RGS5–TGFβ–Smad2/3 axis switches pro- to anti-apoptotic signaling in tumor-residing pericytes, assisting tumor growth

Dasgupta, Shayani; Ghosh, Tithi; Dhar, Jesmita; Bhuniya, Avishek; Nandi, Partha; Das, Arnab; Saha, Akata; Das, Juhina; Guha, Ipsita; Banerjee, Saptak; Chakravarti, Mohona; Dasgupta, Partha; Alam, Neyaz; Chakrabarti, Jayanta; Majumdar, Subrata; Chakrabarti, Pinak; Storkus, Walter J.; Baral, Rathindranath; Bose, Anamika

doi:10.1038/s41418-021-00801-3

Cited by 28 publications

(35 citation statements)

References 84 publications

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“…Moreover, it forms complex with Smad2/3 and enter nucleus. The RGS5‐pSmad2/3 complex further modulates Smad‐dependent transcription 25 . In vivo NLGP treatment for four times at an interval of 7 days had shown to greatly reduce RGS5 nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor-lysate (1 μg/ml) was used in in vitro cultures for mimicking TME as previously described. 25 2. 5 | In vitro pericyte generation C3H10T1/2 cells on reaching ~100% confluency were treated with mrPDGFβ (1ng/ml) (eBiosciences, San Diego, CA) for 48 h in DMEM low-glucose medium as described previously 23 to differentiate them into pericytes.…”

Section: Preparation Of Tumor Supernatant Tumor Fragments and Tumor L...mentioning

confidence: 99%

“…7,31 In our recent study, we observed that with the growth of tumor, expression of RGS5 and frequency of RGS5-expressing NG2 + pericytes increased proportionally, which is associated with abnormal tumor vasculature and decreased cellular apoptosis of tumorresiding RGS5 high pericytes. 23,25 Therefore, to delineate association between vascular normalization and pericyte population, an integral constituent of blood vessels and TME, we analyzed the expression of CD31 and NG2 in B16-F10 melanoma tumors isolated from PBS versus NLGP treated mice by flow-cytometry. Along with the significant downregulation in CD31 expression from ~60% to ~25%, NLGP treatment found to reduce NG2 + pericyte population significantly from ~70% to ~50% (Figure 1A,B) in comparison to PBS-treated control.…”

Section: Nlgp Reciprocally Regulates Rgs5 Low and Rgs5 High Pericytes...mentioning

confidence: 99%

“…Moreover, our recent work suggested critical role of TGFβ in modulation of RGS5-mediated apoptosis in tumor-pericytes. 25 To further validate the role of NLGP in normalizing TGFβ effect on RGS5high pericytes, we performed rescue experiment. We observed that apoptosis of RGS5 high pericytes abrogated upon supplementation of rTGFβ exposed to NLGP treated tumor-lysate, in contrast to RGS5 high pericytes exposed to TGFβ neutralized PBS treated tumor-lysate (Figure 3C) Considering the various cellular sources of TGFβ within TME, we isolated Tregs, TAMs, ECs and pericytes (RGS5 + NG2 + ) from NLGP-and PBS-treated B16-F10 melanoma.…”

Section: Tgfβ Downregulation Within Tme By Nlgp Promotes Apoptosis Of...mentioning

confidence: 99%

“…Moreover, in our recent study, we observed in the presence of extrinsic TGFβ, RGS5 binds with Smad2/3 (a TGFβ downstream mediator) in RGS5 high pericytes and thus prevents TGFβ-dependent transcription of apoptotic genes. 25 Therefore, to study this protein-protein association in RGS5 high pericytes, exposed to different TME i.e., PBS and NLGP, we isolated RGS5 + NG2 + pericytes from the respective tumors. Immunoprecipitation with RGS5 and subsequent western-blotting with pSmad2/3 showed decreased association in NLGP-treated RGS5 + NG2 + pericytes (Figure 5E).…”

Section: Nlgp Treatment Prevents Rgs5 Nuclear Translocationmentioning

confidence: 99%

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NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

et al. 2022

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Altered RGS5‐associated intracellular pericyte signaling and its abnormal crosstalk with endothelial cells (ECs) result chaotic tumor‐vasculature, prevent effective drug delivery, promote immune‐evasion and many more to ensure ultimate tumor progression. Moreover, the frequency of lethal‐RGS5high pericytes within tumor was found to increase with disease progression, which signifies the presence of altered cell death pathway within tumor microenvironment (TME). In this study, we checked whether and how neem leaf glycoprotein (NLGP)‐immunotherapy‐mediated tumor growth restriction is associated with modification of pericytes' signaling, functions and its interaction with ECs. Analysis of pericytes isolated from tumors of NLGP treated mice suggested that NLGP treatment promotes apoptosis of NG2+RGS5high‐fuctionally altered pericytes by downregulating intra‐tumoral TGFβ, along with maintenance of more matured RGS5neg pericytes. NLGP‐mediated inhibition of TGFβ within TME rescues binding of RGS5 with Gαi and thereby termination of PI3K‐AKT mediated survival signaling by downregulating Bcl2 and initiating pJNK mediated apoptosis. Limited availability of TGFβ also prevents complex‐formation between RGS5 and Smad2 and rapid RGS5 nuclear translocation to mitigate alternate immunoregulatory functions of RGS5high tumor‐pericytes. We also observed binding of Ang1 from pericytes with Tie2 on ECs in NLGP‐treated tumor, which support re‐association of pericytes with endothelium and subsequent vessel stabilization. Furthermore, NLGP‐therapy‐ associated RGS5 deficiency relieved CD4+ and CD8+ T cells from anergy by regulating ‘alternate‐APC‐like’ immunomodulatory characters of tumor‐pericytes. Taken together, present study described the mechanisms of NLGP's effectiveness in normalizing tumor‐vasculature by chiefly modulating pericyte‐biology and EC‐pericyte interactions in tumor‐host to further strengthen its translational potential as single modality treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Preparation Of Tumor Supernatant Tumor Fragments and Tumor L...mentioning

