bims-cagime 2023-10-08 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2023‒10‒08
twenty-six papers selected by
Kıvanç Görgülü, Technical University of Munich

Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy.
KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer.
Oncogenic dependency plays a dominant role in the immune response to cancer.
S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy.
Therapeutic developments in pancreatic cancer.
Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas.
Comprehensive quantification of metabolic flux during acute cold stress in mice.
Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer.
Molecular Mechanisms of Intratumoral Nerve Recruitment and Perineural Invasion Elucidated with Spatial Transcriptomics and CRISPR Activation.
Validation of Dual Energy X-ray Absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma.
Understanding and leveraging phenotypic plasticity during metastasis formation.
Anxiolytics cause anxiety in pancreatic cancer.
A disordered region controls cBAF activity via condensation and partner recruitment.
S100PBP is regulated by mutated KRAS and plays a tumour suppressor role in pancreatic cancer.
Neutrophil elastase remodels mammary tumors to facilitate lung metastasis.
WNT enhancing signals in pancreatic cancer are transmitted by LGR6.
Comprehensive Genomic Analysis Stratified by KRAS Status in Patients with Pancreatic Adenocarcinoma and Its Prognostic Significance.
Activation of AMPK ameliorates acute severe pancreatitis by suppressing pancreatic acinar cell necroptosis in obese mice models.
Spatial single-cell mass spectrometry defines zonation of the hepatocyte proteome.
Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity.
Restricting mealtime ameliorates neurodegeneration.
Atg5 knockout induces alternative autophagy via the downregulation of Akt expression.
Evolutionary fingerprints of EMT in pancreatic cancers.
Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.
A deep learning model to triage and predict adenocarcinoma on pancreas cytology whole slide imaging.
ALFI: Cell cycle phenotype annotations of label-free time-lapse imaging data from cultured human cells.

J Cell Biol. 2023 Dec 04. pii: e202303078. [Epub ahead of print]222(12):

Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy.

Jake Cross, Joanne Durgan, David G McEwan, Matthew Tayler, Kevin M Ryan, Oliver Florey.

Cells harness multiple pathways to maintain lysosome integrity, a central homeostatic process. Damaged lysosomes can be repaired or targeted for degradation by lysophagy, a selective autophagy process involving ATG8/LC3. Here, we describe a parallel ATG8/LC3 response to lysosome damage, mechanistically distinct from lysophagy. Using a comprehensive series of biochemical, pharmacological, and genetic approaches, we show that lysosome damage induces non-canonical autophagy and Conjugation of ATG8s to Single Membranes (CASM). Following damage, ATG8s are rapidly and directly conjugated onto lysosome membranes, independently of ATG13/WIPI2, lipidating to PS (and PE), a molecular hallmark of CASM. Lysosome damage drives V-ATPase V0-V1 association, direct recruitment of ATG16L1 via its WD40-domain/K490A, and is sensitive to Salmonella SopF. Lysosome damage-induced CASM is associated with formation of dynamic, LC3A-positive tubules, and promotes robust LC3A engagement with ATG2, a lipid transfer protein central to lysosome repair. Together, our data identify direct ATG8 conjugation as a rapid response to lysosome damage, with important links to lipid transfer and dynamics.

DOI: https://doi.org/10.1083/jcb.202303078
bioRxiv. 2023 Sep 23. pii: 2023.09.21.558891. [Epub ahead of print]

KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer.

Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Madelaine S Theady, Jungho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Yong Zhou, Hong Zhao, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A DePinho, Wantong Yao, Haoqiang Ying.

KRAS G12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRAS G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS G12C -driven PDAC model. Compared to the classical KRAS G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'do-not-eat-me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS G12D -driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC.Significance: Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS G12C inhibitor in PDAC. We generated an autochthonous KRAS G12C -driven PDAC model, which revealed allele-specific biology of the KRAS G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRAS G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.

DOI: https://doi.org/10.1101/2023.09.21.558891
Proc Natl Acad Sci U S A. 2023 Oct 10. 120(41): e2308635120

Oncogenic dependency plays a dominant role in the immune response to cancer.

