Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression

Dauer, Patricia; Zhao, Xianda; Gupta, Vineet; Sharma, Nikita; Kesh, Kousik; Gnamlin, Prisca; Dudeja, Vikas; Vickers, Selwyn M.; Banerjee, Sulagna; Saluja, Ashok K.

doi:10.1158/0008-5472.can-17-2320

Cited by 95 publications

(73 citation statements)

References 38 publications

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“…RNAs derived from SH4 with (#4 and #5) or without (Mock; two samples) B4GALNT1 over-expression were analyzed by RNA sequencing as described in ref. [76][77][78] . Quality tested with Bioanalyzer 2100 (Agilent Technologies, USA).…”

Section: In Vivo Tumorigenesismentioning

confidence: 99%

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Yoshida

Koodie

Jacobsen

et al. 2020

Sci Rep

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β-1,4-N-Acetyl-Galactosaminyltransferase 1 (B4GALNT1) encodes the key enzyme B4GALNT1 to generate gangliosides GM2/GD2. GM2/GD2 gangliosides are surface glycolipids mainly found on brain neurons as well as peripheral nerves and skin melanocytes and are reported to exacerbate the malignant potential of melanomas. In order to elucidate the mechanism, we performed functional analyses of B4GALNT1-overexpressing cells. We analyzed ganglioside pattern on four melanoma and two neuroblastoma cell lines by high performance liquid chromatography (HPLC). We overexpressed B4GALNT1 in GM2/GD2-negative human melanoma cell line (SH4) and confirmed production of GM2/GD2 by HPLC. They showed higher anchorage independence growth (AIG) in colony formation assay, and exhibited augmented motility. In vitro, cell proliferation was not affected by GM2/GD2 expression. In vivo, GM2/GD2-positive SH4 clones showed significantly higher tumorigenesis in NOD/ Scid/IL2Rγ-null mice, and immunostaining of mouse CD31 revealed that GM2/GD2 induced remarkable angiogenesis. No differences were seen in melanoma stem cell and Epithelial-Mesenchymal Transition markers between GM2/GD2-positive and -negative SH4 cells. We therefore concluded that B4GALNT1, and consequently GM2/GD2, enhanced tumorigenesis via induction of angiogenesis, AIG, and cell motility. RNA-Seq suggested periostin as a potential key factor for angiogenesis and AIG. These findings may lead to development of novel therapy for refractory melanoma.abundant in the nervous system, especially brain neurons 14 . They also exist in peripheral nerves and skin melanocytes 15,16 . These molecules are reported to have important biological functions, such as intercellular communication, cell cycling, cell growth, adhesion, differentiation, and cell motility [17][18][19] . Gangliosides are not only detected at high levels in tumors of neuroectodermal cell origin but also related to the biological and clinical behavior of many kinds of tumors 20 . Recently, some analysis revealed that patients with higher expression of B4GALNT1 and GM2/GD2 correlated with poorer prognosis in renal cell carcinoma (TCGA data set; Human Protein Atlas), neuroblastoma 21 , and melanoma 22 . Thus, B4GALNT1 gene is considered to be key tumor-associated antigens [23][24][25][26][27] , indicating that their expression is a meaningful marker for metastatic condition and are potential therapeutic targets for melanoma.Our findings indicate the involvement of B4GALNT1 and GM2/GD2 in tumor establishment and progression as well as a potential direction of therapeutic approach via controlling B4GALNT1, and consequently GM2/GD2 expression in cancers such as melanoma. Scientific RepoRtS |(2020) 10:1199 | https://doi.Generation of GM2/GD2-positive SH4 melanoma clones. The SH4 cells were transfected with expression vectors with or without B4GALNT1 gene cassette, to establish GM2/GD2-positive and -negative SH4 clones. Two GM2/GD2-high clones were selected by single cell isolation (#4 and #5, Fig. S2A). These two clones showed significa...

