Editorial

3 pages, 190 KiB

Open AccessEditorial

by Maria Flavia Di Renzo and Simona Corso

Cancers 2020, 12(12), 3779; https://doi.org/10.3390/cancers12123779 - 15 Dec 2020

Cited by 6 | Viewed by 1283

For many decades, basic and preclinical cancer research has been based on the use of established, commercially available cell lines, originally derived from patients’ samples but adapted to grow indefinitely in artificial culture conditions, and on xenograft models developed by injection of these [...] Read more.

For many decades, basic and preclinical cancer research has been based on the use of established, commercially available cell lines, originally derived from patients’ samples but adapted to grow indefinitely in artificial culture conditions, and on xenograft models developed by injection of these cells in immunocompromised animals [...] Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

Research

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25 pages, 6479 KiB

Open AccessArticle

A Platform of Patient-Derived Microtumors Identifies Individual Treatment Responses and Therapeutic Vulnerabilities in Ovarian Cancer

by Nicole Anderle, André Koch, Berthold Gierke, Anna-Lena Keller, Annette Staebler, Andreas Hartkopf, Sara Y. Brucker, Michael Pawlak, Katja Schenke-Layland and Christian Schmees

Cancers 2022, 14(12), 2895; https://doi.org/10.3390/cancers14122895 - 12 Jun 2022

Cited by 6 | Viewed by 2954

Abstract

In light of the frequent development of therapeutic resistance in cancer treatment, there is a strong need for personalized model systems representing patient tumor heterogeneity, while enabling parallel drug testing and identification of appropriate treatment responses in individual patients. Using ovarian cancer as [...] Read more.

In light of the frequent development of therapeutic resistance in cancer treatment, there is a strong need for personalized model systems representing patient tumor heterogeneity, while enabling parallel drug testing and identification of appropriate treatment responses in individual patients. Using ovarian cancer as a prime example of a heterogeneous tumor disease, we developed a 3D preclinical tumor model comprised of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) to identify individual treatment vulnerabilities and validate chemo-, immuno- and targeted therapy efficacies. Enzymatic digestion of primary ovarian cancer tissue and cultivation in defined serum-free media allowed rapid and efficient recovery of PDM, while preserving histopathological features of corresponding patient tumor tissue. Reverse-phase protein array (RPPA)-analyses of >110 total and phospho-proteins enabled the identification of patient-specific sensitivities to standard, platinum-based therapy and thereby the prediction of potential treatment-responders. Co-cultures of PDM and autologous TILs for individual efficacy testing of immune checkpoint inhibitor treatment demonstrated patient-specific enhancement of cytotoxic TIL activity by this therapeutic approach. Combining protein pathway analysis and drug efficacy testing of PDM enables drug mode-of-action analyses and therapeutic sensitivity prediction within a clinically relevant time frame after surgery. Follow-up studies in larger cohorts are currently under way to further evaluate the applicability of this platform to support clinical decision making. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

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18 pages, 2324 KiB

Open AccessArticle

Preclinical Head and Neck Squamous Cell Carcinoma Models for Combined Targeted Therapy Approaches

by Nina Schoenwaelder, Mareike Krause, Thomas Freitag, Björn Schneider, Sarah Zonnur, Annette Zimpfer, Anne Sophie Becker, Inken Salewski, Daniel Fabian Strüder, Heiko Lemcke, Christina Grosse-Thie, Christian Junghanss and Claudia Maletzki

Cancers 2022, 14(10), 2484; https://doi.org/10.3390/cancers14102484 - 18 May 2022

Cited by 1 | Viewed by 1857

Abstract

This study aimed to refine combined targeted approaches on well-characterized, low-passage tumor models. Upon in vivo xenografting in immunodeficient mice, three cell lines from locally advanced or metastatic HNSCC were established. Following quality control and basic characterization, drug response was examined after therapy [...] Read more.

