Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Citation Format: Herve Tiriac, Pascal Belleau, Dannielle Engle, Dennis Plenker, Astrid Deschenes, Tim Somerville, Fieke Froeling, Richard Moffitt, Jennifer Knox, Alexander Krasnitz, Steven Gallinger, David Tuveson. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C57.

Abstract:The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8 + T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8 + T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8 + T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.not peer-reviewed)

In the version of this Article originally published, in the fourth affiliation, 'Los Angeles' should have read 'Louisiana' . This has been corrected in all online versions of the Article. 822NATURE CELL BIOLOGY VOLUME 18 | NUMBER 7 | JULY 2016 © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . A l l r i g h t s r e s e r v e d .

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Parallels between embryonic development, stem cells, and cancer have long been recognized. The proliferative and invasive characteristics of the most lethal forms of breast cancer and their lack of differentiated characteristics resemble aspects of embryonic mammogenesis, raising the possibility that they share molecular mechanisms. We have identified, isolated and characterized a fetal mammary population with concentrated mammary stem cell activity and shown that it exhibits gene expression similarities to certain human breast cancer molecular subtypes. Limiting dilution transplantation analyses demonstrate that a robust increase in fetal mammary stem cell (fMaSC) activity is evident after embryonic day 16 (E16), coincident with invasion of the rudiment through the mesenchyme and into the fat pad precursor. Markers used to enrich adult MaSCs enabled isolation of a population at E18.5 that is highly enriched for fMaSCs and capable of serial transplantation in vivo and clonal, multilineage sphere formation in vitro. Genome-wide expression profiling and single cell analyses revealed candidate pathways in both the epithelial and stromal compartments with relevance to fMaSC activity and cancer. Notably, ErbB and FGF signaling were critical and synergistic for the in vitro growth of spheres derived from the fMaSC-enriched population, and fMaSCs expressed elevated ErbB2, 3, and 4 relative to adult MaSC enriched populations. We explored molecular links between fetal mammary development and cancer further by analyzing the expression of fetal gene signatures in archived breast cancer array data and in breast cancer cell lines. We identified gene expression modules correlating with certain cell lines, intrinsic breast cancer subtypes and clinical outcome. These studies advance the attractive hypothesis that regulatory pathways governing fMaSC function and embryonic mammogenesis that are deregulated in certain types of human cancer can be targeted in the development of new therapies and prognostic metrics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1015. doi:1538-7445.AM2012-1015