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Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis

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Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis Author Manuscript Published OnlineFirst on June 26, 2018; DOI: 10.1158/1078-0432.CCR-18-0329 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Endoglin expression on cancer-associated fibroblasts regulates invasion and stimulates colorectal cancer metastasis Madelon Paauwe1,2,3, Mark J.A. Schoonderwoerd2#, Roxan F.C.P. Helderman2#, Tom. J. Harryvan2, Arwin Groenewoud4, Gabi W. van Pelt5, Rosalie Bor1,2, Danielle M. Hemmer1, Henri H. Versteeg3, B. Ewa Snaar-Jagalska4, Charles P. Theuer6, James C.H. Hardwick2, Cornelis F.M. Sier5, Peter ten Dijke1,7, Lukas J.A.C. Hawinkels1,2* Departments of 1Molecular Cell Biology and Cancer Genomics Center Netherlands, 2Gastroenterology-Hepatology, 3Thrombosis & Hemostasis, Leiden University Medical Center, Leiden, The Netherlands, 4Institute of Biology, Leiden University, Leiden, The Netherlands, 5Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands, 6Tracon Pharmaceuticals, San Diego, CA, USA, 7Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden # Equal contribution Running title: CAF-specific endoglin expression regulates CRC invasion *Corresponding author Lukas J.A.C. Hawinkels Leiden University Medical Center, Dept. of Gastroenterology-Hepatology PO-Box 9600; post zone C4-P, 2300 RC Leiden Phone +31 71 526 6736 [email protected] Disclosures C.H. Theuer is full time employee of Tracon Pharmaceuticals. All other authors declare no conflicts of interest. 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2018; DOI: 10.1158/1078-0432.CCR-18-0329 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of relevance TRC105 is an endoglin neutralizing antibody targeting the TGF-β co-receptor endoglin and is currently being tested in clinical trials as anti-angiogenic therapy. TRC105 prevents binding of BMP-9 to endoglin, which controls (tumor)angiogenesis. In the study described here we show that endoglin is also expressed on cancer-associated fibroblasts (CAFs) and reveal a role for this receptor in CAF invasion. Treatment with TRC105 reduced invasive capacity of CAFs in vitro and metastatic spread of CRC in vivo. These results underline the potential of TRC105 to be more than a “classic anti-angiogenic drug”, targeting both the endothelium as well as CAFs, thereby limiting metastatic spread on multiple levels. Ongoing phase II and III clinical trials will further elucidate TRC105s potential anti-metastatic effects and added value for cancer patients. Abstract Purpose: Cancer-associated fibroblasts (CAFs) are a major component of the colorectal cancer (CRC) tumor microenvironment. CAFs play an important role in tumor progression and metastasis, partly through the transforming growth factor-β (TGF-β) signaling pathway. We investigated whether the TGF-β family co-receptor endoglin is involved in CAF-mediated invasion and metastasis. Experimental design: CAF-specific endoglin expression was studied in CRC resection specimens using immunohistochemistry and related to metastases-free survival. Endoglin-mediated invasion was assessed in vitro by transwell invasion, using primary CRC-derived CAFs. Effects of CAF-specific endoglin expression on tumor cell invasion were investigated in a CRC zebrafish model, while liver metastases were assessed in a mouse model. Results: CAFs specifically at invasive borders of CRC express endoglin and increased expression intensity correlated with increased disease stage. Endoglin-expressing CAFs were also detected in lymph node and liver metastases, suggesting a role in CRC metastasis formation. In stage-II CRC, CAF-specific endoglin expression at invasive borders correlated with poor metastasis-free survival. In vitro experiments revealed that endoglin is indispensable for bone morphogenetic 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2018; DOI: 10.1158/1078-0432.CCR-18-0329 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. protein (BMP)-9-induced signaling and CAF survival. Targeting endoglin using the neutralizing antibody TRC105 inhibited CAF invasion in vitro. In zebrafish, endoglin-expressing fibroblasts enhanced colorectal tumor cell infiltration into the liver and decreased survival. Finally, CAF- specific endoglin targeting with TRC105 decreased metastatic spread of CRC cells to the mouse liver. Conclusions: Endoglin-expressing CAFs contribute to CRC progression and metastasis. TRC105 Treatment inhibits CAF invasion and tumor metastasis, indicating an additional target beyond the angiogenic endothelium, possibly contributing to beneficial effects reported during clinical evaluations. Keywords Endoglin, colorectal cancer, cancer-associated fibroblasts, metastasis, TRC105 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2018; DOI: 10.1158/1078-0432.CCR-18-0329 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 8,5% of all cancer deaths1. Ninety percent of all cancer patients die from metastatic disease. Therefore, patients at risk to develop metastatic disease (stage-III/IV) are eligible for (neo)adjuvant (chemo)-radiation therapy2. However, a significant proportion of patients with localized disease will still develop metastases, emphasizing that a better understanding of the mechanism underlying tumor metastasis is needed. The tumor stroma can account for ≥50% of the tumor mass and its extent is predictive for worse patient survival in CRC patients3. The tumor stroma, or tumor microenvironment (TME), is composed of endothelial cells, pericytes, immune cells and cancer-associated fibroblasts (CAFs)4. CAFs interact with all other cells in the TME via direct cell-cell contact and secretion of cytokines5, 6, thereby stimulating tumor progression and ultimately metastasis7. Therefore, CAFs are considered a potential novel target for cancer therapy. Transforming growth factor-β (TGF-β) mediates the transdifferentiation of resident fibroblasts into CAFs8, 9, as indicated by increased expression of α-smooth muscle actin (αSMA) and fibroblast activation protein (FAP)10. Endoglin is a co-receptor for TGF-β and bone morphogenetic protein (BMP)-9 that, upon ligand binding, can facilitate Smad1 phosphorylation11. Endoglin is highly expressed on the surface of activated endothelial cells and indispensable for developmental angiogenesis12-14. Furthermore, endoglin microvessel density is correlated with tumor progression and metastases in CRC15, 16. Different mutations in the endoglin gene have been reported in TCGA for CRC, although the affected cell types were not specified. The endoglin neutralizing antibody TRC105 binds human endoglin with high affinity, competitively inhibits BMP-9 binding17 and induces antibody-dependent cell-mediated cytotoxicity18, 19. Currently, TRC105 is in phase 3 clinical trials in patients with advanced cancer as anti-angiogenic therapy. Although endoglin expression on endothelial cells has been extensively studied and is the focus of targeted cancer therapy, endoglin is also expressed on other cells in the TME. Therefore, in this study we investigated the role of endoglin expression on CAFs. We show that CAFs, located specifically at invasive borders of colorectal tumors and in metastatic lesions, express endoglin. 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2018; DOI: 10.1158/1078-0432.CCR-18-0329 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. We further demonstrate that targeting endoglin on CAFs with TRC105 modulates CAF function and that endoglin regulates tumor invasiveness in zebrafish and liver metastases in vivo. Taken together, our data suggest an additional working mechanism for endoglin targeted therapy on CAFs, besides targeting the endothelium and highlights its therapeutic potential. Materials and methods Patient samples Paraffin-embedded tissue samples were obtained from the Department of Pathology, Leiden University Medical Center (LUMC), used according to the guidelines of the Medical Ethical Committee of the LUMC and conducted in accordance to the Declaration of Helsinki and the Code of Conduct for responsible use of Human Tissue and Medical Research as drawn up by the Federation of Dutch Medical Societies in 2011. This Code permits the further use of coded residual (historical) tissue and data from the diagnostic process for scientific purposes. Permission is granted by implementing an opt-out procedure for the patients, written informed consent is in that case not needed. The first cohort consisted of 25 adenomas, 140 stage-II and 94 stage-III tumors from treatment naive CRC patients and the same number of adjacent normal tissue samples. Patient characteristics have been included as Supplementary table S1). The second cohort consisted of 31 patients of which resection specimens of the primary tumor, lymph node
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