TY - JOUR
T1 - Human tumor microenvironment chip evaluates the consequences of platelet extravasation and combinatorial antitumor-antiplatelet therapy in ovarian cancer
AU - Saha, Biswajit
AU - Mathur, Tanmay
AU - Tronolone, James J.
AU - Chokshi, Mithil
AU - Lokhande, Giriraj K.
AU - Selahi, Amirali
AU - Gaharwar, Akhilesh K.
AU - Afshar-Kharghan, Vahid
AU - Sood, Anil K.
AU - Bao, Gang
AU - Jain, Abhishek
N1 - Publisher Copyright:
© 2021 The Authors.
PY - 2021/7
Y1 - 2021/7
N2 - Platelets extravasate from the circulation into tumor microenvironment, enable metastasis, and confer resistance to chemotherapy in several cancers. Therefore, arresting tumor-platelet cross-talk with effective and atoxic antiplatelet agents in combination with anticancer drugs may serve as an effective cancer treatment strategy. To test this concept, we create an ovarian tumor microenvironment chip (OTME-Chip) that consists of a platelet-perfused tumor microenvironment and which recapitulates platelet extravasation and its consequences. By including gene-edited tumors and RNA sequencing, this organ-on-chip revealed that platelets and tumors interact through glycoprotein VI (GPVI) and tumor galectin-3 under shear. Last, as proof of principle of a clinical trial, we showed that a GPVI inhibitor, Revacept, impairs metastatic potential and improves chemotherapy. Since GPVI is an antithrombotic target that does not impair hemostasis, it represents a safe cancer therapeutic. We propose that OTME-Chip could be deployed to study other vascular and hematological targets in cancer.
AB - Platelets extravasate from the circulation into tumor microenvironment, enable metastasis, and confer resistance to chemotherapy in several cancers. Therefore, arresting tumor-platelet cross-talk with effective and atoxic antiplatelet agents in combination with anticancer drugs may serve as an effective cancer treatment strategy. To test this concept, we create an ovarian tumor microenvironment chip (OTME-Chip) that consists of a platelet-perfused tumor microenvironment and which recapitulates platelet extravasation and its consequences. By including gene-edited tumors and RNA sequencing, this organ-on-chip revealed that platelets and tumors interact through glycoprotein VI (GPVI) and tumor galectin-3 under shear. Last, as proof of principle of a clinical trial, we showed that a GPVI inhibitor, Revacept, impairs metastatic potential and improves chemotherapy. Since GPVI is an antithrombotic target that does not impair hemostasis, it represents a safe cancer therapeutic. We propose that OTME-Chip could be deployed to study other vascular and hematological targets in cancer.
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U2 - 10.1126/sciadv.abg5283
DO - 10.1126/sciadv.abg5283
M3 - Article
C2 - 34290095
AN - SCOPUS:85110973759
SN - 2375-2548
VL - 7
JO - Science Advances
JF - Science Advances
IS - 30
M1 - eabg5283
ER -