bims-tuchim 2022-02-06 papers

bims-tuchim

Biomed News

on Tumor-on-chip models

Issue of 2022–02–06
eleven papers selected by
Philipp Albrecht, Friedrich Schiller University

Novel systemic treatment approaches for metastatic pancreatic cancer.
From organ-on-chip to body-on-chip: The next generation of microfluidics platforms for in vitro drug efficacy and toxicity testing.
Identification of treatment-induced vulnerabilities in pancreatic cancer patients using functional model systems.
Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy.
Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment.
TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer.
Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer.
Mapping the switch that drives the pre-metastatic niche.
PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer.
Three-dimensional imaging mass cytometry for highly multiplexed molecular and cellular mapping of tissues and the tumor microenvironment.
APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis.

Expert Opin Investig Drugs. 2022 Feb 04.

Novel systemic treatment approaches for metastatic pancreatic cancer.

Klara Dorman, Volker Heinemann, Sebastian Kobold, Michael von Bergwelt-Baildon, Stefan Boeck.

   INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) has a 5-year overall survival rate of 10 %, emphasizing the need for more effective therapies, especially in metastatic disease. The immunosuppressive tumor microenvironment, poor vascularization, and dense tumor stroma typical for PDAC are hurdles that need to be overcome by novel drugs. Investigations are moving towards more targeted treatments including immunotherapy and cell-based approaches.
AREAS COVERED: This article reviews emerging drugs in clinical development for metastatic PDAC, focusing on cellular therapies and novel treatments targeting metabolism, tumor stroma, oncogenic pathways and immunosuppression. With immunotherapy and CAR T cell therapy on the rise in hematological malignancies, the transfer to solid tumors remains intriguing. Multiple exciting clinical trials investigating innovative therapeutic strategies for PDAC are currently ongoing and reviewed herein. ClinicalTrials.gov, conference abstracts and PubMed were searched in August 2021 and assessed for information on ongoing and published clinical studies.
EXPERT OPINION: With many challenges to overcome, the optimal therapy for patients with metastatic PDAC is likely to consist of a combination of different agents. We are slowly moving from entity-dependent approaches to ones more focused on molecular and pathological features. Increasingly personalized treatment plans tailored to each patient may be the future of PDAC therapy.

Keywords:  Pancreatic cancer; cellular therapy; immunotherapy; metastatic; novel drugs; targeted therapy

DOI:  https://doi.org/10.1080/13543784.2022.2037552
Prog Mol Biol Transl Sci. 2022 ;pii: S1877-1173(21)00159-9. [Epub ahead of print]187(1): 41-91

From organ-on-chip to body-on-chip: The next generation of microfluidics platforms for in vitro drug efficacy and toxicity testing.

Jerome Lacombe, Maria Soldevila, Frederic Zenhausern.

  The high failure rate in drug development is often attributed to the lack of accurate pre-clinical models that may lead to false discoveries and inconclusive data when the compounds are eventually tested in clinical phase. With the evolution of cell culture technologies, drug testing systems have widely improved, and today, with the emergence of microfluidics devices, drug screening seems to be at the dawn of an important revolution. An organ-on-chip allows the culture of living cells in continuously perfused microchambers to reproduce physiological functions of a particular tissue or organ. The advantages of such systems are not only their ability to recapitulate the complex biochemical interactions between different human cell types but also to incorporate physical forces, including shear stress and mechanical stretching or compression. To improve this model, and to reproduce the absorption, distribution, metabolism, and elimination process of an exogenous compound, organ-on-chips can even be linked fluidically to mimic physiological interactions between different organs, leading to the development of body-on-chips. Although these technologies are still at a young age and need to address a certain number of limitations, they already demonstrated their relevance to study the effect of drugs or toxins on organs, displaying a similar response to what is observed in vivo. The purpose of this review is to present the evolution from organ-on-chip to body-on-chip, examine their current use for drug testing and discuss their advantages and future challenges they will face in order to become an essential pillar of pharmaceutical research.

