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Engineered Therapeutics to Reprogram the Tumour Microenvironment

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The cellular and noncellular components of the tumour microenvironment (TME) control cancer cell differentiation, proliferation, invasion, and metastasis. Cells within the TME such as cancer-associated fibroblasts (CAFs), tumour-associated macrophages (TAMs), and other immune cells secrete factors that interact with cancer cells and stimulate their proliferation and migration. These factors also negatively affect the therapeutic outcome of anti-cancer therapies. Our research goal is to develop engineered therapeutics which can target and reprogram specific cells of the TME in order to reverse their pro-tumourigenic and pro-metastatic activity. In the past years, we have focused on CAFs and TAMs as key target cells within the TME . CAFs are the prominent cell type responsible for inducing desmoplasia (fibrosis) by producing abundant extracellular matrix (ECM) components. Pancreatic cancer is one the deadliest cancer type which is characterized with enormous fibrosis. This fibrotic tissue acts as a physical barrier for the penetration of anti-cancer therapies into the tumour. We have identified ITGA5 , a fibronectin receptor, overexpressed on CAFs in human pancreatic tumours and contribute to fibrogenesis and ECM remodeling. To block the ITGA5 receptor, we designed engineered therapeutic peptides which showed reduced activation of CAFs and the ECM production. In vivo, these peptides reduced desmoplasia (collagen deposition) and thereby enhanced the efficacy of gemcitabine in different mouse tumour xenograft and genetically-engineered KPC mouse tumour model. Recently, in another study, we have developed engineered “tail-flipping” liposomes to target and re-program TAMs to induce anti-cancer effects. We introduced a phospholipid (PAPC) into liposomes which could flip the charged hydrophilic tail to the liposome surface and engage with scavenger receptors overexpressed on TAMs. Furthermore, we delivered a peptidoglycan, a component of bacterial cell wall, to TAMs using these liposomes and thereby re-program TAMs into anti-tumoural phenotype in vivo. Altogether, these studies show that re-programming of specific cells within the TME using engineered therapeutics is a vital approach to treat hard-to-treat cancer types.

References:

1. Heinrich MA, Mostafa A.M.R.H, Morton J, Hawinkels L.W.M.M., Prakash J. (2021) Mimicking complexity and heterogeneity of pancreatic cancer: 3D in vitro to in vivo models. Advanced Drug Delivery Review 174, 265-293.

2. Kuninty PR, Bansal R, De Geus G, Mardhian DF, Schnittert J, van Baarlen J, Storm G, Bijlsma M, van Laarhoven H, Metselaar JM, Kuppen PJK , Vahrmeijer A, Ostman A, Sier CFM , Prakash J. (2019) ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer. Science Advances Sep 4;5(9):eaax2770. doi: 10.1126/sciadv.aax2770.

3. Kuninty PR, Binnemars-Postma KA, Jarray A, Heinrich MA, Pednekar K, ten Hoopen H, Storm G, van Hoogevest P, den Otter WK, Prakash J. (2022) Cancer immune therapy using engineered ‛tail-flipping’ nanoliposomes targeting alternatively activated macrophages. Nature Communications (in press)

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