This study aimed to refine combined targeted approaches on well-characterized, low-passage tumor models. Upon in vivo xenografting in immunodeficient mice, three cell lines from locally advanced or metastatic HNSCC were established. Following quality control and basic characterization, drug response was examined after therapy with 5-FU, Cisplatin, and cyclin-dependent kinase inhibitors (abemaciclib, THZ1). Our cell lines showed different in vitro growth kinetics, morphology, invasive potential, and radiosensitivity. All cell lines were sensitive to 5-FU, Cisplatin, and THZ1. One cell line (HNSCC48 P0 M1) was sensitive to abemaciclib. Here, Cyto-FISH revealed a partial CDKN2a deletion, which resulted from a R58* mutation. Moreover, this cell line demonstrated chromosome 12 polysomy, accompanied by an increase in CDK4-specific copy numbers. In HNSCC16 P1 M1, we likewise identified polysomy-associated CDK4-gains. Although not sensitive to abemaciclib per se, the cell line showed a G1-arrest, an increased number of acidic organelles, and a swollen structure. Notably, intrinsic resistance was conquered by Cisplatin because of cMYC and IDO-1 downregulation. Additionally, this Cisplatin-CDKI combination induced HLA-ABC and PD-L1 upregulation, which may enhance immunogenicity. Performing functional and molecular analysis on patient-individual HNSCC-models, we identified CDK4-gains as a biomarker for abemaciclib response prediction and describe an approach to conquer intrinsic CDKI resistance. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

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16 pages, 10414 KiB

Open AccessArticle

Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer

by Sandra Wagner, Nicola T. Beger, Stephanie Matschos, Antonia Szymanski, Randy Przybylla, Florian Bürtin, Friedrich Prall, Michael Linnebacher and Christina S. Mullins

Cancers 2021, 13(18), 4717; https://doi.org/10.3390/cancers13184717 - 21 Sep 2021

Cited by 6 | Viewed by 1930

Abstract

The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding [...] Read more.

The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding metastases of 10 CRC patients were compared. Cell line characteristics and chemosensitivity were investigated pairwise for primary and metastatic tumours of four patients. PDX models of one patient were treated in vivo for proof of concept. Driver mutations did not differ between primaries and metastases, while the latter accumulated additional mutations. In vitro chemosensitivity testing revealed no differences for responses to 5-FU and oxaliplatin between primary and metastatic cell lines. However, irinotecan response differed significantly: the majority of metastases-derived cell lines was less sensitive to irinotecan than their matching primary counterpart. Therapy recommendations based on these findings were compared to clinical treatment response and mostly in line with the predicted outcome. Therefore, primary tumour cell models seem to be a good tool for drug response testing and conclusion drawing for later metastases. With further data from tumour-derived cell models, such predictions could improve clinical treatment decisions, both recommending likely effective therapeutic options while excluding ineffective treatments. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

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19 pages, 8814 KiB

Open AccessArticle

Recruitment, Infiltration, and Cytotoxicity of HLA-Independent Killer Lymphocytes in Three-Dimensional Melanoma Models

by Ilenia Iaia, Loretta Gammaitoni, Giulia Cattaneo, Lidia Giraudo, Chiara Donini, Erika Fiorino, Luca Primo, Fabrizio Carnevale-Schianca, Massimo Aglietta, Alberto Puliafito and Dario Sangiolo

Cancers 2021, 13(10), 2302; https://doi.org/10.3390/cancers13102302 - 11 May 2021

Cited by 3 | Viewed by 2289

Abstract

Cancer adoptive cell therapy (ACT) with HLA-independent tumor killer lymphocytes is a promising approach, with intrinsic features potentially addressing crucial tumor-escape mechanisms of checkpoint inhibitors. Cytokine-induced Killer (CIK) and Natural Killer (NK) lymphocytes share similar tumor-killing mechanisms, with preclinical evidence of intense activity [...] Read more.

