Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer

Gavert, Nancy; Zwang, Yaara; Weiser, Roi; Greenberg, Orli; Halperin, Sharon; Jacobi, Oded; Mallel, Giuseppe; Berger, Arieh; Stossel, Erez; Rotin, Daniil; Grinshpun, Albert; Kamer, Iris; Bar, Jair; Pines, Guy; Saidian, Daniel; Bar, Ilana; Golan, Shay; Rosenbaum, Eli; Nadu, Andrei; Ben-Ami, Eytan; Weitzen, Rony; Nechushtan, Hovav; Golan, Talia; Brenner, Baruch; Nissan, Aviram; Margalit, Ofer; Hershkovitz, Dov; Lahat, Guy; Straussman, Ravid

doi:10.1038/s43018-021-00325-2

Cited by 29 publications

(31 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To directly compare viability of the whole tumor ecosystem pre- and post-culture, a five-tiered scoring system was utilized for subsequent classification (Fig. 2 L, adapted from Gavert et al 21 : 1 for less than 10%, 2 for 10–34%, 3 for 35–50%, 4 for 51–80% and 5 for more than 80% viable cells). Interestingly, 40% of the cultured samples shared same viability scores compared to the respective baselines and in 40%, only slight alterations were detected.…”

Section: Resultsmentioning

confidence: 99%

Patient-derived head and neck tumor slice cultures: a versatile tool to study oncolytic virus action

Runge

Mayr²,

Schwaiger³

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Head and neck cancer etiology and architecture is quite diverse and complex, impeding the prediction whether a patient could respond to a particular cancer immunotherapy or combination treatment. A concomitantly arising caveat is obviously the translation from pre-clinical, cell based in vitro systems as well as syngeneic murine tumor models towards the heterogeneous architecture of the human tumor ecosystems. To bridge this gap, we have established and employed a patient-derived HNSCC (head and neck squamous cell carcinoma) slice culturing system to assess immunomodulatory effects as well as permissivity and oncolytic virus (OV) action. The heterogeneous contexture of the human tumor ecosystem including tumor cells, cancer-associated fibroblasts and immune cells was preserved in our HNSCC slice culturing approach. Importantly, the immune cell compartment remained to be functional and cytotoxic T-cells could be activated by immunostimulatory antibodies. In addition, we uncovered that a high proportion of the patient-derived HNSCC slice cultures were susceptible to the OV VSV-GP. More specifically, VSV-GP infects a broad spectrum of tumor-associated lineages including epithelial and stromal cells and can induce apoptosis. In sum, this human tumor ex vivo platform might complement pre-clinical studies to eventually propel cancer immune-related drug discovery and ease the translation to the clinics.

show abstract

Section: Resultsmentioning

confidence: 99%

Patient-derived head and neck tumor slice cultures: a versatile tool to study oncolytic virus action

Runge

Mayr²,

Schwaiger³

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…It needs to be recognized that data generated from established cell lines are dependent on extrapolation for their clinical relevance and translatability. Future investigations focusing on the development of stem cell models from patient-derived therapy-resistant tumor samples, tumor organoids [ 55 , 56 , 57 , 58 , 59 , 60 ] and ex vivo organ culture explants [ 61 , 62 ] may reduce the need for extrapolation, and facilitate the discovery of novel efficacious compounds.…”

Section: Future Researchmentioning

confidence: 99%

Stem Cell Models for Breast and Colon Cancer: Experimental Approach for Drug Discovery

Telang¹

2022

IJMS

View full text Add to dashboard Cite

The progression of the early stages of female breast and colon cancer to metastatic disease represents a major cause of mortality in women. Multi-drug chemotherapy and/or pathway selective targeted therapy are notable for their off-target effects and are associated with spontaneous and/or acquired chemotherapy resistance and the emergence of premalignant chemo-resistant cancer-initiating stem cells. The stem cell populations are responsible for the evolution of therapy-resistant metastatic disease. These limitations emphasize an unmet need to develop reliable drug-resistant cancer stem cell models as novel experimental approaches for therapeutic alternatives in drug discovery platforms. Drug-resistant stem cell models for breast and colon cancer subtypes exhibit progressive growth in the presence of cytotoxic chemo-endocrine therapeutics. The resistant cells exhibit upregulated expressions of stem cell-selective cellular and molecular markers. Dietary phytochemicals, nutritional herbs and their constituent bioactive compounds have documented growth inhibitory efficacy for cancer stem cells. The mechanistic leads for the stem cell-targeted efficacy of naturally occurring agents validates the present experimental approaches for new drug discovery as therapeutic alternatives for therapy-resistant breast and colon cancer. The present review provides a systematic discussion of published evidence on (i) conventional/targeted therapy for breast and colon cancer, (ii) cellular and molecular characterization of stem cell models and (iii) validation of the stem cell models as an experimental approach for novel drug discovery of therapeutic alternatives for therapy-resistant cancers.

show abstract

“…A number of recent studies have highlighted the characterization required to ensure faithful alignment between human tumors and preclinical models, in terms of the biological signaling and therapeutic responses in both. (9)(10)(11) Integrity and robustness in aligning models with human tumors is critical in the era of precision medicine, where treatments are tailored for the biology underpinning specific cancer subtypes. Furthermore, signature development and testing is increasingly performed in disease-matched preclinical models, using in vitro, in vivo or ex vivo systems, enabling almost absolute control over the experimental conditions employed during biology-driven GES development.…”

Section: Words: 248 Introductionmentioning

confidence: 99%

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data

Fisher

Byrne

Leslie

et al. 2022

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Precise mechanism-based gene expression signatures (GESs) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling. Experimental Design: Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single cell RNA-Seq and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets. Results: Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment. Conclusions: Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples.

show abstract

Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer

Cited by 29 publications

References 55 publications

Patient-derived head and neck tumor slice cultures: a versatile tool to study oncolytic virus action

Patient-derived head and neck tumor slice cultures: a versatile tool to study oncolytic virus action

Stem Cell Models for Breast and Colon Cancer: Experimental Approach for Drug Discovery

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data

Contact Info

Product

Resources

About