Overexpression of CD36 in mammary fibroblasts suppresses colony growth in breast cancer cell lines

Cheng, Qingsu; Jabbari, Kosar; Winkelmaier, Garrett; Andersen, Cody; Yaswen, Paul; Khoshdeli, Mina; Parvin, Bahram

doi:10.1016/j.bbrc.2020.03.061

Cited by 9 publications

(17 citation statements)

References 29 publications

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“…Recombinant protein activin A downregulated the CD36 expression in normal FBs; however, once activin A was removed, the CD36 expression level increased. This was an extension of earlier results that increased production of activin A by tumor cells downregulating the CD36 expression in FBs, which induces the FBs to secrete more activin A and to initiate a positive feedback loop [19]. Since downregulation of CD36 is one of the CAF markers [9], it is plausible that the tumor microenvironment can be reprogrammed by factors secreted by the CD36 + FBs to induce tumor suppression and, in turn, decrease the production of activin A per our earlier findings [19].…”

Section: Discussionsupporting

confidence: 74%

“…Motivated by the above insights, in earlier work [19], we showed that CD36 in normal primary mammary FBs is downregulated as a result of exposure to activin A; and overexpression of CD36 in FBs in cocultures with 3D colonies, either inhibits colony growth or reverses aberrant basal and lateral polarities, as a function of the breast cancer subtypes. In this study, we further investigate how the signaling from the CD36 + FBs induces growth suppression for reprogramming the microenvironment.…”

Section: Introductionmentioning

confidence: 82%

“…Hs578T Are Sensitive to the CM of CD36 + FBs MDA-MB-231, originating from a patient with adenocarcinoma pathology, represents a mesenchymal phenotype and grows along a two-dimensional plane on Matrigel [24]. Previously, we showed that coculture of CD36 + FBs with MDA-MB-231 induced growth suppression in the absence of direct epithelial-fibroblast contact in Boyden chambers [19]. Here, 3D colonies of MDA-MB-231 cells were exposed to the CM of primary normal, CD36 + , or CD36 − FBs.…”

Section: The Triple-negative Breast Cancer (Tnbc) Cell Lines Mda-mb-231 Bt-549 Andmentioning

confidence: 99%

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Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines

Jabbari

Winkelmaier

Andersen

et al. 2021

Cancers

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Reprogramming the tumor stroma is an emerging approach to circumventing the challenges of conventional cancer therapies. This strategy, however, is hampered by the lack of a specific molecular target. We previously reported that stromal fibroblasts (FBs) with high expression of CD36 could be utilized for this purpose. These studies are now expanded to identify the secreted factors responsible for tumor suppression. Methodologies included 3D colonies, fluorescent microscopy coupled with quantitative techniques, proteomics profiling, and bioinformatics analysis. The results indicated that the conditioned medium (CM) of the CD36+ FBs caused growth suppression via apoptosis in the triple-negative cell lines of MDA-MB-231, BT549, and Hs578T, but not in the ERBB2+ SKBR3. Following the bioinformatic analysis of the CM of CD36+ versus CD36− FBs, we determined KLF10 as one of the transcription factors responsible for growth suppression. We also identified FBLN1, SLIT3, and PENK as active ligands, where their minimum effective concentrations were determined. Finally, in MDA-MB-231, we showed that a mixture of FBLN1, SLIT3, and PENK could induce an amount of growth suppression similar to the CM of CD36+ FBs. In conclusion, our findings suggest that these ligands, secreted by CD36+ FBs, can be targeted for breast cancer treatment.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 82%

Section: The Triple-negative Breast Cancer (Tnbc) Cell Lines Mda-mb-231 Bt-549 Andmentioning

confidence: 99%

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Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines

Jabbari

Winkelmaier

Andersen

et al. 2021

Cancers

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“…Another possible function might, therefore, be that CD36 on the surface of fibroblasts is activated by collagen to induce a paracrine gene-program, which in turn inhibits capillary growth. Indeed, Cd36 expressing fibroblasts counteract breast cancer cell growth in an organoid co-culture model by triggering the expression and release of unknown paracrine factors by fibroblasts [4]. However, as an in depth investigation of CD36 in cardiac fibroblasts exceeded the scope of this study, further work will be necessary to explore the mechanism of CD36 dependent effects in cardiac fibroblasts.…”

Section: Discussionmentioning

confidence: 94%

Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis

et al. 2021

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Heart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling remain poorly understood. Cardiac fibroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fibroblasts during stress is not known. Here, we show that fibroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specific single or double deletion of Gata4 and Gata6 in stress activated fibroblasts, we found a reduced myocardial capillarization in mice with Gata4/6 double deletion following pressure overload, while single deletion of Gata4 or Gata6 had no effect. Importantly, we confirmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fibroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fibroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identified a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fibroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.

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“…Its biological functions involve lipid uptake, immune recognition, inflammation, molecular adhesion and apoptosis, inflammatory response, apoptosis phagocytosis, angiogenesis, energy metabolism, and tumor metastasis [2][3][4]. CD36 not only promotes tumor metastasis and treatment resistance by promoting lipid uptake and FA oxidation, but also inhibits angiogenesis by binding with TSP-1, thus inducing tumor microvascular endothelial cell apoptosis or blocking the vascular endothelial growth factor receptor 2 pathway [5][6][7]. In addition, CD36-driven lipid metabolism reprogramming and the function of tumor-associated immune cells lead to tumor immune tolerance and tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Prognostic and immunological role of CD36: A pan-cancer analysis

Chen¹,

Liao²,

Huang³

et al. 2021

J. Cancer

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CD36 plays a critical role in lipid metabolism, which is closely associated with human immunity. However, the role of CD36 in cancer remains unclear. We performed a pan-cancer analysis to elucidate the potential role of CD36 in cancer by investigating its prognostic value and current predictors for the efficacy of immune checkpoint inhibitors (ICIs) in multiple cancer types. CD36 expression in cancer cell lines, tumor tissue, and their adjacent normal tissues displayed heterogeneity among different cancers. Immunohistochemistry was used to detect CD36 expression and confirmed the results. CD36 expression significantly affects prognosis in the six cancer types. High CD36 expression was marginally associated with poorer prognosis in four of them and improved prognosis in the remaining two types. CD36 expression was significantly correlated with the 6 immune infiltrates in most cancer types. In addition, CD36 gene expression was positively correlated with Stromal score, Immune score, and ESTIMATE score. A total of 47 immune checkpoint genes were collected and their relationship with CD36 expression was analyzed. CD36 expression was significantly associated with multiple stimulatory and inhibitory checkpoint molecules with a disease-specific pattern. As to the genes reported to positively relate to the efficacy of ICIs, CD36 expression was positively correlated with most of them but negatively associated with a small proportion of cancer type-specific patterns. Concerning the genes negatively related to the efficacy of ICIs, CD36 expression was positively correlated with NRP1 and TNFSF15 in multiple cancers. CD36 expression was negatively correlated with tumor neoantigen burden in most cancer types. However, CD36 expression was negatively correlated with tumor mutation burden in most cancer types. The correlation between CD36 expression and the four methyltransferases was also significant in multiple cancers, but also with a cancer type-specific pattern. In summary, the current study found CD36 expression and its prognostic value in multiple cancer types. In addition, the expression of CD36 was significantly associated with current predictors for the efficacy of ICIs. The practical application value of CD36 is disease specific.

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Overexpression of CD36 in mammary fibroblasts suppresses colony growth in breast cancer cell lines

Cited by 9 publications

References 29 publications

Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines

Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines

Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis

Prognostic and immunological role of CD36: A pan-cancer analysis

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