Spatially confined sub-tumor microenvironments in pancreatic cancer

Grünwald, Barbara; Devisme, Antoine; Andrieux, Geoffroy; Vyas, Foram; Aliar, Kazeera; McCloskey, Curtis W.; Macklin, Andrew; Jang, Gun Ho; Denroche, Robert E.; Romero, Joan M.; Bavi, Prashant; Bronsert, Peter; Notta, Faiyaz; O’Kane, Grainne M.; Wilson, Julie M.; Knox, Jennifer J.; Tamblyn, Laura; Udaskin, Molly L.; Radulovich, Nikolina; Fischer, Sandra E.; Boerries, Melanie; Gallinger, Steven; Kislinger, Thomas; Khokha, Rama

doi:10.1016/j.cell.2021.09.022

Cited by 239 publications

(260 citation statements)

References 59 publications

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“…Coordination between basal/mesenchymal malignant cell states and immune responses may be a broadly relevant phenomenon given our observations in other basal-like tumors and recent work in glioblastoma ( Hara et al, 2021 ). A recent publication further supports the idea that local TME variation can influence clinical outcomes in PDAC ( Grünwald et al, 2021 ), while our work provides direct evidence that TME signals are critical drivers of malignant cell state and that cell state dictates drug sensitivity. Larger cohorts of longitudinal single-cell measurements, both spatially resolved and transcriptome-wide, from individual patients undergoing therapy are needed to fully assess variation in the TME, the kinetics of cell state plasticity, and their consequences for therapeutic response.…”

Section: Discussionsupporting

confidence: 85%

“…While PDAC subtyping studies have largely recovered common expression features, it remains unclear whether these bulk RNA-seq state measurements mask heterogeneity at the single-cell level, which features derive from malignant versus non-malignant cells, and how well they are recapitulated in laboratory models. Moreover, the PDAC tumor microenvironment (TME) includes numerous non-malignant immune and stromal cell types ( Balachandran et al, 2019 ; Bernard et al, 2019 ; Elyada et al, 2019 ; Grünwald et al, 2021 ; Ligorio et al, 2019 ), but their variation across different sites of disease and their effects on malignant cell state and therapeutic response is not well characterized. Given the lack of mutational biomarkers for PDAC, understanding how cell state is shaped by the local TME and whether cell state can be used as a tractable biomarker for therapy selection remains of critical importance.…”

Section: Introductionmentioning

confidence: 99%

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Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer

Raghavan

Winter

Navia

et al. 2021

Cell

271

273

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SUMMARY Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo , we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo -relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer

Raghavan

Winter

Navia

et al. 2021

Cell

271

273

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“…Another interesting aspect of CAF heterogeneity is their discrete spatial localization in the PDAC microenvironment. Grünwald et al [54] characterized this heterogeneity in the context of overall stromal heterogeneity in resected human PDAC specimens, as well as in biopsies from metastatic PDAC lesions. The authors classified the PDAC TME into two main, histologically distinguishable entities-the 'Deserted' TME, with an acellular appearance and thin, spindle-shaped fibroblasts, and the 'Reactive' TME, with active fibroblasts and abundant inflammatory infiltrate; an intermediate TME state between these two could also be identified.…”

Section: Caf Heterogeneitymentioning

confidence: 99%

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

Vaish

Jain

Are

et al. 2021

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

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“…The next wave of studies anticipated in the near future will undoubtedly shed further light on which model systems and assays carry the greatest predictive power. Several published studies have described the composition and transcriptional evolution of PDAC organoids and primary tumors at a single-cell resolution [57,71,74,101]. However, these studies have not yet revealed the extent to which subclonal resistance mechanisms contributing to tumor escape occur and could be identified at baseline or emerge as a response to treatment.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the total ductal cell-type-enriched proteome derived from pancreatic cancer tissue differs markedly from the corresponding ductalenriched proteome derived from adjacent non-malignant pancreatic tissue [68]. The tumor stroma may act as both a physical barrier impairing drug delivery [69] and play a key role in the development of biochemical drug resistance [57,59,70,71]. Specific CAF subsets were also found to associate with immunotherapy responses [72,73].…”

Section: Co-culturesmentioning

confidence: 99%

Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring

Mäkinen

Vähä‐Koskela

Juusola

et al. 2022

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative approaches are being tested. Organoids can be derived within a short enough time window to allow testing of several anticancer agents, which opens up the possibility for functional precision medicine for pancreatic cancer. At the same time, organoid model systems are being refined to better mimic the cancer, for example, by incorporation of components of the tumor microenvironment. We review some of the latest developments in pancreatic cancer organoid research and in novel treatment design. We also summarize our own current experiences with pancreatic cancer organoid drug sensitivity and resistance testing (DSRT) in 14 organoids from 11 PDAC patients. Our data show that it may be necessary to include a cell death read-out in ex vivo DSRT assays, as metabolic viability quantitation does not capture actual organoid killing. We also successfully adapted the organoid platform for drug combination synergy discovery. Lastly, live organoid culture 3D confocal microscopy can help identify individual surviving tumor cells escaping cell death even during harsh combination treatments. Taken together, the organoid technology allows the development of novel precision medicine approaches for PDAC, which paves the way for clinical trials and much needed new treatment options for pancreatic cancer patients.

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Spatially confined sub-tumor microenvironments in pancreatic cancer

Cited by 239 publications

References 59 publications

Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer

Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring

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