confidence: 99%

Section: Nlgp Reciprocally Regulates Rgs5 Low and Rgs5 High Pericytes...mentioning

confidence: 99%

Section: Tgfβ Downregulation Within Tme By Nlgp Promotes Apoptosis Of...mentioning

confidence: 99%

Section: Nlgp Treatment Prevents Rgs5 Nuclear Translocationmentioning

confidence: 99%

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NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

et al. 2022

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Biomaterial‐Based Gene Delivery to Central Nervous System Cells for the Treatment of Spinal Cord Injury

McGuire,

Stasiewicz,

Woods

et al. 2023

Advanced NanoBiomed Research

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Spinal cord injury (SCI) is a devastating traumatic injury often causing permanent loss of function. The challenge of treating SCI stems from the development of a complex pathophysiology at the site of injury, involving multiple biochemical cascades, widespread inflammation, blood supply interruption, inhibitory scar formation, and poor regrowth of injured axons. Clinical options are limited to surgical stabilization and attempt to ameliorate secondary damage following injury. Gene therapy has significant potential to tackle multiple aspects of SCI and improve functional outcomes. The emergence of a diverse array of biomaterial‐based nonviral nanoparticle vectors capable of delivering gene‐modifying nucleic acids offers the potential to improve the efficiency and specificity of genetic cargos for spinal cord regeneration. In this review, the progress that has been made in the field of SCI repair and the different types of nanoparticles and nucleic acid cargoes that have been used are outlined, placing a particular focus on the different cell types and pathways targeted. While many challenges remain, a perspective on the future of the field of nanoparticle‐mediated gene delivery for SCI is provided, including using biomaterial scaffolds engineered specifically for SCI to deliver gene therapeutics and the exciting opportunities that exist in the post‐COVID landscape.

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Endosialin-positive tumor-derived pericytes promote tumor progression through impeding the infiltration of CD8+ T cells in clear cell renal cell carcinoma

Lü

Zhang

et al. 2023

Cancer Immunol Immunother

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Background Immune checkpoint blockade (ICB) therapy can be effective against clear cell renal cell carcinoma (ccRCC), but many patients show no benefit. Tumor-derived pericytes (TDPs) may promote tumor progression by influencing T cells and are an immunotherapy target; however, they may comprise functionally distinct subtypes. We aimed to identify markers of tumor-promoting TDPs and develop TDP-targeting strategies to enhance ICB therapy effectiveness against ccRCC. Methods We analyzed the relationship between endosialin (EN) expression and cytotoxic T-lymphocyte (CTL) infiltration in ccRCC tumor samples using flow cytometry and in a ccRCC-bearing mice inhibited for EN via knockout or antibody-mediated blockade. The function of ENhigh TDPs in CTL infiltration and tumor progression was analyzed using RNA-sequencing (RNA-seq) data from ccRCC tissue-derived TDPs and single-cell RNA-seq (scRNA-seq) data from an online database. The role of EN in TDP proliferation and migration and in CTL infiltration was examined in vitro. Finally, we examined the anti-tumor effect of combined anti-EN and anti-programmed death 1 (PD-1) antibodies in ccRCC-bearing mice. Results High EN expression was associated with low CTL infiltration in ccRCC tissues, and inhibition of EN significantly increased CTL infiltration in ccRCC-bearing mice. RNA-seq and scRNA-seq analyses indicated that high EN expression represented the TDP activation state. EN promoted TDP proliferation and migration and impeded CTL infiltration in vitro. Finally, combined treatment with anti-EN and anti-PD-1 antibodies synergistically enhanced anti-tumor efficacy. Conclusion ENhigh TDPs are in an activated state and inhibit CTL infiltration into ccRCC tissues. Combined treatment with anti-EN and anti-PD-1 antibodies may improve ICB therapy effectiveness against ccRCC.

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RGS5–TGFβ–Smad2/3 axis switches pro- to anti-apoptotic signaling in tumor-residing pericytes, assisting tumor growth

Cited by 28 publications

References 84 publications

NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

Biomaterial‐Based Gene Delivery to Central Nervous System Cells for the Treatment of Spinal Cord Injury

Endosialin-positive tumor-derived pericytes promote tumor progression through impeding the infiltration of CD8+ T cells in clear cell renal cell carcinoma

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