Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma

Mascharak, Shamik; Guo, Jason L.; Foster, Deshka S.; Khan, Anum; Davitt, Michael F.; Nguyen, Alan T.; Burcham, Austin R.; Chinta, Malini S.; Guardino, Nicholas J.; Griffin, Michelle; Lopez, David M.; Miller, Elisabeth; Januszyk, Michael; Raghavan, Shyam S.; Longacre, Teri A.; Delitto, Daniel J.; Norton, Jeffrey A.; Longaker, Michael T.

doi:10.1016/j.xcrm.2023.101248

Cited by 14 publications

(7 citation statements)

References 56 publications

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“…Manipulating stromal signals can dramatically affect tumor progression, warranting a deep understanding of the cellular interaction partners within the tumor microenvironment 4,5,39 . The current model of PDAC growth is dominated by the dense and heterogeneous stromal reaction surrounding the bulk of the tumor cells 40,41 . In addition to stromal invasion, neurotropism and vascular invasion have been suggested as important anatomic trajectories of PDAC cells 42,43 .…”

Section: Discussionmentioning

confidence: 99%

“…Motivated by the stroma-dominant morphology of PDAC, most recent studies on the subtypes and tumor-stromal interactions have focused on studying the tumor cells surrounded by desmoplastic stroma 19,22,40,41 . Many current approaches utilize laser-capture microdissection to enrich tumor cell content prior to RNA sequencing and thus exclude potential areas of lobular invasion.…”

Section: Discussionmentioning

confidence: 99%

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A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

Söderqvist,

Viljamaa,

Geyer

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type characterized by a particularly extensive stroma. While different types of cancer-associated fibroblasts (CAFs) in this desmoplastic stroma have been described, areas of early invasion and nascent stroma are understudied. Here, we identify a distinctive PDAC niche within the pancreatic lobules, a compartment dominated by pancreatic exocrine cells and slender stroma. Cellular interaction profiling using machine learning on whole slide images of human PDAC reveals that the tumor invasion front in the lobules is dominated by specific interactions of tumor cells and exocrine cells that have undergone acinar-to-ductal metaplasia (ADM). Multiplex protein and mRNA stains confirm that tumor growth in the lobules is closely linked to ADM in the lobules, and reveal stromal protein gradients from the gracile lobular stroma to the characteristic desmoplastic stroma. We identify nascent CAFs (nCAFs), co-expressing expressing nerve growth factor receptor (NGFR) and platelet-derived growth factor receptor alpha (PDGFRa) that are absent in the mature, desmoplastic stroma. Lobular invasion and nCAFs are intertwined with phenotypic changes of the cancer cells, such that tumor cells in lobules express classical subtype markers, while those embedded in the desmoplastic are on the basal end of the phenotypic continuum. In mice, the PDAC subtype – basal or classical – similarly depends on tissue location, suggesting microenvironmental factors rather than clonal selection as important drivers of tumor phenotype identity. Clinically, our results mandate factoring in tumor tissue location when calling PDAC subtypes. Biologically, they identify pancreatic lobules as a distinctive tissue niche associated with nascent stroma, and they suggest that lobular colonization by tumor cells is a significant route of PDAC progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

Söderqvist,

Viljamaa,

Geyer

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…(14,32) This tool allows for unbiased, quantitative assessment of the complex architecture of fibrotic tissue, and allows for specimens to be objectively compared on the basis of their ECM ultrastructure. We have previously validated this image analysis pipeline in multiple fibrotic conditions across species (including mouse, pig, and human) (14,(32)(33)(34)(35)(36) and have shown that the fibrotic ECM features measured by our algorithm are clinically relevant (strongly predictive of highly clinically significant differences in patient survival in pancreatic cancer (32)).…”

Section: Tension Offloading Prevents and Mitigates Fibrotic Shifts In...mentioning

confidence: 99%

“…Each group (n = 3 samples per group) were imaged at random unique locations (300 locations for each pig group, 50 for each xenograft group), and then run through using an inhouse image-processing algorithm as previously describe. (52) In brief, color deconvolution was performed to characterize collage fibers by absorbance in red, green and blue channels. Orthonormal transformation followed to the contribution of each color to a given image.…”

Section: Ecm Ultrastructure Quantitative Analysismentioning

confidence: 99%

A tension offloading patch mitigates dermal fibrosis induced by pro-fibrotic skin injections

Wan,

Talbott,

Griffin

et al. 2024

Preprint

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Skin fibrosis is a clinical problem with devastating impacts but limited treatment options. In the setting of diabetes, insulin administration often causes local dermal fibrosis, leading to a range of clinical sequelae including impeded insulin absorption. Mechanical forces are important drivers of fibrosis and, clinically, physical tension offloading at the skin level using an elastomeric patch significantly reduces wound scarring. However, it is not known whether tension offloading could similarly prevent skin fibrosis in the setting of pro-fibrotic injections. Here, we develop a porcine model using repeated local injections of bleomycin to recapitulate key features of insulin-induced skin fibrosis. Using histologic, tissue ultrastructural, and biomechanical analyses, we show that application of a tension-offloading patch both prevents and rescues existing skin fibrosis from bleomycin injections. By applying single-cell transcriptomic analysis, we find that the fibrotic response to bleomycin involves shifts in myeloid cell dynamics from favoring putatively pro-regenerative to pro-fibrotic myeloid subtypes; in a mechanomodulatory in vitro platform, we show that these shifts are mechanically driven and reversed by exogenous IL4. Finally, using a human foreskin xenograft model, we show that IL4 treatment mitigates bleomycin-induced dermal fibrosis. Overall, this study highlights that skin tension offloading, using an FDA cleared, commercially available patch, could have significant potential clinical benefit for the millions of patients dependent on insulin.

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“…It is unclear why NCs are extremely metastatic. Desmoplasia, characterized by the recruitment of cancer-associated fibroblasts and pervasive deposition of extracellular matrix proteins, is strongly associated with metastatic potential in common cancers such as pancreatic ductal adenocarcinoma (PDAC) [56][57][58] . Desmoplastic histological features have been reported in a number of human NC case reports and are routinely observed in clinical diagnostic practice [59][60][61] , yet, have never been characterized at the molecular level.…”

Section: Mouse Ncs Have High Metastasis Potentialmentioning

confidence: 99%

Brd4::Nutm1fusion gene initiates NUT carcinomain vivo

Zheng,

Elnegiry,

Luo

et al. 2023

Preprint

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Nut carcinoma (NC) is an aggressive cancer with no effective treatment. The majority (70%) of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a BRD4-NUTM1 fusion gene. However, because the BRD4-NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, there is no experimental evidence of the oncogenic potential of this fusion gene to initiate NC. We report here the first genetically engineered mouse model (GEMM) for NUT carcinoma. By inducing a chromosome translocation event mirroring the human event in mouse epithelial progenitors, we demonstrated that the Brd4-Nutm1 fusion gene could induce aggressive head and neck, and skin carcinomas in mice. The tumors present similar histopathological and molecular features to human NC. As the sole immunocompetent GEMM for NC, the model will have a far-reaching impact on understanding NC oncogenesis and developing NC treatment, including targeted therapies and immune therapies in a preclinical setting, which will benefit NC patients through translational research.

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Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma

Cited by 14 publications

References 56 publications

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

A tension offloading patch mitigates dermal fibrosis induced by pro-fibrotic skin injections

Brd4::Nutm1fusion gene initiates NUT carcinomain vivo

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