Cancer adoptive cell therapy (ACT) with HLA-independent tumor killer lymphocytes is a promising approach, with intrinsic features potentially addressing crucial tumor-escape mechanisms of checkpoint inhibitors. Cytokine-induced Killer (CIK) and Natural Killer (NK) lymphocytes share similar tumor-killing mechanisms, with preclinical evidence of intense activity against multiple solid tumors and currently testing in clinical studies. To improve the effective clinical translation of such ACT approaches, several fundamental questions still need to be addressed within appropriate preclinical contexts, capable of overcoming limitations imposed by most traditional two-dimensional assays. Here, we developed a novel experimental approach to explore, dissect, and visualize the interactions of CIK and NK lymphocytes with melanoma tumors in vitro in 3D. Primary melanoma cells were assembled into small tumors that were dispersed in a 3D matrix and challenged with patient-derived CIK or the NK-92 cell line. By means of imaging-based methods, we reported, visualized, and quantitatively measured the recruitment of CIK and NK on the 3D targets, their infiltration, and cytotoxic activity. Our results support the effective tumor recruitment and tumor infiltration by CIK and NK. Such features appeared dependent on the specific geometric aspects of the environment but can be explained in terms of directional migration toward the tumor, without invoking major feedback components. Overall, our 3D platform allows us to monitor the processes of tumor recruitment, infiltration, and killing by means of live measurements, revealing important kinetic aspects of ACT with CIK and NK against melanoma. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

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21 pages, 6557 KiB

Open AccessArticle

A Novel Multidrug-Resistant Cell Line from an Italian Intrahepatic Cholangiocarcinoma Patient

by Caterina Peraldo-Neia, Annamaria Massa, Francesca Vita, Marco Basiricò, Chiara Raggi, Paola Bernabei, Paola Ostano, Laura Casorzo, Mara Panero, Francesco Leone, Giuliana Cavalloni and Massimo Aglietta

Cancers 2021, 13(9), 2051; https://doi.org/10.3390/cancers13092051 - 23 Apr 2021

Cited by 8 | Viewed by 2517

Abstract

Chemotherapy resistance is a relevant clinical issue in tumor treatment, in particular in biliary tract carcinoma (BTC), for which there are no effective therapies, neither in the first nor in the second line. The development of chemoresistant cell lines as experimental models to [...] Read more.

Chemotherapy resistance is a relevant clinical issue in tumor treatment, in particular in biliary tract carcinoma (BTC), for which there are no effective therapies, neither in the first nor in the second line. The development of chemoresistant cell lines as experimental models to investigate the mechanisms of resistance and identify alternative druggable pathways is mandatory. In BTC, in which genetics and biological behavior depend on the etiology, ethnicity, and anatomical site of origin, the creation of models that better recapitulate these characteristics is even more crucial. Here we have established and characterized an intrahepatic cholangiocarcinoma (iCCA) cell line derived from an Italian patient, called 82.3. Cells were isolated from a patient-derived xenograft (PDX) and, after establishment, immunophenotypic, biological, genetic, molecular characteristics, and tumorigenicity in vivo in NOD/SCID mice were investigated. 82.3 cells exhibited epithelial morphology and cell markers (EPCAM, CK7, and CK19); they also expressed different cancer stem markers (CD44, CD133, CD49b, CD24, Stro1, PAX6, FOXA2, OCT3/4), α–fetoprotein and under anchorage-independent and serum-free conditions were capable of originating cholangiospheres. The population doubling time was approximately 53 h. In vitro, they demonstrated a poor ability to migrate; in vivo, 82.3 cells retained their tumorigenicity, with a long latency period (16 weeks). Genetic identity using DNA fingerprinting analysis revealed 16 different loci, and the cell line was characterized by a complex hyperdiploid karyotype. Furthermore, 82.3 cells showed cross-resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin; in fact, their genetic profile showed that 60% of genes (n = 168), specific for drug resistance and related to the epithelial-mesenchymal transition, were deregulated in 82.3 cells compared to a control iCCA cell line sensitive to chemotherapeutics. RNA sequencing analysis revealed the enrichment for genes associated with epithelial to mesenchymal transition (EMT), vasculature development, and extracellular matrix (ECM) remodeling, underlining an aggressive phenotype. In conclusion, we have created a new iCCA cell line of Caucasian origin: this could be exploited as a preclinical model to study drug resistance mechanisms and to identify alternative therapies to improve the prognosis of this tumor type. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

