Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer

Many cancer studies now recognize that disease initiation, progression, and response to treatment are strongly influenced by the microenvironmental niche. Widespread desmoplasia, or fibrosis, is fundamental to pancreatic cancer development, growth, metastasis, and treatment resistance. This fibrotic landscape is largely regulated by cancer-associated fibroblasts (CAFs), which deposit and remodel extracellular matrix (ECM) in the tumor microenvironment (TME). This review will explore the prognostic and functional value of the stromal compartment in predicting outcomes and clinical prognosis in pancreatic ductal adenocarcinoma (PDAC). We will also discuss the major dynamic stromal alterations that occur in the pancreatic TME during tumor development and progression, and how the stromal ECM can influence cancer cell phenotype, metabolism, and immune response from a biochemical and biomechanical viewpoint. Lastly, we will provide an outlook on the latest clinical advances in the field of anti-fibrotic co-targeting in combination with chemotherapy or immunotherapy in PDAC, providing insight into the current challenges in treating this highly aggressive, fibrotic malignancy.

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Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells

BMC Cancer ◽

10.1186/s12885-020-07722-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Fumihiko Matsuzawa ◽

Hirofumi Kamachi ◽

Tatsuzo Mizukami ◽

Takahiro Einama ◽

Futoshi Kawamata ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Cancer Cell ◽

Morphological Changes ◽

Pancreatic Cancer Cells ◽

Cell Invasiveness ◽

And Migration ◽

Migration Capacity

Abstract Background Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. Methods We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. Results Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. Conclusions Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

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Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01796-4 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Paulo L. Pfitzinger ◽

Laura Fangmann ◽

Kun Wang ◽

Elke Demir ◽

Engin Gürlevik ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Tumor Stage ◽

Ache Inhibitors ◽

Impact On Survival ◽

The Impact ◽

Ache Expression ◽

Cholinergic Activation

Abstract Background Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/−physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

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Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer

PLoS ONE ◽

10.1371/journal.pone.0140253 ◽

2015 ◽

Vol 10 (10) ◽

pp. e0140253 ◽

Cited By ~ 4

Author(s):

Jamie D. Weyandt ◽

Benjamin L. Lampson ◽

Sherry Tang ◽

Matthew Mastrodomenico ◽

Diana M. Cardona ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Genetically Engineered ◽

Wild Type ◽

Genetically Engineered Mouse Model

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Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1009010107 ◽

2010 ◽

Vol 107 (46) ◽

pp. 19997-20002 ◽

Cited By ~ 125

Author(s):

F. Su ◽

K. R. Kozak ◽

S. Imaizumi ◽

F. Gao ◽

M. W. Amneus ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Tumor Development ◽

Apolipoprotein A ◽

Mimetic Peptides

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873 Pharmacologic macrophage depletion affects metastasis formation by modulating systemic immune responses in a genetic pancreatic cancer model

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0873 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A926-A926

Author(s):

Heidi Griesmann ◽

Christof Drexel ◽

Nada Milosevic ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Mouse Model ◽

Immune Cells ◽

Tumour Progression ◽

Metastasis Formation ◽

Macrophage Depletion ◽

Genetic Mouse Model ◽

Liposomal Clodronate

BackgroundTumour-associated macrophages (TAM) play an important role in mediating tumour progression. In pancreatic cancer, infiltrating macrophages have been identified not only in invasive tumours, but also in early preinvasive pancreatic intraepithelial neoplasias and are known to mediate tumour progression.MethodsWe aimed to study the impact of pharmacological macrophage depletion by liposomal clodronate in the genetic mouse model of pancreatic cancer (KPC mouse: LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre). KPC mice were treated with liposomal clodronate or control liposomes from week 8 to week 20. Tumour and metastasis formation as well as alterations in local and circulating immune cells and cytokines were analysed.ResultsTreatment with liposomal clodronate effectively reduced CD11b-positive macrophages both in the pancreas and other organs such as liver, lung and spleen. Tumour incidence and size was only slightly reduced. However, metastasis formation in the liver und lungs was markedly diminished after macrophage depletion. Reduced macrophage count was associated with significant alterations in circulating growth factors and mediators known to be secreted by macrophages and associated with angiogenesis, most prominently VEGF. Moreover, application of liposomal clodronate led to marked alterations in circulating immune cells, among them reduced regulatory T cells.ConclusionsPharmacological depletion of macrophages in a genetic mouse model of pancreatic cancer markedly reduced metastasis formation and is associated with modulated profile of both secreted mediators and regulatory T cells. Pharmacological modulation of infiltrating macrophages represents a promising avenue for antimetastatic therapeutic approaches.

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Mouse model and human patient data suggest critical roles for Pten and p53 in suppressing POLE mutant tumor development

10.1101/2021.10.10.463847 ◽

2021 ◽

Author(s):

Vivian S Park ◽

Meijuan JS Sun ◽

Wesley D Frey ◽

Leonard G Williams ◽

Karl P Hodel ◽

...

Keyword(s):

Dna Damage ◽

Mouse Model ◽

Genome Stability ◽

Nuclear Dna ◽

Tumor Development ◽

Base Substitution ◽

Human Patient ◽

Mutation Burden ◽

P53 Activation ◽

Subsequent Loss

Mutations in the exonuclease domain of POLE are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. Pole+/P286R;Trp53+/- mice showed accelerated cancer mortality compared to Pole+/P286R;Trp53+/+ mice. Cells from Pole+/P286R mice showed increased p53 activation, and subsequent loss of p53 permitted rapid growth, implicating canonical p53 loss of heterozygosity in POLE mutant tumor growth. Somewhat surprisingly, however, p53 status had no effect on tumor mutation burden or single base substitution signatures in POLE mutant tumors from mice or humans. Pten has important roles in maintaining genome stability. We find that PTEN mutations are highly enriched in human POLE mutant tumors, including many in POLE signature contexts. One such signature mutation, PTEN-F341V, was previously shown in a mouse model to specifically decrease nuclear Pten and lead to increased DNA damage. We found tumors in Pole+/P286R mice that spontaneously acquired PtenF341V mutations and were associated with significantly reduced nuclear Pten and elevated DNA damage. Taken together with recent published work, our results support the idea that POLE-mediated hypermutagenesis is necessary, but not entirely sufficient, for tumorigenesis. Disabling surveillance of nuclear DNA damage is a likely sufficient factor.

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CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Journal of Oncology ◽

10.1155/2019/9681698 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Alessandra Righetti ◽

Matteo Giulietti ◽

Berina Šabanović ◽

Giulia Occhipinti ◽

Giovanni Principato ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Stromal Cells ◽

Tumor Invasion ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Tumor Development ◽

Physiological Role ◽

Mesenchymal Transition ◽

Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

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