bims-tuchim 2021-10-24 papers

Cancer Discov. 2021 Oct 22.

Sub-Tumor Microenvironments Influence PDAC Progression and Therapy Response.

Two distinct tumor microenvironment (TME) states exist in pancreatic cancer and are linked to patient outcome.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-151

Front Bioeng Biotechnol. 2021 ;9 697657

Three-Dimensional In Vitro Lymphangiogenesis Model in Tumor Microenvironment.

Youngkyu Cho, Kyuhwan Na, Yesl Jun, Jihee Won, Ji Hun Yang, Seok Chung.

Lymphangiogenesis is a stage of new lymphatic vessel formation in development and pathology, such as inflammation and tumor metastasis. Physiologically relevant models of lymphatic vessels have been in demand because studies on lymphatic vessels are required for understanding the mechanism of tumor metastasis. In this study, a new three-dimensional lymphangiogenesis model in a tumor microenvironment is proposed, using a newly designed macrofluidic platform. It is verified that controllable biochemical and biomechanical cues, which contribute to lymphangiogenesis, can be applied in this platform. In particular, this model demonstrates that a reconstituted lymphatic vessel has an in vivo-like lymphatic vessel in both physical and biochemical aspects. Since biomechanical stress with a biochemical factor influences robust directional lymphatic sprouting, whether our model closely approximates in vivo, the initial lymphatics in terms of the morphological and genetic signatures is investigated. Furthermore, attempting an incorporation with a tumor spheroid, this study successfully develops a complex tumor microenvironment model for use in lymphangiogenesis and reveals the microenvironment factors that contribute to tumor metastasis. As a first attempt at a coculture model, this reconstituted model is a novel system with a fully three-dimensional structure and can be a powerful tool for pathological drug screening or disease model.

Keywords: interstitial flow; lymphangiogenesis; lymphatic vessel; organ-on-a-chip; tumor microenvironment

DOI: https://doi.org/10.3389/fbioe.2021.697657

Cell Rep. 2021 Oct 19. pii: S2211-1247(21)01319-X. [Epub ahead of print]37(3): 109852

Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer.

Sophie C Lodestijn, Daniël M Miedema, Kristiaan J Lenos, Lisanne E Nijman, Saskia C Belt, Khalid El Makrini, Maria C Lecca, Cynthia Waasdorp, Tom van den Bosch, Maarten F Bijlsma, Louis Vermeulen.

Effective treatments for pancreatic ductal adenocarcinoma (PDAC) are lacking, and targeted agents have demonstrated limited efficacy. It has been speculated that a rare population of cancer stem cells (CSCs) drives growth, therapy resistance, and rapid metastatic progression in PDAC. These CSCs demonstrate high clonogenicity in vitro and tumorigenic potential in vivo. However, their relevance in established PDAC tissue has not been determined. Here, we use marker-independent stochastic clonal labeling, combined with quantitative modeling of tumor expansion, to uncover PDAC tissue growth dynamics. We find that in contrast to the CSC model, all PDAC cells display clonogenic potential in situ. Furthermore, the proximity to activated cancer-associated fibroblasts determines tumor cell clonogenicity. This means that the microenvironment is dominant in defining the clonogenic activity of PDAC cells. Indeed, manipulating the stroma by Hedgehog pathway inhibition alters the tumor growth mode, revealing that tumor-stroma crosstalk shapes tumor growth dynamics and clonal architecture.

Keywords: PDAC; cancer stem cells; lineage tracing; pancreatic cancer; stem cell dynamics; stroma

DOI: https://doi.org/10.1016/j.celrep.2021.109852

Cells. 2021 Oct 13. pii: 2734. [Epub ahead of print]10(10):

siRNA Nanoparticle Targeting PD-L1 Activates Tumor Immunity and Abrogates Pancreatic Cancer Growth in Humanized Preclinical Model.

Jae Yun Jung, Hyun Jin Ryu, Seung-Hwan Lee, Dong-Young Kim, Myung Ji Kim, Eun Ji Lee, Yeon-Mi Ryu, Sang-Yeob Kim, Kyu-Pyo Kim, Eun Young Choi, Hyung Jun Ahn, Suhwan Chang.

Pancreatic cancer is characterized by late detection, frequent drug resistance, and a highly metastatic nature, leading to poor prognosis. Antibody-based immunotherapy showed limited success for pancreatic cancer, partly owing to the low delivery rate of the drug into the tumor. Herein, we describe a poly(lactic-co-glycolic acid;PLGA)-based siRNA nanoparticle targeting PD-L1 (siPD-L1@PLGA). The siPD-L1@PLGA exhibited efficient knockdown of PD-L1 in cancer cells, without affecting the cell viability up to 6 mg/mL. Further, 99.2% of PDAC cells uptake the nanoparticle and successfully blocked the IFN-gamma-mediated PD-L1 induction. Consistently, the siPD-L1@PLGA sensitized cancer cells to antigen-specific immune cells, as exemplified by Ovalbumin-targeting T cells. To evaluate its efficacy in vivo, we adopted a pancreatic PDX model in humanized mice, generated by grafting CD34+ hematopoeitic stem cells onto NSG mice. The siPD-L1@PLGA significantly suppressed pancreatic tumor growth in this model with upregulated IFN-gamma positive CD8 T cells, leading to more apoptotic tumor cells. Multiplex immunofluorescence analysis exhibited comparable immune cell compositions in control and siPD-L1@PLGA-treated tumors. However, we found higher Granzyme B expression in the siPD-L1@PLGA-treated tumors, suggesting higher activity of NK or cytotoxic T cells. Based on these results, we propose the application of siPD-L1@PLGA as an immunotherapeutic agent for pancreatic cancer.

Keywords: PD-L1; humanized NSG; immunotherapy; nanoparticle; pancreatic cancer; siRNA

DOI: https://doi.org/10.3390/cells10102734