Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers

Rajbhandari, Nirakar; Lin, Wei‐Xia; Wehde, Barbara L.; Triplett, Aleata A.; Wagner, Kay Uwe

doi:10.1016/j.celrep.2017.02.013

Cited by 52 publications

(50 citation statements)

References 28 publications

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“…45 Combinations of such pharmacologic agents that induce death of dormant cells and anti-stromal agents could be repurposed to prevent cancer recurrence caused by dormant pancreatic cancer cells. 46,47 Collectively, these studies show how primary tumor can induce early stromal alterations in other tissues to promote cancer spread. This highlights the need for assessing antistromal agents in combination with chemotherapy in the neoadjuvant and adjuvant settings to reduce the risk of tumor dissemination 22,39À41,48À50 ( Figure 1A).…”

Section: Targeting Mechanical Features Of the Extracellular Matrixmentioning

confidence: 87%

Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer

et al. 2018

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Pancreatic cancer is accompanied by a fibrotic reaction that alters interactions between tumor cells and the stroma to promote tumor progression. Consequently, strategies to target the tumor stroma might be used to treat patients with pancreatic cancer. We review recently developed approaches for reshaping the pancreatic tumor stroma and discuss how these might improve patient outcomes. We also describe relationships between the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and discuss the implications for the development of stromal compartment-specific therapies.

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Section: Targeting Mechanical Features Of the Extracellular Matrixmentioning

confidence: 87%

Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer

et al. 2018

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Section: The Role Of the Igf Axis In Bone Metastasesmentioning

confidence: 99%

“…IGF-1 and IGF-2 have been shown to mediate tumor cell dormancy in bone in models of pancreatic cancer and osteosarcoma (58,59). In a murine pancreatic cancer model, the activation of IGF-1/AKT signaling was a common survival mechanism in dormant cancer cells that had survived ablation of the oncogenic drivers KRAS and MYC (58). In clinical osteosarcomas and a mouse model of MYC-driven osteosarcoma, IGF-2 expression increased following chemotherapy, and prolonged IGF-2 exposure induced a dormancy-like state, characterized by attenuated responsiveness of the IGF axis to IGF-2, with low levels of AKT-mTOR activity, cell-cycle arrest, and autophagy (59).…”

Section: The Role Of the Igf Axis In Bone Metastasesmentioning

confidence: 99%

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Rieunier

Macaulay

et al. 2019

Clinical Cancer Research

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Bone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. Via activation of the IGF-1 receptors (IGF-1R) and variant insulin receptors, IGFs promote cancer progression, aggressiveness, and treatment resistance. Of specific relevance to bone biology, IGFs contribute to the homing, dormancy, colonization, and expansion of bone metastases. Furthermore, preclinical evidence suggests that tumor cells can be primed to metastasize to bone by a high IGF-1 environment in the primary tumor, suggesting that bone metastases may reflect IGF dependency. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. Indeed, anti-IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors, and anti-IGF-1/2 antibodies have demonstrated antitumor activity in preclinical models of prostate and breast cancer metastases, either alone or in combination with other agents. Several studies suggest that such treatments can inhibit bone metastases without affecting growth of the primary tumor. Although previous trials of anti-IGF-1R drugs have generated negative results in unselected patients, these considerations suggest that future clinical trials of IGF-targeted agents may be warranted in patients with bone metastases.

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“…In cases where primary or metastatic cancers regress and residual tumor cells remain dormant following a Dox-induced suppression of the oncogene, it can be expected that the constitutively active EF1-tTA will effectively reactivate an oncogene in virtually all quiescent tumor cells following Dox withdrawal. This reawakening of tumor cells may lead to cancer recurrence or even cell death depending on the differentiation state of a dormant cancer cell [23][24][25] .…”

Section: Discussionmentioning

confidence: 99%

Efficient tissue-type specific expression of target genes in a tetracycline-controlled manner from the ubiquitously active Eef1a1 locus

Sakamoto

Rädler

Wehde

et al. 2020

Sci Rep

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Using an efficient gene targeting approach, we developed a novel mouse line that expresses the tetracycline-controlled transactivator (tTA) from the constitutively active Eef1a1 locus in a Cre recombinase-inducible manner. The temporally and spatially controlled expression of the EF1-LSL-tTA knockin and activation of tTA-driven responder transgenes was tested using four transgenic lines that express Cre under tissue-specific promoters of the pancreas, mammary gland and other secretory tissues, as well as an interferon-inducible promoter. In all models, the endogenous Eef1a1 promoter facilitated a cell-type-specific activation of target genes at high levels without exogenous enhancer elements. The applicability of the EF1-LSL-tTA strain for biological experiments was tested in two studies related to mammary gland development and tumorigenesis. First, we validated the crucial role of active STAT5 as a survival factor for functionally differentiated epithelial cells by expressing a hyperactive STAT5 mutant in the mammary gland during postlactational remodeling. In a second experiment, we assessed the ability of the EF1-tTA to initiate tumor formation through upregulation of mutant KRAS. The collective results show that the EF1-LSL-tTA knockin line is a versatile genetic tool that can be applied to constitutively express transgenes in specific cell types to examine their biological functions at defined developmental stages.

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Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers

Cited by 52 publications

References 28 publications

Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer

Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

Efficient tissue-type specific expression of target genes in a tetracycline-controlled manner from the ubiquitously active Eef1a1 locus

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