Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

Ligorio, Matteo; Sil, Srinjoy; Malagon-Lopez, Jose; Nieman, Linda T.; Misale, Sandra; Pilato, Mauro Di; Ebright, Richard Y.; Karabacak, Murat; Kulkarni, Anupriya S.; Liu, Ann; Jordan, Nicole Vincent; Franses, Joseph W.; Philipp, Julia; Kreuzer, Johannes; Desai, Niyati; Arora, Kshitij S.; Rajurkar, Mihir; Horwitz, E. P.; Neyaz, Azfar; Tai, Eric C.; Magnus, Neelima K.C.; Vo, Kevin D.; Yashaswini, Chittampalli; Marangoni, Francesco; Boukhali, Myriam; Fatherree, Jackson P.; Damon, Leah J.; Xega, Kristina; Desai, Rushil; Choz, Melissa; Bersani, Francesca; Langenbucher, Adam; Thapar, Vishal; Morris, Robert T.; Wellner, Ulrich F.; Schilling, Oliver; Lawrence, Michael S.; Liss, Andrew S.; Rivera, Miguel N.; Benes, Cyril H.; Maheswaran, Shyamala; Haber, Daniel A.; Fernández‐del‐Castillo, Carlos; Ferrone, Cristina R.; Haas, Wilhelm; Aryee, Martin J.; Ting, David T.

doi:10.1016/j.cell.2019.05.012

Cited by 400 publications

(364 citation statements)

References 45 publications

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“…Tumor grading did not reveal an association with animal survival (median survival 155 days versus 187 days, log-rank p = 0.09; Figure 1B). Importantly, diverse grading of KPC-derived tumors resembles PDAC heterogeneity as observed in patients [26,30]. Together, these results demonstrated no prognostic value of tumor grading based on overall survival in the KPC cohort.…”

Section: Association Of Tumor Grading and Survival Not Confirmedmentioning

confidence: 74%

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Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer

Hasselluhn¹,

Klein²,

Patzak³

et al. 2019

Cells

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The KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (α-SMA/Ki67) were assessed. Univariate analysis using the Kaplan–Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (ρ = −0.84). Ki67 and PHH3 synergized as proliferation markers (ρ = 0.54), while SPARC expression was positively correlated with HA content (ρ = 0.37). MVD and MLA were correlated with each other (ρ = 0.31), while MLA positively correlated with CC3 (ρ = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (α-SMA + Ki67; ρ = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia.

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Section: Association Of Tumor Grading and Survival Not Confirmedmentioning

confidence: 74%

“…PDAC heterogeneity does not only cover the mutational landscape of epithelial tumor cells, but also affects the tumor microenvironment and ECM composition [30]. Major ECM proteins of the PDAC microenvironment include collagen and HA.…”

Section: Quantity Of Collagen and Hyaluronic Acid Is Not Associated Wmentioning

confidence: 99%

Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer

Hasselluhn¹,

Klein²,

Patzak³

et al. 2019

Cells

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“…The authors also reported that loss of ROBO2 with concomitant increased ROBO1 expression signalling was correlated with poor disease-free survival in patients with PDAC [119]. In addition, Ligorio and colleagues recently reported that mitogen-activated protein kinase (MAPK) and STAT3 signalling is upregulated in a subpopulation of highly proliferative and invasive PDAC cancer cells, and that this phenotype is due to CAF-derived paracrine TGFb signalling [121]. Collectively, these studies suggest that IL-1 and/or TGF-b could be targeted to reduce the proportion of the prometastatic CAF subpopulations in vivo, therefore impairing tumourigenesis ( Figure 5A).…”

Section: Targeting Interactions Between Cafs and Their Surrounding MImentioning

confidence: 95%

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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“…Increased tension between tumor cells resulted in elevated FAK1 signaling, increased phosphorylated-STAT3 and increased fibrosis, which were again reduced following FAK1 inhibition (Laklai et al, 2016). Further evidence reinforces the relationship between CAF, STAT3 signaling, and PDAC progression as a recent study elucidated that CAFs induce PDAC tumor cellintrinsic STAT3 signaling, resulting in a more invasive and proliferative phenotype (Ligorio et al, 2019). These studies reveal the tight association between stroma and tumor in promoting tumor progression and support the notion that a fibrotic stroma can contribute to exclusion of cytotoxic T cells.…”

Section: Recruitment Of Immunosuppressive Populationsmentioning

confidence: 54%

Modulation of the immune microenvironment by tumor-intrinsic oncogenic signaling

Nguyen

Spranger

2019

Journal of Cell Biology

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The development of cancer immunotherapies has been guided by advances in our understanding of the dynamics between tumor cells and immune populations. An emerging consensus is that immune control of tumors is mediated by cytotoxic CD8+ T cells, which directly recognize and kill tumor cells. The critical role of T cells in tumor control has been underscored by preclinical and clinical studies that observed that T cell presence is positively correlated with patient response to checkpoint blockade therapy. However, the vast majority of patients do not respond or develop resistance, frequently associated with exclusion of T cells from the tumor microenvironment. This review focuses on tumor cell–intrinsic alterations that blunt productive anti-tumor immune responses by directly or indirectly excluding effector CD8+ T cells from the tumor microenvironment. A comprehensive understanding of the interplay between tumors and the immune response holds the promise for increasing the response to current immunotherapies via the development of rational novel combination treatments.

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Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

Cited by 400 publications

References 45 publications

Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer

Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer

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

Modulation of the immune microenvironment by tumor-intrinsic oncogenic signaling

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