Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets

Large, Tessa Y.S. Le; Mantini, G.; Meijer, Laura L.; Pham, Thang V.; Funel, Niccola; Grieken, Nicole C.T. van; Kok, Bart; Knol, Jaco C.; Laarhoven, Hanneke W. M. van; Piersma, Sander R.; Jiménez, Connie R.; Kazemier, Geert; Giovannetti, Elisa; Bijlsma, Maarten F.

doi:10.1172/jci.insight.138290

Cited by 40 publications

(33 citation statements)

References 71 publications

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“…These observations illustrate that morphological intratumor heterogeneity is common, as reported by others [9,10,119]. Collectively, observations in this study concur with the widespread intratumor heterogeneity that has been described recently at the transcriptional and proteomics level [120][121][122]. Moreover, intratumor heterogeneity has also been reported for several of the individual features analyzed in this study: amount of hyaluronan [77,102] and collagen [19], degree of collagen alignment [19,65], expression of CD44 [34], CD133 [50], ALDH1 [99] and MMP14 [123], and proliferative activity [97,106].…”

Section: Discussionsupporting

confidence: 93%

Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence

Sántha

Lenggenhager

Finstadsveen

et al. 2021

Cancers

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Inter- and intratumor heterogeneity is an important cause of treatment failure. In human pancreatic cancer (PC), heterogeneity has been investigated almost exclusively at the genomic and transcriptional level. Morphological heterogeneity, though prominent and potentially easily assessable in clinical practice, remains unexplored. This proof-of-concept study aims at demonstrating that morphological heterogeneity reflects structural and functional divergence. From the wide morphological spectrum of conventional PC, four common and distinctive patterns were investigated in 233 foci from 39 surgical specimens. Twenty-six features involved in key biological processes in PC were analyzed (immuno-)histochemically and morphometrically: cancer cell proliferation (Ki67) and migration (collagen fiber alignment, MMP14), cancer stem cells (CD44, CD133, ALDH1), amount, composition and spatial arrangement of extracellular matrix (epithelial proximity, total collagen, collagen I and III, fibronectin, hyaluronan), cancer-associated fibroblasts (density, αSMA), and cancer-stroma interactions (integrins α2, α5, α1; caveolin-1). All features differed significantly between at least two of the patterns. Stromal and cancer-cell-related features co-varied with morphology and allowed prediction of the morphological pattern. In conclusion, morphological heterogeneity in the cancer-cell and stromal compartments of PC correlates with structural and functional diversity. As such, histopathology has the potential to inform on the operationality of key biological processes in individual tumors.

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Section: Discussionsupporting

confidence: 93%

Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence

Sántha

Lenggenhager

Finstadsveen

et al. 2021

Cancers

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“…Other highly phosphorylated RTKs which were identified in our phosphoproteomic screen, including their down-stream regulatory proteins, were MET and EPHA2, two known modulators of oncogenic pathways and EGFR-resistant markers [ 47 ]. Additionally, these kinases have previously been established as possible targets by our group, validating the phosphoproteome approach [ 16 , 48 ]. The enrichment of multiple targetable kinases opens the door for future combination studies of TKIs.…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

Large

Bijlsma

Hassouni

et al. 2021

J Exp Clin Cancer Res

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Background Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. Aberrant tyrosine kinase activity influences tumor growth and is regulated by phosphorylation. We investigated phosphorylated kinases as target in PDAC. Methods Mass spectrometry-based phosphotyrosine proteomic analysis on PDAC cell lines was used to evaluate active kinases. Pathway analysis and inferred kinase activity analysis was performed to identify novel targets. Subsequently, we investigated targeting of focal adhesion kinase (FAK) in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Tyrosine phosphoproteomics upon treatment was performed to evaluate signaling. An orthotopic model of PDAC was used to evaluate the combination of defactinib with nab-paclitaxel. Results PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases to various degree. The non-receptor kinase, FAK, was identified in all cell lines by our phosphotyrosine proteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. Conclusions Our study shows high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel against this devastating disease.

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“…Successful dissection of tumor and stromal compartment is reported in Figure S3. Recent studies showed the impact of LMD on the quality of both mRNA and protein content in PDAC specimens [61,62], and might explain why a not laser-assisted microdissection did not result in the association of hENT-1 expression levels with disease-specific survival, as reported by Jiraskova and collaborators in a retrospective study on a cohort of 69 resected PDAC patients treated with gemcitabine [63]. Of note, the data of this study also suggested a limited proportional dependence between hENT-1 gene expression evaluated by qRT-PCR in FFPE samples and protein levels as assessed by immunohistochemistry with the 10D7G2 antibody [63].…”

Section: Evaluation Of the Study "Hent-1 Status In Pdac Patients-are We Ready Yet?"mentioning

confidence: 99%

“…Figure 3. Impact of laser-microdissection on mRNA expression levels of hENT-1 in PDAC samples (A) Representative pictures of PDAC epithelium and stroma before and after laser-assisted microdissection, performed on frozen tissue with the Leica LDM7000 microscope, as described previously[62]. (B) Comparison between hENT-1 gene expression values in microdissected (LMD) and non-microdissected (no LMD) samples from 22 PDAC tissues.…”

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confidence: 99%

“Open Sesame?”: Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer

Randazzo

Papini

Mantini

et al. 2020

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

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Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets

Cited by 40 publications

References 71 publications

Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence

Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

“Open Sesame?”: Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer

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