Jinyu Li, Stephen D'Amico, Varvara Kirillov, Oleksi Petrenko, Nancy C Reich.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies. Advanced PDAC is considered incurable. Nearly 90% of pancreatic cancers are caused by oncogenic KRAS mutations. The mechanisms of primary or acquired resistance to KRAS inhibition are currently unknown. Here, we propose that oncogenic dependency, rather than KRAS mutation per se, plays a dominant role in the immune response to cancer, including late-stage PDAC. Classifying tumor samples according to KRAS activity scores allows accurate prediction of tumor immune composition and therapy response. Dual RAS/MAPK pathway blockade combining KRAS and MEK inhibitors is more effective than the selective KRAS inhibitor alone in attenuating MAPK activation and unblocking the influx of T cells into the tumor. Lowering KRAS activity in established tumors promotes immune infiltration, but with a limited antitumor effect, whereas combining KRAS/MEK inhibition with immune checkpoint blockade achieves durable regression in preclinical models. The results are directly applicable to stratifying human PDAC based on KRAS dependency values and immune cell composition to improve therapeutic design.

Keywords:  KRAS; PDAC; metastasis

DOI:  https://doi.org/10.1073/pnas.2308635120
Mol Cell. 2023 Oct 05. pii: S1097-2765(23)00699-8. [Epub ahead of print]83(19): 3485-3501.e11

S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy.

Xue Huang, Jia Yao, Lu Liu, Jing Chen, Ligang Mei, Jingjing Huangfu, Dong Luo, Xinyi Wang, Changhai Lin, Xiaorong Chen, Yi Yang, Sheng Ouyang, Fujing Wei, Zhuolin Wang, Shaolin Zhang, Tingxiu Xiang, Dante Neculai, Qiming Sun, Eryan Kong, Edward W Tate, Aimin Yang.

  p62 is a well-characterized autophagy receptor that recognizes and sequesters specific cargoes into autophagosomes for degradation. p62 promotes the assembly and removal of ubiquitinated proteins by forming p62-liquid droplets. However, it remains unclear how autophagosomes efficiently sequester p62 droplets. Herein, we report that p62 undergoes reversible S-acylation in multiple human-, rat-, and mouse-derived cell lines, catalyzed by zinc-finger Asp-His-His-Cys S-acyltransferase 19 (ZDHHC19) and deacylated by acyl protein thioesterase 1 (APT1). S-acylation of p62 enhances the affinity of p62 for microtubule-associated protein 1 light chain 3 (LC3)-positive membranes and promotes autophagic membrane localization of p62 droplets, thereby leading to the production of small LC3-positive p62 droplets and efficient autophagic degradation of p62-cargo complexes. Specifically, increasing p62 acylation by upregulating ZDHHC19 or by genetic knockout of APT1 accelerates p62 degradation and p62-mediated autophagic clearance of ubiquitinated proteins. Thus, the protein S-acylation-deacylation cycle regulates p62 droplet recruitment to the autophagic membrane and selective autophagic flux, thereby contributing to the control of selective autophagic clearance of ubiquitinated proteins.

Keywords:  APT1; S-acylation; ZDHHC19; autophagy; autophagy receptor; liquid-liquid phase separation; p62 droplet; p62 protein; protein posttranslational modification; selective autophagy

DOI:  https://doi.org/10.1016/j.molcel.2023.09.004
Nat Rev Gastroenterol Hepatol. 2023 Oct 05.

Therapeutic developments in pancreatic cancer.

Z Ian Hu, Eileen M O'Reilly.

Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence and is one of the most lethal human malignancies. Much is known regarding the biology and pathophysiology of PDAC, but translating this knowledge to the clinic to improve patient outcomes has been challenging. In this Review, we discuss advances and practice-changing trials for PDAC. We briefly review therapeutic failures as well as ongoing research to refine the standard of care, including novel biomarkers and clinical trial designs. In addition, we highlight contemporary areas of research, including poly(ADP-ribose) polymerase inhibitors, KRAS-targeted therapies and immunotherapies. Finally, we discuss the future of pancreatic cancer research and areas for improvement in the next decade.

DOI: https://doi.org/10.1038/s41575-023-00840-w
J Pathol. 2023 Oct 05.

Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas.

Ryota Ando, Yukihiro Shiraki, Yuki Miyai, Hiroki Shimizu, Kazuhiro Furuhashi, Shun Minatoguchi, Katsuhiro Kato, Akira Kato, Tadashi Iida, Yasuyuki Mizutani, Kisuke Ito, Naoya Asai, Shinji Mii, Nobutoshi Esaki, Masahide Takahashi, Atsushi Enomoto.