Keywords:  ADME process; Body-on-chip; Drug development; Microfluidics; Microphysiological systems; Organ-on-chip; Toxicity

DOI:  https://doi.org/10.1016/bs.pmbts.2021.07.019
EMBO Mol Med. 2022 Feb 04. e14876

Identification of treatment-induced vulnerabilities in pancreatic cancer patients using functional model systems.

Katja Peschke, Hannah Jakubowsky, Arlett Schäfer, Carlo Maurer, Sebastian Lange, Felix Orben, Raquel Bernad, Felix N Harder, Matthias Eiber, Rupert Öllinger, Katja Steiger, Melissa Schlitter, Wilko Weichert, Ulrich Mayr, Veit Phillip, Christoph Schlag, Roland M Schmid, Rickmer F Braren, Bo Kong, Ihsan Ekin Demir, Helmut Friess, Roland Rad, Dieter Saur, Günter Schneider, Maximilian Reichert.

  Despite the advance and success of precision oncology in gastrointestinal cancers, the frequency of molecular-informed therapy decisions in pancreatic ductal adenocarcinoma (PDAC) is currently neglectable. We present a longitudinal precision oncology platform based on functional model systems, including patient-derived organoids, to identify chemotherapy-induced vulnerabilities. We demonstrate that treatment-induced tumor cell plasticity in vivo distinctly changes responsiveness to targeted therapies, without the presence of a selectable genetic marker, indicating that tumor cell plasticity can be functionalized. By adding a mechanistic layer to precision oncology, adaptive processes of tumors under therapy can be exploited, particularly in highly plastic tumors, such as pancreatic cancer.

Keywords:  functional screening; pancreatic cancer; precision oncology; therapy-induced vulnerabilities; tumor cell plasticity

DOI:  https://doi.org/10.15252/emmm.202114876
Cancer Cell. 2022 Jan 27. pii: S1535-6108(22)00004-6. [Epub ahead of print]

Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy.

Assia Asrir, Claire Tardiveau, Juliette Coudert, Robin Laffont, Lucas Blanchard, Elisabeth Bellard, Krystle Veerman, Sarah Bettini, Fanny Lafouresse, Estefania Vina, Dorian Tarroux, Severine Roy, Isabelle Girault, Irma Molinaro, Frédéric Martins, Jean-Yves Scoazec, Nathalie Ortega, Caroline Robert, Jean-Philippe Girard.

  Recruitment of lymphocytes into tumors is critical for anti-tumor immunity and efficacious immunotherapy. We show in murine models that tumor-associated high endothelial venules (TA-HEVs) are major sites of lymphocyte entry into tumors at baseline and upon treatment with anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB). TA-HEV endothelial cells (TA-HECs) derive from post-capillary venules, co-express MECA-79+ HEV sialomucins and E/P-selectins, and are associated with homing and infiltration into tumors of various T cell subsets. Intravital microscopy further shows that TA-HEVs are the main sites of lymphocyte arrest and extravasation into ICB-treated tumors. Increasing TA-HEC frequency and maturation increases the proportion of tumor-infiltrating stem-like CD8+ T cells, and ameliorates ICB efficacy. Analysis of tumor biopsies from 93 patients with metastatic melanoma reveals that TA-HEVs are predictive of better response and survival upon treatment with anti-PD-1/anti-CTLA-4 combination. These studies provide critical insights into the mechanisms governing lymphocyte trafficking in cancer immunity and immunotherapy.

Keywords:  CD8(+) T cells; CTLA-4; HEV; PD-1; cancer immunotherapy; high endothelial venule; immune checkpoint blockade; lymphocyte trafficking; tumor blood vessels; tumor immunology; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.ccell.2022.01.002
Nat Cancer. 2022 Jan 31.

Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment.

