Orthotopic Patient-Derived Pancreatic Cancer Xenografts Engraft Into the Pancreatic Parenchyma, Metastasize, and Induce Muscle Wasting to Recapitulate the Human Disease

Go, Kristina L.; Delitto, Daniel; Judge, Sarah M.; Gerber, M.; George, Thomas J.; Behrns, Kevin E.; Hughes, Steven J.; Judge, Andrew R.; Treviño, José G.

doi:10.1097/mpa.0000000000000843

Cited by 37 publications

(43 citation statements)

References 32 publications

(34 reference statements)

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“…When tumours reached 1.5 cm in diameter, they were resected, portioned into two‐by‐two millimetre sections, and implanted into mice orthotopically, sutured to the pancreas. The surgical procedure was performed using previously described methods . Although not tested here, others have shown a high degree of genetic stability in PDXs when compared with the original pancreatic cancer specimen, and we have previously demonstrated that PDXs retain morphological characteristics of the original pancreatic cancer specimen .…”

Section: Methodsmentioning

confidence: 99%

“…This native environment is crucial in determining the biological behaviour of both the tumour and subsequent systemic response that induces cachexia . Tumour metastasis to the liver and lungs occurs in this model, which has been shown to be an important factor in the cachectic syndrome and is not a common feature in many pre‐clinical cancer cachexia models . Furthermore, by transplanting tumours from PDAC patients into mice, cachexia is investigated through the lens of soluble factors derived from a patient tumour, which likely varies between individual cancer patients .…”

Section: Introductionmentioning

confidence: 99%

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Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Nosacka

Delitto

et al. 2020

J cachexia sarcopenia muscle

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Background Cancer cachexia is a life‐threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre‐clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre‐clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient‐derived xenograft (PDX) mice. Methods To create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice. Results Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome‐wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up‐regulated in the DIA were enriched for extracellular matrix protein‐encoding genes and genes related to the inflammatory response, while down‐regulated genes were enriched for mitochondria related protein‐encoding genes. Conversely, the TA showed up‐regulation of canonical atrophy‐associated pathways such as ubiquitin‐mediated protein degradation and apoptosis, and down‐regulation of genes encoding extracellular matrix proteins. Conclusions These data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Nosacka

Delitto

et al. 2020

J cachexia sarcopenia muscle

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“…This has the obvious advantage of allowing the study of organ-specific tumor microenvironment with increased accuracy and higher genetic heterogeneity and stability compared to the traditional xenograft models, similarly to GEM models. In particular, this was demonstrated for both orthotopic and subcutaneous engraftment of patient-derived pancreatic tumor (154,155). However, some data suggested that orthotopic engraftment of pancreatic tumor cells within mice's pancreas could induce systemic inflammation distinct from that observed in subcutaneous engraftments, leading toward more severe SM wasting [e.g., (154)].…”

Section: Discrepancies: From the Laboratory To The Clinical Practicementioning

confidence: 99%

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

2020

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Cancer cachexia (CC) is a multifactorial syndrome characterized by systemic inflammation, uncontrolled weight loss and dramatic metabolic alterations. This includes myofibrillar protein breakdown, increased lipolysis, insulin resistance, elevated energy expediture, and reduced food intake, hence impairing the patient's response to anti-cancer therapies and quality of life. While a decade ago the syndrome was considered incurable, over the most recent years much efforts have been put into the study of such disease, leading to the development of potential therapeutic strategies. Several important improvements have been reached in the management of CC from both the diagnostic-prognostic and the pharmacological viewpoint. However, given the heterogeneity of the disease, it is impossible to rely only on single variables to properly treat patients presenting this metabolic syndrome. Moreover, the cachexia symptoms are strictly dependent on the type of tumor, stage and the specific patient's response to cancer therapy. Thus, the attempt to translate experimentally effective therapies into the clinical practice results in a great challenge. For this reason, it is of crucial importance to further improve our understanding on the interplay of molecular mechanisms implicated in the onset and progression of CC, giving the opportunity to develop new effective, safe pharmacological treatments. In this review we outline the recent knowledge regarding cachexia mediators and pathways involved in skeletal muscle (SM) and adipose tissue (AT) loss, mainly from the experimental cachexia standpoint, then retracing the unimodal treatment options that have been developed to the present day.

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“…This previous work has focused on the effects of nicotine in PDAC cells. Up to 80% of PDAC tumor volume is, however, composed of tumor-associated stroma (TAS) [15]. The vast array of signaling that occurs in the tumor microenvironment between TAS and cancer cells has been poorly characterized, and the role of nicotine in TAS is largely unstudied.…”

Section: Introductionmentioning

confidence: 99%

Nicotine Induces IL-8 Secretion from Pancreatic Cancer Stroma and Worsens Cancer-Induced Cachexia

Underwood

Zhang

Cameron

et al. 2020

Cancers

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Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.

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Orthotopic Patient-Derived Pancreatic Cancer Xenografts Engraft Into the Pancreatic Parenchyma, Metastasize, and Induce Muscle Wasting to Recapitulate the Human Disease

Abstract: Through the orthotopic implantation technique described, we demonstrate a highly reproducible model that recapitulates both local and systemic aspects of human PC.

Cited by 37 publications

References 32 publications

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

Nicotine Induces IL-8 Secretion from Pancreatic Cancer Stroma and Worsens Cancer-Induced Cachexia

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