Oscillatory Hypoxia Can Induce Senescence of Adipose-Derived Mesenchymal Stromal Cells Potentiating Invasive Transformation of Breast Epithelial Cells

Sep 21, 2026

Obesity is strongly linked to breast cancer occurrence, metastasis, and therapy resistance, and breast tumors often contain abundant adipose tissue within a hypoxic microenvironment. This study shows that adipose tissue-derived mesenchymal stromal cells (ASCs) can be recruited by hypoxia and promote metastatic transition. Using a high-sensitivity nanopatterned invasion assay and RNA sequencing, the work demonstrates that ASCs increase invasion and migration, and that fluctuating/oscillating hypoxia induces ASC senescence, further elevating invasive potential in conditioned epithelial cells.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Tumor microenvironment and stromal control

Obesity, adipose content, and hypoxia

Hypoxia-driven recruitment of ASCs

cancers Article Oscillatory Hypoxia Can Induce Senescence of Adipose-Derived Mesenchymal Stromal Cells Potentiating Invasive Transformation of Breast Epithelial Cells Ashkan Novin 1,2, Khadija Wali 1, Aditya Pant 1, Shaofei Liu 1, Wenqiang Du 2, Yamin Liu 2, Lichao Wang 3, Ming Xu 3,4, Binsheng Wang 4, Yasir Suhail 1,2 and Kshitiz 1,2,5, * 1 Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA; [novin@uconn.edu](novin@uconn.edu) (A.N.); [wali@uchc.edu](wali@uchc.edu) (K.W.); [pant_aditya@yahoo.com](pant_aditya@yahoo.com) (A.P.); [shaofei.liu_sr@uconn.edu](shaofei.liu_sr@uconn.edu) (S.L.); [yasir.suhail@uconn.edu](yasir.suhail@uconn.edu) (Y.S.) 2 Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA; [wdu@uchc.edu](wdu@uchc.edu) (W.D.); [yamin.liu@uconn.edu](yamin.liu@uconn.edu) (Y.L.) 3 Department of Immunology, University of Connecticut Health, Farmington, CT 06032, USA; [licwang@uchc.edu](licwang@uchc.edu) (L.W.); [mixu@uchc.edu](mixu@uchc.edu) (M.X.) 4 Center for Aging Research, University of Connecticut Health, Farmington, CT 06032, USA; [binwang@uchc.edu](binwang@uchc.edu) 5 NEAG Comprehensive Cancer Center, University of Connecticut Health, Farmington, CT 06032, USA * Correspondence: [kshitiz@uchc.edu](kshitiz@uchc.edu) Citation: Novin, A.; Wali, K.; Pant, A.; Liu, S.; Du, W.; Liu, Y.; Wang, L.; Xu, M.; Wang, B.; Suhail, Y.; et al. Oscillatory Hypoxia Can Induce Senescence of Adipose-Derived Mesenchymal Stromal Cells Potentiating Invasive Transformation of Breast Epithelial Cells. Cancers 2024, 16, 969. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers16050969 Academic Editors: Stephan Joel Reshkin and Rosa Angela Cardone Received: 1 January 2024 Revised: 20 February 2024 Accepted: 23 February 2024 Published: 28 February 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . Simple Summary: Obesity is associated with increased occurrence and metastasis of breast cancer. Breast cancers are also very hypoxic and rich in adipose (fat) tissue. We found that adipocyte-derived stromal cells (ASCs) can transform normal breast epithelial cells to become invasive, potentiating them toward a cancerous state. We also found that unstable or fluctuating hypoxia, which is common in the tumor environment, can cause ASCs to become senescent, with an additive effect on breast epithelial potentiation to an invasive state. Abstract: Obesity is strongly associated with occurrence, metastasis, and resistance to therapy in breast cancers, which also exhibit high adipose content in the tumor microenvironment. Adipose tissue-derived mesenchymal stromal cells (ASCs) are recruited to breast cancer by many mechanisms, including hypoxia, and contribute to metastatic transition of the cancer. Breast cancers are characterized by regions of hypoxia, which can be temporally unstable owing to a mismatch between oxygen supply and consumption. Using a high-sensitivity nanopatterned stromal invasion assay, we found that ASCs could promote stromal invasion of not only breast cancer cell lines but also MCF10A1, a cell line derived from untransformed breast epithelium. RNA sequencing of MCF10A1 cells conditioned with medium from ASCs revealed upregulation of genes associated with increased cell migration, chemotaxis, and metastasis. Furthermore, we found that fluctuating or oscillating hypoxia could induce senescence in ASCs, which could result in an increased invasive potential in the treated MCF10A1 cells. These findings highlight the complex interplay within the breast cancer microenvironment, hypoxia

FAQs

How does oscillatory or fluctuating hypoxia affect adipose-derived stromal cells?

Fluctuating/oscillating hypoxia can induce senescence in adipose-derived mesenchymal stromal cells (ASCs). This senescence contributes to increased invasive potential in treated epithelial cells.

What role do ASCs play in breast cancer progression described in the study?

ASCs are recruited to breast cancer, including to hypoxic regions, and they promote stromal invasion and metastatic transition. They also can potentiate transformation toward an invasive phenotype.

Which experimental approaches support the findings?

A high-sensitivity nanopatterned stromal invasion assay was used to assess invasion changes, and RNA sequencing of conditioned MCF10A1 cells identified gene upregulation linked to migration, chemotaxis, and metastasis.

Sep 21, 2026

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