Modulation of Early Neutrophil Granulation: The Circulating Tumor Cell-Extravesicular Connection in Pancreatic Ductal Adenocarcinoma

Harrys Kishore Charles Jacob; John Lalith Charles Richard; Rossana Signorelli; Tyler Kashuv; Shweta Lavania; Utpreksha Vaish; Ranjitha Boopathy; Ashley Middleton; Melinda Minucci Boone; Ramakrishnan Sundaram; Vikas Dudeja; Ashok Kumar Saluja

doi:10.3390/cancers13112727

Modulation of Early Neutrophil Granulation: The Circulating Tumor Cell-Extravesicular Connection in Pancreatic Ductal Adenocarcinoma

Cancers (Basel). 2021 May 31;13(11):2727. doi: 10.3390/cancers13112727.

Authors

Harrys Kishore Charles Jacob^{1

2}, John Lalith Charles Richard³, Rossana Signorelli⁴, Tyler Kashuv⁵, Shweta Lavania^{1

2}, Utpreksha Vaish⁶, Ranjitha Boopathy⁷, Ashley Middleton^{1

2}, Melinda Minucci Boone⁸, Ramakrishnan Sundaram^{1

2}, Vikas Dudeja^{1

2

7}, Ashok Kumar Saluja^{1

2}

Affiliations

¹ Departments of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
² Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
³ School of Biosciences, Engineering and Technology (SBET), VIT Bhopal University, Madhya Pradesh 466114, India.
⁴ Department of Biology, University of Miami, Miami, FL 33146, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33146, USA.
⁶ Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
⁷ Department of Life Sciences, Shiv Nadar University, Greater Noida 201304, India.
⁸ Biospecimen Shared Resource, University of Miami, Miami, FL 33136, USA.

Abstract

Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tumor cells, CTCs) either alone or as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell-cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tissue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on companion cells in clusters.

Keywords: circulating tumor cells; clusters; extracellular vesicles; granule mobilization; neutrophil degranulation; pancreatic cancer; reteplase activity.