Abstract LB-144: Tff2 labels pancreatic progenitors that lack proliferative potential during tissue regeneration but can serve as the origin of pancreatic cancer
Bibliographic record
Abstract
Abstract While controversy over the existence of adult pancreatic stem cells persists, it is now appreciated that the acinar compartment of the pancreas harbors heterogeneous progenitors. Recent single-cell analysis also demonstrated the presence of molecularly distinct, albeit morphologically identical, acinar cell sub-lineages. Previously, using lineage-tracing approach, we reported the Dclk1+ facultative progenitors that are critical for pancreatic regeneration. Here, we identified a different pancreatic progenitor-like subpopulation which is labelled by trefoil factor 2 (Tff2), a known progenitor marker and capable of tracing multiple cell lineages in the stomach. In addition, Tff2 molecules have been shown to play a suppressive role in PDAC progression. We utilized constitutive Tff2Cre and inducible Tff2CreERT2-DTR mice which were generated through modification of a BAC allele. We crossed Tff2CreERT2-DTR with reporter mice (R26R-mTmG, -tdTomato) to trace Tff2 labeled cells, and found that Tff2 labels ~2 % of the overall population in the adult acinar compartment, which showed slow proliferation (1 year, descendants <5%) with a proliferative peak at around 6 months. Analysis of Cre recombination of both Tff2CreERT2-DTR and Cre mice revealed proliferative heterogeneity among Tff2+ acinar cells. Interestingly, following caerulein-induced injury, pancreatic ductal ligation and partial pancreatectomy, Tff2 labeled cells, distinct from Dclk1+ acinar cells, did not show increased proliferation but remained unchanged or decreased in the number of clones, suggesting that Tff2+ progenitors are not the major drivers of acinar regeneration in response to injurious stimuli. Quantitative RT-PCR analysis revealed higher expression of Sox9 and c-Met in Tff2+ acinar progenitor-like cells vs. Tff2- acinar cells. Targeted expression of KRasG12D in Tff2+ cells in the adult pancreas through crosses to LSL-KRasG12D mice led to a spectrum of mPanIN formation from 6 to 12 months, but no progression to PDAC within 12 months. Upon caerulein treatment, the progression of PanIN lesions was dramatically accelerated, with approximately 30% of the mice developing aggressive PDAC. Embryonic activation of KRasG12D in Tff2+ cells in Tff2cre mice spontaneously initiated a robust PDAC in the absence of cerulein. Clonal expansion labeled by a multicolor reporter (R26R-Brainbow2.1) showed that PDACs were polyclonal, derived from multiple Tff2+ progenitor cells. Acute pancreatitis induced by caeruelein accelerated tumor development, and significantly shortened the survival of Tff2cre;LSL-Kras mice. Altogether, Tff2 labels a subpopulation of the larger acinar progenitor pool. Tff2+ acinar cells are not facultative progenitors but can serve as a cell of origin for PDAC. Citation Format: Zhengyu Jiang, Bernhard W. Renz, Marina Macchini, Tanaka Takayuki, Ryota Takahashi, Giovanni Valenti, Woosook Kim, Wenju Chang, Yoku Hayakawa, Kosuke Sakitani, Moritz Middelhoff, Zinaida Dubeykovskaya, Timothy Chu, Karan Nagar, Yagnesh Tailor, Chythra R. Chandregowda, Akanksha Anand, Samuel Asfaha, Alina C. Iuga, Timothy C. Wang. Tff2 labels pancreatic progenitors that lack proliferative potential during tissue regeneration but can serve as the origin of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-144. doi:10.1158/1538-7445.AM2017-LB-144
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".