Chiara Falcomatà, Stefanie Bärthel, Sebastian A Widholz, Christian Schneeweis, Juan José Montero, Albulena Toska, Jonas Mir, Thorsten Kaltenbacher, Jeannine Heetmeyer, Jonathan J Swietlik, Jing-Yuan Cheng, Bianca Teodorescu, Oliver Reichert, Constantin Schmitt, Kathrin Grabichler, Andrea Coluccio, Fabio Boniolo, Christian Veltkamp, Magdalena Zukowska, Angelica Arenas Vargas, Woo Hyun Paik, Moritz Jesinghaus, Katja Steiger, Roman Maresch, Rupert Öllinger, Tim Ammon, Olga Baranov, Maria S Robles, Julia Rechenberger, Bernhard Kuster, Felix Meissner, Maximilian Reichert, Michael Flossdorf, Roland Rad, Marc Schmidt-Supprian, Günter Schneider, Dieter Saur.

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.

DOI: https://doi.org/10.1038/s43018-021-00326-1
Nat Cancer. 2021 Nov;2(11): 1185-1203

TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer.

Mengyu Tu, Lukas Klein, Elisa Espinet, Theodoros Georgomanolis, Florian Wegwitz, Xiaojuan Li, Laura Urbach, Adi Danieli-Mackay, Stefan Küffer, Kamil Bojarczuk, Athanasia Mizi, Ufuk Günesdogan, Björn Chapuy, Zuguang Gu, Albrecht Neesse, Uday Kishore, Philipp Ströbel, Elisabeth Hessmann, Stephan A Hahn, Andreas Trumpp, Argyris Papantonis, Volker Ellenrieder, Shiv K Singh.

Large-scale genomic profiling of pancreatic cancer (PDAC) has revealed two distinct subtypes: 'classical' and 'basal-like'. Their variable coexistence within the stromal immune microenvironment is linked to differential prognosis; however, the extent to which these neoplastic subtypes shape the stromal immune landscape and impact clinical outcome remains unclear. By combining preclinical models, patient-derived xenografts, as well as FACS-sorted PDAC patient biopsies, we show that the basal-like neoplastic state is sustained via BRD4-mediated cJUN/AP1 expression, which induces CCL2 to recruit tumor necrosis factor (TNF)-α-secreting macrophages. TNF-α+ macrophages force classical neoplastic cells into an aggressive phenotypic state via lineage reprogramming. Integration of ATAC-, ChIP- and RNA-seq data revealed distinct JUNB/AP1 (classical) and cJUN/AP1 (basal-like)-driven regulation of PDAC subtype identity. Pharmacological inhibition of BRD4 led to suppression of the BRD4-cJUN-CCL2-TNF-α axis, restoration of classical subtype identity and a favorable prognosis. Hence, patient-tailored therapy for a cJUNhigh/TNF-αhigh subtype is paramount in overcoming highly inflamed and aggressive PDAC states.

DOI: https://doi.org/10.1038/s43018-021-00258-w
Nat Cancer. 2021 Jan;2(1): 49-65

Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer.

Yong Li, Yi He, Junya Peng, Zhendong Su, Zeyao Li, Bingjie Zhang, Jing Ma, Meilian Zhuo, Di Zou, Xinde Liu, Xinhong Liu, Wenze Wang, Dan Huang, Mengyue Xu, Jianbin Wang, Haiteng Deng, Jing Xue, Wei Xie, Xun Lan, Mo Chen, Yupei Zhao, Wenming Wu, Charles J David.

Kras-activating mutations display the highest incidence in pancreatic ductal adenocarcinoma. Pancreatic inflammation accelerates mutant Kras-driven tumorigenesis in mice, suggesting high selectivity in the cells that oncogenic Kras transforms, although the mechanisms dictating this specificity are poorly understood. Here we show that pancreatic inflammation is coupled to the emergence of a transient progenitor cell population that is readily transformed in the presence of mutant KrasG12D. These progenitors harbor a proto-oncogenic transcriptional program driven by a transient enhancer network. KrasG12D mutations lock this enhancer network in place, providing a sustained Kras-dependent oncogenic program that drives tumors throughout progression. Enhancer co-option occurs through functional interactions between the Kras-activated transcription factors Junb and Fosl1 and pancreatic lineage transcription factors, potentially accounting for inter-tissue specificity of oncogene transformation. The pancreatic ductal adenocarcinoma cell of origin thus provides an oncogenic transcriptional program that fuels tumor progression beyond initiation, accounting for the intra-tissue selectivity of Kras transformation.

