bims-tuchim 2022-01-23 papers

Proc Natl Acad Sci U S A. 2022 Jan 25. pii: e2119463119. [Epub ahead of print]119(4):

Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.

Zhikai Wang, Philip Moresco, Ran Yan, Jiayun Li, Ya Gao, Daniele Biasci, Min Yao, Jordan Pearson, Jaclyn F Hechtman, Tobias Janowitz, Raza M Zaidi, Matthew J Weiss, Douglas T Fearon.

Cancer immunotherapy frequently fails because most carcinomas have few T cells, suggesting that cancers can suppress T cell infiltration. Here, we show that cancer cells of human pancreatic ductal adenocarcinoma (PDA), colorectal cancer, and breast cancer are coated with transglutaminase-2 (TGM2)-dependent covalent CXCL12-keratin-19 (KRT19) heterodimers that are organized as filamentous networks. Since a dimeric form of CXCL12 suppresses the motility of human T cells, we determined whether this polymeric CXCL12-KRT19 coating mediated T cell exclusion. Mouse tumors containing control PDA cells exhibited the CXCL12-KRT19 coating, excluded T cells, and did not respond to treatment with anti-PD-1 antibody. Tumors containing PDA cells not expressing either KRT19 or TGM2 lacked the CXCL12-KRT19 coating, were infiltrated with activated CD8+ T cells, and growth was suppressed with anti-PD-1 antibody treatment. Thus, carcinomas assemble a CXCL12-KRT19 coating to evade cancer immune attack.

Keywords: CXCL12; T cells; cancer immunology; keratin-19; transglutaminase-2

DOI: https://doi.org/10.1073/pnas.2119463119

Bioengineering (Basel). 2022 Jan 11. pii: 28. [Epub ahead of print]9(1):

Organ on Chip Technology to Model Cancer Growth and Metastasis.

Giorgia Imparato, Francesco Urciuolo, Paolo Antonio Netti.

Organ on chip (OOC) has emerged as a major technological breakthrough and distinct model system revolutionizing biomedical research and drug discovery by recapitulating the crucial structural and functional complexity of human organs in vitro. OOC are rapidly emerging as powerful tools for oncology research. Indeed, Cancer on chip (COC) can ideally reproduce certain key aspects of the tumor microenvironment (TME), such as biochemical gradients and niche factors, dynamic cell-cell and cell-matrix interactions, and complex tissue structures composed of tumor and stromal cells. Here, we review the state of the art in COC models with a focus on the microphysiological systems that host multicellular 3D tissue engineering models and can help elucidate the complex biology of TME and cancer growth and progression. Finally, some examples of microengineered tumor models integrated with multi-organ microdevices to study disease progression in different tissues will be presented.

Keywords: 3D tissue; cancer on chip; metastasis; organ on chip; tumor microenvironment

DOI: https://doi.org/10.3390/bioengineering9010028

Sci Rep. 2022 Jan 17. 12(1): 791

Fibroblast-mediated uncaging of cancer cells and dynamic evolution of the physical microenvironment.

Chang Liu, Michael Mak.

Stromal cells are prominent in solid tumor microenvironments and contribute to tumor progression. In particular, fibroblasts are common cell types in the tumor stroma that play important roles in remodeling the extracellular matrix (ECM). Here, we perform co-culture experiments with tumor cells and fibroblasts embedded in 3D collagen I matrices. We investigate the impact of fibroblasts on the migratory behavior of neighboring tumor cells and on the evolution of the surrounding ECM. We find that fibroblasts increase tumor cell motility and facilitate the transition from confined to diffusive tumor cell motions, indicative of an uncaging effect. Furthermore, the ECM is globally and locally remodeled substantially with the presence of fibroblasts. Moreover, these fibroblast-mediated phenomena are in part dependent on matrix metalloproteinases.

DOI: https://doi.org/10.1038/s41598-021-03134-w

Biomedicines. 2022 Jan 11. pii: 146. [Epub ahead of print]10(1):

Synergistic Analysis of Circulating Tumor Cells Reveals Prognostic Signatures in Pilot Study of Treatment-Naïve Metastatic Pancreatic Cancer Patients.

Sarah Owen, Emily Prantzalos, Valerie Gunchick, Vaibhav Sahai, Sunitha Nagrath.

Pancreatic ductal adenocarcinoma is typically diagnosed at late stages and has one of the lowest five-year survival rates of all malignancies. In this pilot study, we identify signatures related to survival and treatment response found in circulating tumor cells (CTCs). Patients with poor survival had increased mutant KRAS expression and deregulation of connected pathways such as PI3K-AKT and MAPK signaling. Further, in a subset of these patients, expression patterns of gemcitabine resistance mechanisms were observed, even prior to initiating treatment. This work highlights the need for identifying patients with these resistance profiles and designing treatment regimens to circumvent these mechanisms.

Keywords: CTC; gene expression profiling; liquid biopsy; mutant KRAS; pancreatic cancer

DOI: https://doi.org/10.3390/biomedicines10010146

STAR Protoc. 2022 Mar 18. 3(1): 101079

Normal and tumor-derived organoids as a drug screening platform for tumor-specific drug vulnerabilities.

Camilla Calandrini, Jarno Drost.

Patient-derived tumor organoids can be predictive of patient's treatment responses, and normal tissue-derived organoids allow for drug toxicity testing. Combining both types of organoids therefore enables screening for tumor-specific drug vulnerabilities. Here, we provide a detailed protocol for organoid drug screening using, as proof-of-principle, patient-derived malignant rhabdoid tumor organoids. The protocol can be adapted for drug testing on any tumor and/or normal tissue-derived organoid culture. For complete details on the use and execution of this protocol, please refer to Calandrini et al. (2021).

