Genetically diverse mouse platform to xenograft cancer cells

Sargent, Jennifer; Warner, Mark A.; Low, Benjamin E.; Schott, William H.; Hoffert, Todd; Coleman, David L.; Woo, Xing Yi; Sheridan, Todd; Erattupuzha, Sonia; Philip, Vivek M.; Philip, Vivek; Chuang, Jeffrey H.; Wiles, Michael V.; Hasham, Muneer G.

doi:10.1242/dmm.049457

Cited by 11 publications

(23 citation statements)

References 57 publications

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“…As previously published, the tumors grew at different rates and sizes (Sargent et al, 2022). We chose the largest, the median, and the smallest tumor size within each strain to perform tandem mass spectrometry-based proteomics analysis to determine the changes in protein expression in both the xenograVed cancer-cell line and in the host cells that compose the microenvironment.…”

Section: The Host Strain Determines Protein Expression Of Xenogra0ed ...mentioning

confidence: 99%

Methods to study xenografted human cancer in genetically diverse mice

Hasham,

Sargent,

Warner

et al. 2024

Preprint

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Xenografting human cancer tissues into mice to test new cures against cancers is critical for understanding and treating the disease. However, only a few inbred strains of mice are used to study cancers, and derivatives of mainly one strain, mostly NOD/ShiLtJ, are used for therapy efficacy studies. As it has been demonstrated when human cancer cell lines or patient-derived tissues (PDX) are xenografted into mice, the neoplastic cells are human but the supporting cells that comprise the tumor (the stroma) are from the mouse. Therefore, results of studies of xenografted tissues are influenced by the host strain. We previously published that when the same neoplastic cells are xenografted into different mouse strains, the pattern of tumor growth, histology of the tumor, number of immune cells infiltrating the tumor, and types of circulating cytokines differ depending on the strain. Therefore, to better comprehend the behavior of cancer in vivo, one must xenograft multiple mouse strains. Here we describe and report a series of methods that we used to reveal the genes and proteins expressed when the same cancer cell line, MDA-MB-231, is xenografted in different hosts. First, using proteomic analysis, we show how to use the same cell line in vivo to reveal the protein changes in the neoplastic cell that help it adapt to its host. Then, we show how different hosts respond molecularly to the same cell line. We also find that using multiple strains can reveal a more suitable host than those traditionally used for a difficult to xenograft PDX. In addition, using complex trait genetics, we illustrate a feasible method for uncovering the alleles of the host that support tumor growth. Finally, we demonstrate that Diversity Outbred mice, the epitome of a model of mouse-strain genetic diversity, can be xenografted with human cell lines or PDX using 2-deoxy-D-glucose treatment.

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Section: The Host Strain Determines Protein Expression Of Xenogra0ed ...mentioning

confidence: 99%

Methods to study xenografted human cancer in genetically diverse mice

Hasham,

Sargent,

Warner

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are a number of xenograft models; however, the most prevailing in CSC research are the patient-derived xenografts (PDX) and the cell line-derived xenograft (CDX) models. In these models, mice are engrafted with either patient or cell line-derived cells, respectively [ 80 , 81 , 82 , 83 , 84 ]. It has been shown that CSCs, even when injected at low numbers, have the capacity to efficiently generate tumors that are heterologous and which exhibit similar histological properties as the tumor of origin.…”

Section: Cancer Stem Cells (Cscs)mentioning

confidence: 99%

The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression

Tsochantaridis

Roupas

Mohlin

et al. 2023

Life

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Cancer is a multifactorial, complex disease exhibiting extraordinary phenotypic plasticity and diversity. One of the greatest challenges in cancer treatment is intratumoral heterogeneity, which obstructs the efficient eradication of the tumor. Tumor heterogeneity is often associated with the presence of cancer stem cells (CSCs), a cancer cell sub-population possessing a panel of stem-like properties, such as a self-renewal ability and multipotency potential. CSCs are associated with enhanced chemoresistance due to the enhanced efflux of chemotherapeutic agents and the existence of powerful antioxidant and DNA damage repair mechanisms. The distinctive characteristics of CSCs make them ideal targets for clinical therapeutic approaches, and the identification of efficient and specific CSCs biomarkers is of utmost importance. Aldehyde dehydrogenases (ALDHs) comprise a wide superfamily of metabolic enzymes that, over the last years, have gained increasing attention due to their association with stem-related features in a wide panel of hematopoietic malignancies and solid cancers. Aldehyde dehydrogenase 1B1 (ALDH1B1) is an isoform that has been characterized as a marker of colon cancer progression, while various studies suggest its importance in additional malignancies. Here, we review the basic concepts related to CSCs and discuss the potential role of ALDH1B1 in cancer development and its contribution to the CSC phenotype.

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“…Still, they are limited by complex genetic background variations, differences in treatment histories, and, most importantly, the lack of suitable controls 14 . Most importantly, the tumor growth characteristics identified in PDX models were found to be more dependent on the mouse strain than tumor type 15 , suggesting the PDX model may generate many artificial readouts irrelevant to primary human tumors.…”

Section: Introductionmentioning

confidence: 99%

A multidimensional atlas of human glioblastoma organoids reveals highly coordinated molecular networks and effective drugs

Wang

Sun

Shao

et al. 2023

Preprint

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Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM organoid (LEGO: Laboratory Engineered Glioblastoma Organoid) and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO based drug screen. This study provides novel human GBM models and a research path toward effective GBM therapy.

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Genetically diverse mouse platform to xenograft cancer cells

Cited by 11 publications

References 57 publications

Methods to study xenografted human cancer in genetically diverse mice

Methods to study xenografted human cancer in genetically diverse mice

The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression

A multidimensional atlas of human glioblastoma organoids reveals highly coordinated molecular networks and effective drugs

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