Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer

Buschhaus, Johanna M.; Rajendran, Shrila; Humphries, Brock A.; Cutter, Alyssa C.; Muniz, Ayse; Ciavattone, Nicholas; Buschhaus, Alexander; Cañeque, Tatiana; Nwosu, Zeribe C.; Sahoo, Debashis; Bevoor, Avinash S.; Shah, Yatrik M.; Lyssiotis, Costas A.; Ghosh, Pradipta; Wicha, Max S.; Rodriguez, Raphaël; Luker, Gary D.

doi:10.1038/s41388-022-02385-9

Cited by 23 publications

(18 citation statements)

References 61 publications

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“…Estrogen has been proved to be effective in preventing postoperative re-adhesion, restoring menstruation, and improving endometrial thickness in patients with injured endometrium [ 26 ]. Exogenous estrogen plays an important role in promoting the differentiation of endometrial basal stem cells during IUA treatment [ 27 ]. Our previous study have demonstrated that estrogen may prevent the occurrence and development of IUA by inhibiting the TGF-β1 induced EMT and activating the Wnt/β-catenin pathway [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells combined with estrogen synergistically promote endometrial regeneration and reverse EMT via Wnt/β-catenin signaling pathway

Lei

Cao

et al. 2022

Reprod Biol Endocrinol

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Background Intrauterine adhesion (IUA) is a clinical disease characterized by the uterine cavity occlusion caused by the damage of the endometrial basal layer. Bone marrow mesenchymal stem cells (BMSCs) transplantation have the potential to promote endometrial regeneration mainly through paracrine ability. Estrogen is an indispensable and important factor in the repair of endometrial damage, which has been reported as a promising and adjunctive therapeutic application for stem cell transplantation therapy. This study aims to investigate the synergistic effect of BMSCs and estrogen on improving the endometrial regeneration and restoring the endometrium morphology in a dual damage model of IUA in rabbits and the underlying molecular mechanisms. Methods BMSCs were isolated and identified by adipogenic and osteogenic differentiation and flow cytometry assays. The rabbit IUA animal model was established by a dual damage method of mechanical curettage and lipopolysaccharide infection. Additionally, we investigated the therapeutic impact of both BMSCs and estrogen either separately or in combination in a rabbit model. The retention of PKH26-labeled BMSCs was observed by vivo fluorescence imaging.The number of endometrial glands and the degree of fibrosis were observed by H&E and Masson staining respectively. Western blotting, Immunohistochemistry and immunofluorescence staining were performed to detect biomarkers related to endometrial epithelium, endometrial fibrosis and EMT. Finally, the protein expression of core molecules of Wnt/β-catenin pathway was detected by Western blotting. Results PKH26-labeled fluorescence results revealed that BMSCs appeared and located in the endometrial glands and extracellular matrix area when orthotopic transplanted into the uterine cavity. Histological assays showed that remarkably increasing the number of endometrial glands and decreasing the area of endometrial fibrosis in the BMSCs combined with estrogen treatment group. Moreover, downregulated expression of fibrosis markers (fibronectin, CollagenI, a-SMA) and interstitial markers (ZEB1, Vimentin, N-cadherin), as well as upregulated E-cadherin expression were found in the combined group. Further study of in vivo staining revealed that fluorescence intensity of CK7 was stronger in the combined group than that of direct BMSCs intrauterine transplantation, while vimentin showed the opposite results. Moreover, the protein levels of β-catenin, Axin2, C-myc, CycinE of Wnt/β-catenin signaling pathway increased in the BMSCs combined with estrogen group than in the other treatment groups. Conclusion BMSCs combined with estrogen can promote the differentiation of stem cells into endometrial epithelial cells to facilitate the regeneration of damaged endometrium. The potential mechanism of the synergistic effect may inhibit the occurrence of EMT by activating the Wnt/β-catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells combined with estrogen synergistically promote endometrial regeneration and reverse EMT via Wnt/β-catenin signaling pathway

