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P4HA2: A link between tumor-intrinsic hypoxia, partial EMT and collective migration

Aggarwal, V and Sahoo, S and Donnenberg, VS and Chakraborty, P and Jolly, MK and Sant, S (2022) P4HA2: A link between tumor-intrinsic hypoxia, partial EMT and collective migration. In: Advances in Cancer Biology - Metastasis, 5 .

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Official URL: https://doi.org/10.1016/j.adcanc.2022.100057


Epithelial-to-mesenchymal transition (EMT), a well-established phenomenon studied across pan-cancer types, has long been known to be a major player in driving tumor invasion and metastasis. Recent studies have highlighted the importance of partial EMT phenotypes in metastasis. Initially thought as a transitional state between epithelial and mesenchymal phenotypic states, partial EMT state is now widely recognized as a key driver of intra-tumoral heterogeneity and phenotypic plasticity, further accelerating tumor metastasis and therapeutic resistance. However, how tumor microenvironment regulates partial EMT phenotypes remains unclear. We have developed unique size-controlled three-dimensional microtumor models that recapitulate tumor-intrinsic hypoxia and the emergence of collectively migrating cells. In this study, we further interrogate these microtumor models to understand how tumor-intrinsic hypoxia regulates partial EMT and collective migration in hypoxic large microtumors fabricated from T47D breast cancer cells. We compared global gene expression profiles of hypoxic, migratory microtumors to that of non-hypoxic, non-migratory microtumors at early and late time-points. Using our microtumor models, we identified unique gene signatures for tumor-intrinsic hypoxia (early versus late), partial EMT and migration (pre-migratory versus migratory phenotype). Through differential gene expression analysis between the microtumor models with an overlap of hypoxia, partial EMT and migration signatures, we identified prolyl 4-hydroxylase subunit 2 (P4HA2), a hypoxia responsive gene, as a central regulator common to hypoxia, partial EMT and collective migration. Further, the inhibition of P4HA2 significantly blocked collective migration in hypoxic microtumors. Thus, using the integrated computational-experimental analysis, we identify the key role of P4HA2 in tumor-intrinsic hypoxia-driven partial EMT and collective migration. © 2022 The Author(s)

Item Type: Journal Article
Publication: Advances in Cancer Biology - Metastasis
Publisher: Elsevier Inc.
Additional Information: The copyright of this article belongs to the Authors.
Keywords: 3D microtumor models; Collective migration; P4HA2; Partial EMT; Tumor microenvironment; Tumor-intrinsic hypoxia
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 12 Mar 2023 06:17
Last Modified: 12 Mar 2023 06:17
URI: https://eprints.iisc.ac.in/id/eprint/80960

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