The prognostic value of stroma in pancreatic cancer in patients receiving adjuvant therapy

Bever, Katherine M.; Sugar, Elizabeth A.; Bigelow, Elaine; Sharma, Rajni; Laheru, Daniel A.; Wolfgang, Christopher L.; Jaffee, Elizabeth M.; Anders, Robert A.; Jesus-Acosta, Ana De; Li, Zheng

doi:10.1111/hpb.12334

Cited by 67 publications

(58 citation statements)

References 17 publications

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“…To investigate impact of PDAC microenvironment on immune composition of the tumor, we initially evaluated stromal volume using whole tumor hematoxylin and eosin-stained sections. When cases were dichotomized around the median stromal volume, there was a statistically significant association of low stromal volume with poor overall survival (Fig 2A and S3) as previously reported (34, 35). Next, we evaluated morphologic features of the stromal compartment consistent with the reported biological diversity of stroma (29).…”

Section: Resultssupporting

confidence: 78%

Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers

Knudsen

Vail

Balaji

et al. 2017

Clinical Cancer Research

160

176

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Purpose Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunological features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy. Experimental design A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunological subtypes of PDAC that were confirmed in the Cancer Genome Atlas data set. Stromal and metabolic characteristics of PDAC cases were evaluated by histological analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neo-antigens were determined by analysis of whole exome sequencing data. Random-forest clustering was employed to define multi-marker subtypes, with univariate and multivariate analyses interrogating prognostic significance. Results PDAC cases exhibited distinct stromal phenotypes that were associated with prognosis, glycolytic and hypoxic biomarkers and immune infiltrate composition. Immune infiltrate was diverse among PDAC cases and enrichment for M2 macrophages and select immune checkpoints regulators were specifically associated with survival. Composite analysis with neo-antigen burden, immunological, and stromal features defined novel subtypes of PDAC that could have bearing on sensitivity to immunological therapy approaches. Additionally, a subtype with low levels of neo-antigens and minimal lymphocyte infiltrate was associated with improved overall survival. Conclusions The mutational burden of PDAC is associated with distinct immunosuppressive mechanisms that are conditioned by the tumor stromal environment. The defined subtypes have significance for utilizing immunotherapy in the treatment of PDAC.

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Section: Resultssupporting

confidence: 78%

Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers

Knudsen

Vail

Balaji

et al. 2017

Clinical Cancer Research

160

176

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“…IHC for SMA was performed as previously described (27). IHC for AnxA2 was conducted with mouse anti-AnxA2(Invitrogen), or mouse anti-P-Y23-AnxA2 antibodies, IHC for Shh with goat-anti-Shh (R&D), and IHC for IGF-1 with rabbit-anti-IGF-1(Abcam) antibodies as described previously (13).…”

Section: Methodsmentioning

confidence: 99%

Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer

et al. 2017

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Understanding how stromal signals regulate the development of pancreatic ductal adenocarcinoma (PDAC) may suggest novel therapeutic interventions in this disease. In this study, we assessed the metastatic role of stromal signals suggested to be important in the PDAC microenvironment. Src and IGF-1R phosphorylated the pro-metastatic molecule Annexin A2 (AnxA2) at Y23 and Y333 in response to stromal signals HGF and IGF-1, respectively, and IGF-1 expression was regulated by the Sonic Hedgehog (Shh) pathway. Both Shh and HGF were heterogeneously expressed in PDAC stroma, and only dual inhibition of these pathways could significantly suppress AnxA2 phosphorylation, PDAC growth and metastasis. Taken together, our results illuminate tumor-stromal interactions which drive metastasis, and provide a mechanism-based rationale for a stroma-directed therapy for PDAC.

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“…Furthermore, depletion of α‐smooth muscle actin (αSMA) expressing myofibroblasts resulted in invasive, undifferentiated tumors with reduced PDAC mouse survival, an observation paralleled by the association between fewer myofibroblasts and worse human patient survival (Ozdemir et al , ). Similarly, high PDAC stromal density has been linked with better patient survival (Bever et al , ). These observations are consistent with PDAC desmoplasia restraining tumor growth.…”

Section: Introductionmentioning

confidence: 99%

ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a Kras G12D/p53 R172H mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three‐dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK‐induced genes that facilitate extracellular matrix remodeling, with greatest fold‐changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13. MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three‐dimensional contexts. Treatment of Kras G12D/p53 R172H PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor‐associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth.

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The prognostic value of stroma in pancreatic cancer in patients receiving adjuvant therapy

Abstract: These results illustrate the complexity of the role of stroma in PDAs. Further exploration of the prognostic ability of the characteristics of stroma is warranted.

Cited by 67 publications

References 17 publications

Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers

Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers

Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer

ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth

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