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Section: In Vivo Tumorigenesismentioning

confidence: 99%

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

Yoshida

Koodie

Jacobsen

et al. 2020

Sci Rep

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“…Such a strategy reduced inflammation and fibrosis in PDAC tumours. In line with this, treating CAFs with Minnelide, a novel prodrug of a plant-derived diterpenoid epoxide called triptolide, reduced TGF-b signalling and pushed CAFs into a more quiescent state [104] ( Figure 4). This treatment also resulted in reduced collagen and HA deposition in the stroma of mouse and patient-derived pancreatic tumours, while improving vasculature patency and drug delivery due to reduced interstitial fluid pressure (IFP) in the tumour [105].…”

Section: Reprogramming Cafs Into Quiescent Fibroblastsmentioning

confidence: 78%

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

et al. 2019

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Cancer-associated fibroblasts (CAFs) are one of the most significant components in the tumour microenvironment (TME), where they can perform several protumourigenic functions. Several studies have recently reported that CAFs are more heterogenous and plastic than was previously thought. As such, there has been a shift in the field to study CAF subpopulations and the emergent functions of these subsets in tumourigenesis. In this review, we explore how different aspects of CAF heterogeneity are defined and how these manifest in multiple cancers, with a focus on pancreatic ductal adenocarcinoma (PDAC). We also discuss therapeutic approaches to selectively target protumourigenic CAF functions, while avoiding normal fibroblasts, providing insight into the future of stromal targeting for the treatment of PDAC and other solid tumours. Cancer-Associated Fibroblasts: Major Players in Pancreatic Tumourigenesis PDAC is one of the most lethal solid malignancies, with a 5-year survival rate of $9% [1]. Widespread fibrotic desmoplasia is one of the cornerstones of PDAC development, progression, metastasis, and treatment resistance, where stromal components of the TME can have fundamental and integrated roles in promoting tumourigenesis [2-6]. This extensive desmoplastic reaction is characterised by the recruitment and activation of CAFs, aberrant extracellular matrix (ECM) deposition and remodelling, tumour angiogenesis, altered blood supply, as well as increased inflammation coupled with altered (and often impaired) innate and adaptive immune responses [4,5,7-9]. CAFs are one of the most prominent and active components in the pancreatic TME [4,5]. During early tumour initiation, reciprocal tumour-stroma signalling drives the reprogramming of mesenchymal cells, such as pancreatic stellate cells (PSCs), into CAFs [6], after which they can perform numerous anti-and protumourigenic functions in the TME. For instance, PDAC CAFs are the chief source of fibrotic matrisomal components, such as collagens, hyaluronic acid (HA), and fibronectin, among others, as recently described by Tian et al. [10]. This fibrosis has downstream biomechanical and biochemical effects in the TME [11], including impaired drug efficacy due to reduced interfibrillar spacing in the interstitium, which leads to reduced vascular patency and poor immune cell infiltration [12-17]. Moreover, CAFs produce several chemokines, cytokines, growth factors, miRNAs, exosomes, and metabolites that can instruct cancer cells and other TME components to promote malignant biology [4,5]. Given the central role of CAFs in the TME, there have been several attempts to target them in combination with other therapeutic approaches, such as chemotherapy or immunotherapy, for the treatment of PDAC. Thus far, this treatment approach has been largely unsuccessful and, in some preclinical studies, harmful. This is best exemplified through the studies of Ö zdemir et al. [18] and Rhim et al. [19], which both found that depletion of CAFs in genetically engineered mouse models (GEMMs) of PDA...

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“…Further characterization showed these CD8 + cells to have low PD1 expression, showing that they were not exhausted (Supplemental Figure 5, D-J). tumor epithelial cells and stromal cells (10,61,62). Thus, treatment with DON, which increases antitumor activity and remodels the ECM to promote infiltration of cytotoxic T cells in combination with anti-PD1 therapy, is a promising strategy for combatting pancreatic cancer.…”

Section: Resultsmentioning

confidence: 99%

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

Sharma

Gupta

Garrido

et al. 2019

Journal of Clinical Investigation

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Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression

Cited by 95 publications

References 38 publications

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

B4GALNT1 induces angiogenesis, anchorage independence growth and motility, and promotes tumorigenesis in melanoma by induction of ganglioside GM2/GD2

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

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