Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers

Horst, Ben; Pradhan, Shrikant; Chaudhary, Roohi; Listik, Eduardo; Quintero-Macias, Liz; Choi, Alex Seok; Southard, Michael; Liu, Yingmiao; Whitaker, Regina S.; Hempel, Nadine; Berchuck, Andrew; Nixon, Andrew B.; Lee, Nam Y.; Henis, Yoav I.; Mythreye, Karthikeyan

doi:10.1038/s42003-022-03495-6

Cited by 11 publications

(10 citation statements)

References 77 publications

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“…Inhibins belong to the TGF-beta family and is comprised of a functional heterodimer with an alpha- and a beta-subunit. Inhibin promotes angiogenesis through TGF-beta receptors (116) and increases vascular permeability through internalization of VE-cadherin (117). Under hypoxic conditions, Inhibin expression is modulated HIF-1a and HIF-2a (118).…”

Section: Discussionmentioning

confidence: 99%

Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

Cantu

Gutierrez

Dong

et al. 2022

Preprint

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Exposure to supraphysiological concentrations of oxygen (hyperoxia) predisposes to bronchopulmonary dysplasia (BPD), which is characterized by abnormal alveolarization and pulmonary vascular development, in preterm neonates. Neonatal hyperoxia exposure is used to recapitulate the phenotype of human BPD in murine models. Male sex is considered an independent predictor for the development of BPD, but the main mechanisms underlying sexually dimorphic outcomes are unknown. Our objective was to investigate sex-specific and cell-type specific transcriptional changes that drive injury in the neonatal lung exposed to hyperoxia at single-cell resolution and delineate the changes in cell-cell communication networks in the developing lung. We used single cell RNA sequencing (scRNAseq) to generate transcriptional profiles of >35000 cells isolated from the lungs of neonatal male and female C57BL/6 mice exposed to 95% FiO2 between PND1-5 (saccular stage of lung development) or normoxia and euthanized at PND7 (alveolar stage of lung development). ScRNAseq identified 22 cell clusters with distinct populations of endothelial, epithelial, mesenchymal, and immune cells. Our data identified that the distal lung vascular endothelium (composed of aerocytes and general capillary endothelial cells) is exquisitely sensitive to hyperoxia exposure with the emergence of an intermediate capillary endothelial population with both aCaP and gCaP markers. We also identified a myeloid derived suppressor cell population from the lung neutrophils. Sexual dimorphism was evident in all lung cell subpopulations but was striking among the lung immune cells. Finally, we identified that the specific intercellular communication networks and the ligand-receptor pairs that are impacted by neonatal hyperoxia exposure.

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Section: Discussionmentioning

confidence: 99%

Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

Cantu

Gutierrez

Dong

et al. 2022

Preprint

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“…Within 12 hours, CA-MSCs and TCs readily formed tunneling nanotubes (TNTs), suggesting that physical contact via TNTs is a significant interaction between CA-MSCs and TCs (Fig 2A). Previous studies have shown that MSCs use TNTs to donate mitochondria to adjacent cells in times of ischemic and metabolic stress 20,21,22,23,25 , which are similar conditions to the hypoxemia and nutrient scarcity of the ovarian tumor microenvironment [24][25][26][27][28][29][30][31][32][33][34][35][36] . To investigate if CA-MSCs donate mitochondria to adjacent ovarian tumor cells via physical interaction, we repeated the IncuCyte experiment along with a red actin stain to highlight TNT formation.…”

Section: Ca-mscs Transfer Mitochondria To Adjacent Tumor Cellsmentioning

confidence: 99%

“…We found that TCs cocultured 1:1 with CA-MSCs under non-adherent conditions exhibited a two-to-four-fold increase in mitochondrial transfer compared to cocultures in standard adherent conditions (Fig2D). Given that MSCs have been shown to donate mitochondria under ischemic stress to cardiomyocytes 20,21,22,23 and that the ovarian tumor microenvironment is hypoxic [24][25][26][27][28][29][30][31][32][33][34][35][36] , we also tested if hypoxia influenced CA-MSC mitochondrial transfer. CA-MSCs and TCs were grown under non-adherent conditions in normoxic (21% O2) or hypoxic (1% O2) conditions.…”

