Injury promotes sarcoma development in a genetically and temporally restricted manner

Mater, David Van; Xu, Eric S.; Reddy, Anupama; Añó, Leonor; Sachdeva, Mohit; Huang, Wesley; Williams, Nerissa; Ma, Yan; Love, Cassandra; Happ, Lanie E.; Davé, Sandeep S.; Kirsch, David G.

doi:10.1172/jci.insight.123687

Cited by 12 publications

(9 citation statements)

References 29 publications

(41 reference statements)

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“…However, the mechanisms for radiation-induced sarcomagenesis may be distinct from radiation-induced lymphomagenesis. The WES provides evidence of radiation-induced oxidative DNA damage and amplification of genes such as Met and Yap1, which are both associated with injury-induced sarcomas (35), suggesting a cell-autonomous mechanism. We suspect that after tumor-initiating cells undergo radiation-induced DNA damage, they begin clonal expansion and develop into a tumor through a selection process shaped by acute and chronically injured surrounding tissue following radiation exposure.…”

Section: Discussionmentioning

confidence: 99%

“…DNA extraction was performed using DNeasy Blood and Tissue Kit or AllPrep DNA/RNA Mini Kit (Qiagen). WES was performed in 2 batches using either previously described methods (batch 1) (35) or the following method (batch 2) (Supplemental Table 1). One mouse in the Kras G12D p53 -/cohort, S45, was excluded from analyses after WES showed no evidence of a deletion of p53 exons 2-10.…”

Section: Wes Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma

Lee¹,

Mowery²,

Daniel³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Section: Wes Methodsmentioning

confidence: 99%

Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma

Lee¹,

Mowery²,

Daniel³

et al. 2019

JCI Insight

Self Cite

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“…In addition, previous studies have highlighted the importance of antiapoptotic proteins, such as B-cell leukemia/lymphoma 2 (Bcl-2) and Bcl-2-like 1 (Bcl-XL), in mediating cell survival upon chemotherapy and radiotherapy 3,4 . Recently, aberrant expression of Yes-associated protein 1 (YAP1) has been observed in a panel of sarcomas including CHS [5][6][7] , yet the precise role of YAP1 in CHS remains to be explored.…”

Section: Introductionmentioning

confidence: 99%

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

et al. 2021

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Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-XL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.

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“…Both UPS and RMS harbor similar genetic alterations, including activation of the Ras pathway and disruptions in common tumor suppressors, such as p53 [18][19][20] . High-fidelity GEMM models of UPS and RMS have been successfully used in determining mechanisms of disease and identifying new treatment paradigms for these aggressive tumors [21][22][23][24][25][26] . Both UPS and RMS GEMM approaches utilize localized Cre activation to drive activation of oncogenic Kras and loss of p53 in LSL-Kras G12D ; p53 Flox/Flox (KP) mice.…”

mentioning

confidence: 99%

Divergent immune landscapes of primary and syngeneic Kras-driven mouse tumor models

Gutierrez

Scherer

McGivney

et al. 2021

Sci Rep

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Immune cells play critical functions in cancer, and mice with intact immune systems are vital to understanding tumor immunology. Both genetically engineered mouse models (GEMMs) and syngeneic cell transplant approaches use immunocompetent mice to define immune-dependent events in tumor development and progression. Due to their rapid and reproducible nature, there is expanded interest in developing new syngeneic tools from established primary tumor models. However, few studies have examined the extent that syngeneic tumors reflect the immune profile of their originating primary models. Here, we describe comprehensive immunophenotyping of two well-established GEMMs and four new syngeneic models derived from these parental primary tumors. To our knowledge, this is the first systematic analysis comparing immune landscapes between primary and orthotopic syngeneic tumors. These models all use the same well-defined human-relevant driver mutations, arise at identical orthotopic locations, and are generated in mice of the same background strain. This allows for a direct and focused comparison of tumor immune landscapes in carefully controlled mouse models. We identify key differences between the immune infiltrate of GEMM models and their corresponding syngeneic tumors. Most notable is the divergence of T cell populations, with different proportions of CD8+ T cells and regulatory T cells across several models. We also observe immune variation across syngeneic tumors derived from the same primary model. These findings highlight the importance of immune variance across mouse modeling approaches, which has strong implications for the design of rigorous and reproducible translational studies.

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Injury promotes sarcoma development in a genetically and temporally restricted manner

Abstract: is on the scientific advisory board of Lumicell Inc., which is a company commercializing intraoperative imaging, and is a cofounder of XRAD Therapeutics, which is developing radiosensitizers.

Cited by 12 publications

References 29 publications

Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma

Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

Divergent immune landscapes of primary and syngeneic Kras-driven mouse tumor models

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