Keywords: Cancer; Cell Biology; Health Sciences; High Throughput Screening; Organoids; Stem Cells

DOI: https://doi.org/10.1016/j.xpro.2021.101079

Sci Adv. 2022 Jan 21. 8(3): eabg6383

Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors.

Rupsa Datta, Sharanya Sivanand, Allison N Lau, Logan V Florek, Anna M Barbeau, Jeffrey Wyckoff, Melissa C Skala, Matthew G Vander Heiden.

Access to electron acceptors supports oxidized biomass synthesis and can be limiting for cancer cell proliferation, but how cancer cells overcome this limitation in tumors is incompletely understood. Nontransformed cells in tumors can help cancer cells overcome metabolic limitations, particularly in pancreatic cancer, where pancreatic stellate cells (PSCs) promote cancer cell proliferation and tumor growth. However, whether PSCs affect the redox state of cancer cells is not known. By taking advantage of the endogenous fluorescence properties of reduced nicotinamide adenine dinucleotide and oxidized flavin adenine dinucleotide cofactors we use optical imaging to assess the redox state of pancreatic cancer cells and PSCs and find that direct interactions between PSCs and cancer cells promote a more oxidized state in cancer cells. This suggests that metabolic interaction between cancer cells and PSCs is a mechanism to overcome the redox limitations of cell proliferation in pancreatic cancer.

DOI: https://doi.org/10.1126/sciadv.abg6383

Front Oncol. 2021 ;11 762184

Patient-Derived Organoids in Precision Medicine: Drug Screening, Organoid-on-a-Chip and Living Organoid Biobank.

Zilong Zhou, Lele Cong, Xianling Cong.

Organoids are in vitro self-assembling, organ-like, three-dimensional cellular structures that stably retain key characteristics of the respective organs. Organoids can be generated from healthy or pathological tissues derived from patients. Cancer organoid culture platforms have several advantages, including conservation of the cellular composition that captures the heterogeneity and pharmacotypic signatures of the parental tumor. This platform has provided new opportunities to fill the gap between cancer research and clinical outcomes. Clinical trials have been performed using patient-derived organoids (PDO) as a tool for personalized medical decisions to predict patients' responses to therapeutic regimens and potentially improve treatment outcomes. Living organoid biobanks encompassing several cancer types have been established, providing a representative collection of well-characterized models that will facilitate drug development. In this review, we highlight recent developments in the generation of organoid cultures and PDO biobanks, in preclinical drug discovery, and methods to design a functional organoid-on-a-chip combined with microfluidic. In addition, we discuss the advantages as well as limitations of human organoids in patient-specific therapy and highlight possible future directions.

Keywords: drug screening; living biobanks; microfluidics; organoids; organoids-on-a-chip; patient-derived organoid

DOI: https://doi.org/10.3389/fonc.2021.762184

Clin Transl Med. 2022 Jan;12(1): e670

Multi-omics analysis of intra-tumoural and inter-tumoural heterogeneity in pancreatic ductal adenocarcinoma.

Xiaoqian Liu, Wenqian Wang, Xiaoding Liu, Zhiwen Zhang, Lianyuan Yu, Ruiyu Li, Dan Guo, Weijing Cai, Xueping Quan, Huanwen Wu, Menghua Dai, Zhiyong Liang.

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is associated with the tumour heterogeneity. To explore intra- and inter-tumoural heterogeneity in PDAC, we analysed the multi-omics profiles of 61 PDAC lesion samples, along with the matched pancreatic normal tissue samples, from 19 PDAC patients. Haematoxylin and Eosin (H&E) staining revealed that diversely differentiated lesions coexisted both within and across individual tumours. Whole exome sequencing (WES) of samples from multi-region revealed diverse types of mutations in diverse genes between cancer cells within a tumour and between tumours from different individuals. The copy number variation (CNV) analysis also showed that PDAC exhibited intra- and inter-tumoural heterogeneity in CNV and that high average CNV burden was associated poor prognosis of the patients. Phylogenetic tree analysis and clonality/timing analysis of mutations displayed diverse evolutionary pathways and spatiotemporal characteristics of genomic alterations between different lesions from the same or different tumours. Hierarchical clustering analysis illustrated higher inter-tumoural heterogeneity than intra-tumoural heterogeneity of PDAC at the transcriptional levels as lesions from the same patients are grouped into a single cluster. Immune marker genes are differentially expressed in different regions and tumour samples as shown by tumour microenvironment (TME) analysis. TME appeared to be more heterogeneous than tumour cells in the same patient. Lesion-specific differentially methylated regions (DMRs) were identified by methylated DNA immunoprecipitation sequencing (MeDIP-seq). Furthermore, the integration analysis of multi-omics data showed that the mRNA levels of some genes, such as PLCB4, were significantly correlated with the gene copy numbers. The mRNA expressions of potential PDAC biomarkers ZNF521 and KDM6A were correlated with copy number alteration and methylation, respectively. Taken together, our results provide a comprehensive view of molecular heterogeneity and evolutionary trajectories of PDAC and may guide personalised treatment strategies in PDAC therapy.

Keywords: cancer evolution; heterogeneity; immunotherapy; molecular targeted therapy; multi-omics analysis; pancreatic ductal adenocarcinoma

DOI: https://doi.org/10.1002/ctm2.670