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Review

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13 pages, 639 KiB

Open AccessReview

Patient-Derived In Vitro Models of Ovarian Cancer: Powerful Tools to Explore the Biology of the Disease and Develop Personalized Treatments

by Chiara Battistini and Ugo Cavallaro

Cancers 2023, 15(2), 368; https://doi.org/10.3390/cancers15020368 - 05 Jan 2023

Cited by 1 | Viewed by 2353

Abstract

Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy worldwide due to a late diagnosis caused by the lack of specific symptoms and rapid dissemination into the peritoneal cavity. The standard of care for OC treatment is surgical cytoreduction followed by platinum-based [...] Read more.

Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy worldwide due to a late diagnosis caused by the lack of specific symptoms and rapid dissemination into the peritoneal cavity. The standard of care for OC treatment is surgical cytoreduction followed by platinum-based chemotherapy. While a response to this frontline treatment is common, most patients undergo relapse within 2 years and frequently develop a chemoresistant disease that has become unresponsive to standard treatments. Moreover, also due to the lack of actionable mutations, very few alternative therapeutic strategies have been designed as yet for the treatment of recurrent OC. This dismal clinical perspective raises the need for pre-clinical models that faithfully recapitulate the original disease and therefore offer suitable tools to design novel therapeutic approaches. In this regard, patient-derived models are endowed with high translational relevance, as they can better capture specific aspects of OC such as (i) the high inter- and intra-tumor heterogeneity, (ii) the role of cancer stem cells (a small subset of tumor cells endowed with tumor-initiating ability, which can sustain tumor spreading, recurrence and chemoresistance), and (iii) the involvement of the tumor microenvironment, which interacts with tumor cells and modulates their behavior. This review describes the different in vitro patient-derived models that have been developed in recent years in the field of OC research, focusing on their ability to recapitulate specific features of this disease. We also discuss the possibilities of leveraging such models as personalized platforms to design new therapeutic approaches and guide clinical decisions. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

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14 pages, 1518 KiB

Open AccessReview

Patient Derived Ex-Vivo Cancer Models in Drug Development, Personalized Medicine, and Radiotherapy

by Ryan Zitter, Rishi Man Chugh and Subhrajit Saha

Cancers 2022, 14(12), 3006; https://doi.org/10.3390/cancers14123006 - 18 Jun 2022

Cited by 3 | Viewed by 2657

Abstract

The field of cancer research is famous for its incremental steps in improving therapy. The consistent but slow rate of improvement is greatly due to its meticulous use of consistent cancer biology models. However, as we enter an era of increasingly personalized cancer [...] Read more.

The field of cancer research is famous for its incremental steps in improving therapy. The consistent but slow rate of improvement is greatly due to its meticulous use of consistent cancer biology models. However, as we enter an era of increasingly personalized cancer care, including chemo and radiotherapy, our cancer models must be equally able to be applied to all individuals. Patient-derived organoid (PDO) and organ-in-chip (OIC) models based on the micro-physiological bioengineered platform have already been considered key components for preclinical and translational studies. Accounting for patient variability is one of the greatest challenges in the crossover from preclinical development to clinical trials and patient derived organoids may offer a steppingstone between the two. In this review, we highlight how incorporating PDO’s and OIC’s into the development of cancer therapy promises to increase the efficiency of our therapeutics. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models)

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