Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function

Begum, Asma; McMillan, Ross; Chang, Yih–Long; Penchev, Vesselin R.; Rajeshkumar, N. V.; Maitra, Anirban; Goggins, Michael; Eshelman, James R.; Wolfgang, Christopher L.; Rasheed, Zeshaan A.; Matsui, William

doi:10.1097/mpa.0000000000001249

Cited by 49 publications

(43 citation statements)

References 42 publications

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“…For example, Kolev et al showed that administration of VS-4718 or VS-6063, two potent FAK inhibitors, to mice bearing TNBC xenografts significantly reduced the CSC population [ 86 ]. Recently, it was shown in PDAC that FAK activation promotes PaCSCs, and short hairpin RNAs against FAK or a small-molecule FAK inhibitor can inhibit PaCSC clonogenic growth [ 87 ]. Thus, the inhibition observed in the PaCSC population in this study with DAS and PP2 may very well be due to the SRC /FAK axis.…”

Section: Discussionmentioning

confidence: 99%

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Alcalá

Mayoral-Varo

Ruiz-Cañas

et al. 2020

IJMS

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The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.

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Section: Discussionmentioning

confidence: 99%

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Alcalá

Mayoral-Varo

Ruiz-Cañas

et al. 2020

IJMS

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“…CAFs have been implicated in promoting stemness in adjacent tumour cells via the secretion of inflammatory cytokines in several tumour types [23,[63][64][65][66][67][68][69], including PDAC [70,71]. More recently, it was reported that certain subpopulations of CAFs specifically regulate stemness in lung and breast tumour cells, thus conferring chemoresistance [72] ( Figure 1E).…”

Section: Caf Heterogeneity In Promoting Stemnessmentioning

confidence: 99%

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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“…Previously described pathways involved in CAF activation include sonic hedgehog, TGF-beta, IL-1, IL-6, and IL-10 [29,43,[55][56][57][58][59]. CAFs are also activated by growth factors and cytokines such as CCL2, PDGF, hepatocyte growth factor, and fibroblast growth factor (FGF) [60]. Once activated CAFs develop a contractile and secretory function, secreting many of the factors known to be further involved in their activation including IL-1 and IL-6 [56].…”

Section: Pdac Caf Heterogeneitymentioning

confidence: 99%

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

Norton

Foster

Chinta

et al. 2020

Cancers

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Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

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Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function

Cited by 49 publications

References 42 publications

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

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

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

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