Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution

Chan-Seng-Yue, Michelle; Kim, Jaeseung C.; Wilson, Gavin; Ng, Karen; Flores-Figueroa, Eugenia; O’Kane, Grainne M.; Connor, Ashton A.; Denroche, Robert E.; Grant, Robert C.; McLeod, Jessica; Wilson, Julie M.; Jang, Gun Ho; Zhang, Amy; Dodd, Anna; Liang, Sheng‐Ben; Borgida, Ayelet; Chadwick, Dianne; Kalimuthu, Sangeetha; Lungu, Ilinca M.; Bartlett, John M.S.; Krzyzanowski, Paul M.; Sandhu, Vandana; Tiriac, Hervé; Froeling, Fieke E. M.; Karasinska, Joanna M.; Topham, James T.; Renouf, Daniel J.; Schaeffer, David F.; Jones, Steven J.M.; Marra, Marco A.; Laskin, Janessa; Chetty, Runjan; Stein, Lincoln; Zogopoulos, George; Haibe‐Kains, Benjamin; Campbell, Peter J.; Tuveson, David A.; Knox, Jennifer J.; Fischer, Sandra E.; Gallinger, Steven; Notta, Faiyaz

doi:10.1038/s41588-019-0566-9

Cited by 391 publications

(594 citation statements)

References 49 publications

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“…Using single cell RNA-seq, Chan-Seng-Yue et al in 2020 [15] confirmed the presence of several subpopulations with differential proliferative and migratory potentials in PDAC. In particular, they observed two ductal subtypes with abnormal and malignant gene expression [15]. Our own unpublished results identified four common cell clusters in patients with a classical PDAC.…”

Section: Discussionmentioning

confidence: 98%

“…RNA profiling of multiple regions or multiple lesions from the same patient also demonstrated intra-tumor heterogeneity of the transformed epithelial compartment [4]. Using single cell RNA-seq, Chan-Seng-Yue et al in 2020 [15] confirmed the presence of several subpopulations with differential proliferative and migratory potentials in PDAC. In particular, they observed two ductal subtypes with abnormal and malignant gene expression [15].…”

Section: Discussionmentioning

confidence: 98%

“…the infiltrated Immunogenic subtype), and delineated a consensual basal-like versus classical dichotomy. However, this two-subtype classification system of PDAC has recently been challenged by several studies showing the coexistence of basal-like and classical cells in the same tumors as well as to the likely existence of intermediate cellular phenotypes [15,17]. In this study, we have used a gradient system that takes this into consideration to classify PDAC.…”

Section: Discussionmentioning

confidence: 99%

“…Single cell RNA sequencing [15] and immunohistochemistry [18] of PDAC revealed intra-tumor heterogeneity where both types of cells (basal-like and classical) frequently co-exist. RNA profiling of multiple regions or multiple lesions from the same patient also demonstrated intra-tumor heterogeneity of the transformed epithelial compartment [4].…”

Section: Discussionmentioning

confidence: 99%

“…It was previously suggested that molecular subtypes of PDAC were associated with responses to chemotherapy, in particular FOLFIRINOX [8,15,16]. Therefore, to evaluate the predictive value of the PAGM to chemotherapy response, it was applied to metastatic patients in the COMPASS trials for which transcriptomic profiles and tumor responses to mFOLFIRINOX were available [16].…”

Section: Pamg Predicts the Response To Mfolfirinox Of Advanced Pdac Pmentioning

confidence: 99%

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Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

Nicolle

Blum

Duconseil

et al. 2020

Preprint

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BACKGROUND: A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumors and allowing a personalized treatment. The goal of this study was to examine whole PDAC transcriptomic profiles to define a signature that would predict aggressiveness and treatment responsiveness better than done until now. METHODS AND PATIENTS: Tumors were obtained from 76 consecutive resectable (n=40) or unresectable (n=36) tumors. PDAC were transplanted in mice to produce patient-drived xenografts (PDX). PDX were classified according to their histology into five groups, from highly undifferentiated to well differentiated. This classification resulted strongly associated with tumors aggressiveness. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n=598) of resected tumors; ii/ 60 advanced tumors obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumors. RESULTS: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumors (e.g. 308 consecutive resected PDAC, HR=0.321 95% CI [0.207;0.5] and 60 locallyadvanced or metastatic PDAC, HR=0.308 95% CI [0.113;0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumor response: -0.67, p-value < 0.001). CONCLUSION: We identified a transcriptomic signature (PAMG) that, unlike all other stratification schemas already proposed, classifies PDAC along a continuous gradient. It can be performed on formalin-fixed paraffin-embedded samples and EUS-guided biopsies showing a strong prognostic value and predicting mFOLFIRINOX responsiveness. We think that PAMG could unify all PDAC preexisting classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pamg Predicts the Response To Mfolfirinox Of Advanced Pdac Pmentioning

confidence: 99%

See 3 more Smart Citations

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

Nicolle

Blum

Duconseil

et al. 2020

Preprint

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Targeting the ubiquitin‐proteasome system in a pancreatic cancer subtype with hyperactive MYC

et al. 2020

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The myelocytomatosis oncogene (MYC) is an important driver in a subtype of pancreatic ductal adenocarcinoma (PDAC). However, MYC remains a challenging therapeutic target, therefore identifying druggable synthetic lethal interactions in MYC-active PDAC may lead to novel precise therapies. First, to identify networks with hyperactive MYC, we profiled transcriptomes of established human cell lines, murine primary PDAC cell lines and accessed publicly available repositories to analyze transcriptomes of primary human PDAC. Networks active in MYC hyperactive subtypes were analyzed by gene set enrichment analysis. Next, we performed an unbiased pharmacological screen to define MYC-associated vulnerabilities. Hits were validated by analysis of drug-response repositories and genetic gain-and loss-of-function experiments. In these experiments, we discovered that the proteasome inhibitor Bortezomib triggers a MYC-associated vulnerability. In addition, by integrating publicly available data, we found the unfolded protein response as a signature connected to MYC. Furthermore, increased sensitivity of MYC-hyperactive PDACs to Bortezomib was validated in genetically modified PDAC cells. In sum, we provide evidence that perturbing the ubiquitin proteasome system might be an option to target MYC hyperactive PDAC cells. Our data provide the rationale to further develop precise targeting of the ubiquitin-proteasome system as a subtype-specific therapeutic approach.

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From Tissue Turnover to the Cell of Origin of Pancreatic Cancer

2023

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Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution

Cited by 391 publications

References 49 publications

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

Targeting the ubiquitin‐proteasome system in a pancreatic cancer subtype with hyperactive MYC

From Tissue Turnover to the Cell of Origin of Pancreatic Cancer

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