Lei

Cao

et al. 2022

Reprod Biol Endocrinol

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“…Heat maps display the differential expression of these genes ( Fig 6E, F ). Of the tumor intrinsic gene response, we previously discovered that co-culture with MSCs upregulated LCN2, an iron sequestering protein, and CD44, a marker of stem-like cells, in breast cancer cells (15). Pathway analysis of the 32-gene borrowed signature recapitulated by stable expression of GIV alone showed enrichment for numerous processes related to response to external stimuli, while the 17-gene signature included vesicular transport and exocytosis ( Supplemental Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

“…We separated cancer cells from stromal cells with human EpCAM (CD326) immunomagnetic beads (#130-061-101, Miltenyi, Auburn, California, USA) for RNA sequencing as described previously (15). We deposited RNA sequencing data to GEO under accession number GSE224322.…”

Section: Rna Sequencing and Differentially Expressed Gene (Deg) Analysismentioning

confidence: 99%

Breast Cancers That Disseminate to Bone Marrow Acquire Aggressive Phenotypes through CX43-related Tumor-Stroma Tunnels

Sinha

Callow

Farfel

et al. 2023

Preprint

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Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Induced genes and proteins in cancer cells, some borrowed and others tumor-intrinsic, were not recapitulated merely by conditioned media from MSCs. Protein-protein interaction networks revealed the rich connectome between ′borrowed′ and ′intrinsic′ components. Bioinformatic approaches prioritized one of the ′borrowed′ components, CCDC88A/GIV, a multi-modular metastasis-related protein which has recently been implicated in driving one of the hallmarks of cancers, i.e., growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced ~20% of both the ′borrowed′ and the ′intrinsic′ gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

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“…We performed cytotoxicity assays on MCF7 cells as described previously( 66 ). Briefly, we seeded 7.5 × 10 3 MCF7 WT or MCF7-GIV cells per well in black wall 96 well plates (ThermoFisher Scientific, catalog number 165305).…”

Section: Methodsmentioning

confidence: 99%

Growth Signaling Autonomy in Circulating Tumor Cells Aids Metastatic Seeding

Sinha

Farfel

Luker

et al. 2022

Preprint

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Self-sufficiency (autonomy) in growth signaling, the earliest recognized hallmark of cancer, is fuelled by the tumor cells ability to secrete-and-sense growth factors; this translates into cell survival and proliferation that is self-sustained by auto-/paracrine secretion. Using breast cancer cells that are either endowed or impaired in growth signaling autonomy, here we reveal how autonomy impacts cancer progression. Autonomy is associated with enhanced molecular programs for stemness, immune evasiveness, proliferation, and epithelial-mesenchymal plasticity (EMP). Autonomy is both necessary and sufficient for anchorage-independent growth factor-restricted proliferation and resistance to anti-cancer drugs and is required for metastatic progression. Transcriptomic and proteomic studies show that autonomy is associated with self-sustained EGFR/ErbB signaling. A gene expression signature is derived (a.k.a., autonomy signature) which revealed that autonomy is induced in circulating tumor cells (CTCs) and particularly CTC clusters, the latter of which carry higher metastatic potential. Autonomy in CTCs tracks therapeutic response and prognosticates outcome. Autonomy is preserved during reversible (but not stable) epithelial-mesenchymal transition (EMT). These data support a role for growth signaling autonomy in multiple processes essential for the blood-borne dissemination of human breast cancer.

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Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer

Cited by 23 publications

References 61 publications

Bone marrow mesenchymal stem cells combined with estrogen synergistically promote endometrial regeneration and reverse EMT via Wnt/β-catenin signaling pathway

Bone marrow mesenchymal stem cells combined with estrogen synergistically promote endometrial regeneration and reverse EMT via Wnt/β-catenin signaling pathway

Breast Cancers That Disseminate to Bone Marrow Acquire Aggressive Phenotypes through CX43-related Tumor-Stroma Tunnels

Growth Signaling Autonomy in Circulating Tumor Cells Aids Metastatic Seeding

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