DOI: https://doi.org/10.1038/s43018-020-00134-z
Nat Cancer. 2020 Jun;1(6): 577-579

Mapping the switch that drives the pre-metastatic niche.

Sabina Kaczanowska, Rosandra N Kaplan.

DOI: https://doi.org/10.1038/s43018-020-0076-9
Nat Cancer. 2020 Jul;1(7): 681-691

PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer.

Soyoung A Oh, Dai-Chen Wu, Jeanne Cheung, Armando Navarro, Huizhong Xiong, Rafael Cubas, Klara Totpal, Henry Chiu, Yan Wu, Laetitia Comps-Agrar, Andrew M Leader, Miriam Merad, Merone Roose-Germa, Soren Warming, Minhong Yan, Jeong M Kim, Sascha Rutz, Ira Mellman.

Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses. Our data identify a unique role for DCs in the PD-L1-PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells.

DOI: https://doi.org/10.1038/s43018-020-0075-x
Nat Cancer. 2022 Jan;3(1): 122-133

Three-dimensional imaging mass cytometry for highly multiplexed molecular and cellular mapping of tissues and the tumor microenvironment.

Cancer Grand Challenges IMAXT Consortium

A holistic understanding of tissue and organ structure and function requires the detection of molecular constituents in their original three-dimensional (3D) context. Imaging mass cytometry (IMC) enables simultaneous detection of up to 40 antigens and transcripts using metal-tagged antibodies but has so far been restricted to two-dimensional imaging. Here we report the development of 3D IMC for multiplexed 3D tissue analysis at single-cell resolution and demonstrate the utility of the technology by analysis of human breast cancer samples. The resulting 3D models reveal cellular and microenvironmental heterogeneity and cell-level tissue organization not detectable in two dimensions. 3D IMC will prove powerful in the study of phenomena occurring in 3D space such as tumor cell invasion and is expected to provide invaluable insights into cellular microenvironments and tissue architecture.

DOI: https://doi.org/10.1038/s43018-021-00301-w
Nat Cancer. 2021 Dec;2(12): 1338-1356

APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis.

Sonja M Wörmann, Amy Zhang, Fredrik I Thege, Robert W Cowan, Dhwani N Rupani, Runsheng Wang, Sara L Manning, Chris Gates, Weisheng Wu, Rena Levin-Klein, Kimal I Rajapakshe, Meifang Yu, Asha S Multani, Ya'an Kang, Cullen M Taniguchi, Katharina Schlacher, Melena D Bellin, Matthew H G Katz, Michael P Kim, Jason B Fleming, Steven Gallinger, Ravikanth Maddipati, Reuben S Harris, Faiyaz Notta, Susan R Ross, Anirban Maitra, Andrew D Rhim.

Despite efforts in understanding its underlying mechanisms, the etiology of chromosomal instability (CIN) remains unclear for many tumor types. Here, we identify CIN initiation as a previously undescribed function for APOBEC3A (A3A), a cytidine deaminase upregulated across cancer types. Using genetic mouse models of pancreatic ductal adenocarcinoma (PDA) and genomics analyses in human tumor cells we show that A3A-induced CIN leads to aggressive tumors characterized by enhanced early dissemination and metastasis in a STING-dependent manner and independently of the canonical deaminase functions of A3A. We show that A3A upregulation recapitulates numerous copy number alterations commonly observed in patients with PDA, including co-deletions in DNA repair pathway genes, which in turn render these tumors susceptible to poly (ADP-ribose) polymerase inhibition. Overall, our results demonstrate that A3A plays an unexpected role in PDA as a specific driver of CIN, with significant effects on disease progression and treatment.

DOI: https://doi.org/10.1038/s43018-021-00268-8