Section: Ca-mscs Transfer Mitochondria To Adjacent Tumor Cellsmentioning

confidence: 99%

“…6 This mitochondrial transfer occurs via physical interaction between the cancer and immune cells, mirroring the heterocellular complexes that form between CA-MSCs and ovarian cancer cells. The ovarian tumor microenvironment is notoriously hypoxic and depleted of nutrients [24][25][26][27][28][29][30][31][32][33][34][35][36] . We thus hypothesized that CA-MSCs donate mitochondria to ovarian cancer cells to overcome this stress, enhancing tumor cell heterogeneity and metastasis.…”

Section: Introductionmentioning

confidence: 99%

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Carcinoma associated mesenchymal stem cells promote ovarian cancer metastasis by increasing tumor heterogeneity through direct mitochondrial transfer

Pressimone

Frisbie

Dyer

et al. 2022

Preprint

Self Cite

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Ovarian cancer is characterized by early, diffuse metastatic spread with most women presenting with extensive abdominal metastasis at the time of diagnosis. Prior work demonstrated carcinoma-associated mesenchymal stem cells (CA-MSCs) enhance ovarian cancer metastasis through a process of direct cellular interaction and formation of heterocellular CA-MSC and tumor cell complexes. In this study, we demonstrated that CA-MSCs enhance metastasis by increasing tumor cell heterogeneity through mitochondrial donation. We showed that CA-MSCs directly interacted with ovarian cancer cells via tunneling nanotubules (TNTs), and CA-MSCs used these TNTs to transfer live mitochondria to adjacent ovarian cancer cells. This mitochondrial donation preferentially occurred with ovarian cancer cells that had the lowest mitochondrial mass, as quantified using live, actively respiring mitochondrial labeling. These mito poor cancer cells demonstrated decreased proliferation, increased sensitivity to chemotherapy, and decreased oxidative phosphorylation compared to mito rich cancer cells. CA-MSCs rescued the phenotypes of mito poor cancer cells, restoring their proliferative capacity, increasing chemotherapy resistance, and increasing oxidative phosphorylation. We validated these findings in a fully autologous system using CA-MSCs and cancer cells derived from the same patient to prevent confounding effects of cellular response to foreign organelle/DNA. Using a knockdown of the mitochondrial motor protein, MIRO1, in CA-MSCs, we demonstrated that mitochondrial transfer is necessary for the CA-MSC-mediated rescue of mito poor cancer cells. Mitochondria of CA-MSC origin persisted in tumor cells over multiple passages. Importantly, CA-MSC mitochondrial donation occurred in vivo, significantly enhanced tumor cell heterogeneity and decreased survival in an orthotopic ovarian cancer mouse model. Collectively, this work identified CA-MSC mitochondrial transfer as a critical mediator of ovarian cancer cell survival, heterogeneity, and metastasis, and blocking CA-MSC mitochondrial transfer represents a unique therapeutic target in ovarian cancer.

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“…Mythreye Karthikeyan (Pathology & Comprehensive Cancer Center, University of Alabama, Birmingham) shared data on the role of the Activin subfamily Inhibin proteins in ovarian cancer 7 . Inhibins are either homodimers or heterodimers comprising various combinations of Inhibin-α, Inhibin-βA (InhibinA), or Inhibin-βB (InhibinB) subunits.…”

Section: Introductionmentioning

confidence: 99%

New aspects of TGF-β superfamily signaling in development and disease (2022 FASEB meeting review)

Newfeld¹,

O’Connor²

2022

Fac Rev

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The 13th Federation of American Societies for Experimental Biology (FASEB) Summer Research Conference, “TGF-β superfamily signaling in development and disease” was convened at the Grand Hotel in Malahide, Ireland in July 2022. The Transforming Growth Factor-β (TGF-β) family of secreted proteins consists of agents of intercellular communication found in all multicellular animals. Attending the meeting was a diverse group of scholars with shared interests in understanding TGF-β signaling mechanisms, normal functions, and the diseases associated with misregulation and mutation. Despite intense study over the previous 35 years, new features of TGF-β activity continue to be discovered. This meeting report offers 21 investigator-provided summaries that illustrate the breadth of the thought-provoking presentations. An emerging theme of the meeting was the power of cross-disciplinary studies, such as one combining immunology, biochemistry, and structural biology, to unravel the secrets of parasitic TGF-β mimics. Please join us at the next meeting.

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Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers

Cited by 11 publications

References 77 publications

Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

Carcinoma associated mesenchymal stem cells promote ovarian cancer metastasis by increasing tumor heterogeneity through direct mitochondrial transfer

New aspects of TGF-β superfamily signaling in development and disease (2022 FASEB meeting review)

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