hand, we found that targeting NETs in the vascular compartment can reduce necrosis (and metastatic spread) in breast, lung, colorectal and skin cancers. That is, the fact that the innate immune system is less precise can, potentially, help us find therapeutic options that could help patients more broadly. So, my goal is to stay in academia and pursue this venue in an independent position.”
 

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