  Pancreatic stellate cells (PSCs) are stromal cells in the pancreas that play an important role in pancreatic pathology. In chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), PSCs are known to get activated to form myofibroblasts or cancer-associated fibroblasts (CAFs) that promote stromal fibroinflammatory reactions. However, previous studies on PSCs were mainly based on the findings obtained using ex vivo expanded PSCs, with few studies that addressed the significance of in situ tissue-resident PSCs using animal models. Their contributions to fibrotic reactions in CP and PDAC are also lesser-known. These limitations in our understanding of PSC biology have been attributed to the lack of specific molecular markers of PSCs. Herein, we established Meflin (Islr), a glycosylphosphatidylinositol-anchored membrane protein, as a PSC-specific marker in both mouse and human by using human pancreatic tissue samples and Meflin reporter mice. Meflin-positive (Meflin+ ) cells contain lipid droplets and express the conventional PSC marker Desmin in normal mouse pancreas, with some cells also positive for Gli1, the marker of pancreatic tissue-resident fibroblasts. Three-dimensional analysis of the cleared pancreas of Meflin reporter mice showed that Meflin+ PSCs have long and thin cytoplasmic protrusions, and are localised on the abluminal side of vessels in the normal pancreas. Lineage tracing experiments revealed that Meflin+ PSCs constitute one of the origins of fibroblasts and CAFs in CP and PDAC, respectively. In these diseases, Meflin+ PSC-derived fibroblasts showed a distinctive morphology and distribution from Meflin+ PSCs in the normal pancreas. Furthermore, we showed that the genetic depletion of Meflin+ PSCs accelerated fibrosis and attenuated epithelial regeneration and stromal R-spondin 3 expression, thereby implying that Meflin+ PSCs and their lineage cells may support tissue recovery and Wnt/R-spondin signalling after pancreatic injury and PDAC development. Together, these data indicate that Meflin may be a marker specific to tissue-resident PSCs and useful for studying their biology in both health and disease. © 2023 The Pathological Society of Great Britain and Ireland.

Keywords:  Islr; Meflin; cancer-associated fibroblast; chronic pancreatitis; fibroblast; fibrosis; pancreas; pancreatic ductal adenocarcinoma; pancreatic stellate cell

DOI:  https://doi.org/10.1002/path.6211
Cell Metab. 2023 Sep 27. pii: S1550-4131(23)00337-6. [Epub ahead of print]

Comprehensive quantification of metabolic flux during acute cold stress in mice.

Marc R Bornstein, Michael D Neinast, Xianfeng Zeng, Qingwei Chu, Jessie Axsom, Chelsea Thorsheim, Kristina Li, Megan C Blair, Joshua D Rabinowitz, Zoltan Arany.

  Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity, but a thorough understanding of the metabolic changes driving CIT is lacking. Here, we present a comprehensive and quantitative analysis of the metabolic response to acute cold exposure, leveraging metabolomic profiling and minimally perturbative isotope tracing studies in unanesthetized mice. During cold exposure, brown adipose tissue (BAT) primarily fueled the tricarboxylic acid (TCA) cycle with fat in fasted mice and glucose in fed mice, underscoring BAT's metabolic flexibility. BAT minimally used branched-chain amino acids or ketones, which were instead avidly consumed by muscle during cold exposure. Surprisingly, isotopic labeling analyses revealed that BAT uses glucose largely for TCA anaplerosis via pyruvate carboxylation. Finally, we find that cold-induced hepatic gluconeogenesis is critical for CIT during fasting, demonstrating a key functional role for glucose metabolism. Together, these findings provide a detailed map of the metabolic rewiring driving acute CIT.

Keywords:  FBP1; brown adipose tissue; cold exposure; flux; gluconeogenesis; glucose; metabolomics; pyruvate carboxylase; thermogenesis

DOI:  https://doi.org/10.1016/j.cmet.2023.09.002
Cancer Cell. 2023 Sep 25. pii: S1535-6108(23)00324-0. [Epub ahead of print]

Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer.

Nirakar Rajbhandari, Michael Hamilton, Cynthia M Quintero, L Paige Ferguson, Raymond Fox, Christian M Schürch, Jun Wang, Mari Nakamura, Nikki K Lytle, Matthew McDermott, Emily Diaz, Hannah Pettit, Marcie Kritzik, Haiyong Han, Derek Cridebring, Kwun Wah Wen, Susan Tsai, Michael G Goggins, Andrew M Lowy, Robert J Wechsler-Reya, Daniel D Von Hoff, Aaron M Newman, Tannishtha Reya.

  Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.

Keywords:  Musashi; Myc; acinar cell carcinoma; adenosquamous carcinoma; cancer; cell of origin stem cells; pancreatic cancer; single cell; tumor evolution

DOI:  https://doi.org/10.1016/j.ccell.2023.09.008
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04370-5. [Epub ahead of print]117(2S): S21

Molecular Mechanisms of Intratumoral Nerve Recruitment and Perineural Invasion Elucidated with Spatial Transcriptomics and CRISPR Activation.

W L Hwang, J Su, C Shiau, P L Wang, J A Guo, N A Lester, J L Barth, H I Hoffman, A Aguirre, T S Hong, J Y Wo, D Ting, L Zheng, M Mino-Kenudson, T Jacks.

PURPOSE/OBJECTIVE(S): Perineural invasion (PNI) is an aggressive manifestation of tumor-nerve interactions associated with postoperative recurrence, metastasis, pain, and decreased survival. Hence, PNI is included in the staging criteria of several malignancies and often an indication for treatment intensification using adjuvant radiotherapy. However, the diverse molecular mechanisms underlying tumor-nerve crosstalk remain largely unknown-hindering the development of new therapies targeting this key pathological process. Moreover, prior studies were limited by a lack of cell-type information, spatial context, and/or a fragmented focus on a small number of pathways.MATERIALS/METHODS: Using pancreatic ductal adenocarcinoma (PDAC) as an exemplar given the exceptionally high frequency of PNI in this malignancy, we performed the first comprehensive, cell-type specific, and spatially resolved whole-transcriptome analysis of human PDAC to identify molecular mediators of tumor-nerve crosstalk and PNI. We constructed 12 custom tissue microarrays (TMAs) derived from matched malignant regions with and without tumor-nerve proximity (n = 288 cores). We performed whole-transcriptome digital spatial profiling (DSP) to independently determine mRNA abundance from the malignant, fibroblast, and nerve compartments through optical sectioning.
RESULTS: We mapped malignant subtypes we previously identified onto the spatial data and found strong (p<0.0001) positive nerve associations with the mesenchymal, basaloid, and neural-like progenitor subtypes and a negative nerve association with the classical subtype. Numerous genes expressed by malignant cells were enriched (e.g., MMP2, PLXND1, NRP1) or depleted (e.g., SEMA3B) in association with radial distance from nerves, including recapitulation of prior literature. To functionally explore these candidate mediators of tumor-nerve crosstalk, we derived genetically-engineered murine organoids (KrasLSL-G12D/+; Trp53FL/FL; Rosa26-dCas9-VPR) and transduced them with guide RNAs to overexpress subtype-specific transcription factors or candidate genes from the spatial analysis. We quantified (1) cancer cell invasion through extracellular matrix using cultured dorsal root ganglia (DRG) sensory neurons as the chemoattractant, and (2) the role of cancer-intrinsic signaling on nerve recruitment/outgrowth by applying conditioned media or exogenous proteins to cultured DRG sensory neurons and tracking their growth with live imaging.
CONCLUSION: Our results suggest that the mechanisms enabling cancer cells to recruit nerves into the tumor microenvironment are distinct from those facilitating perineural invasion. This study has transformed our understanding of how cancer cells and the peripheral nervous system collaborate to promote tumor growth, survival, and dissemination, and is now guiding prioritization of therapeutic strategies that synergize with adjuvant radiotherapy in the burgeoning field of cancer neuroscience.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.244
bioRxiv. 2023 Sep 19. pii: 2023.09.17.558153. [Epub ahead of print]

Validation of Dual Energy X-ray Absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma.

Zachary R Sechrist, Grace Lee, Edward M Schwarz, Calvin L Cole.

Noninvasive imaging is central to preclinical, in vivo models of pancreatic ductal adenocarcinoma (PDAC). While bioluminescent imaging (BLI) is a gold standard, its signal is dependent on the metabolic activity of tumor cells. In contrast, dual energy X-ray absorptiometry (DEXA) is a direct measure of body composition. Thus, we aimed to assess its potential for longitudinal quantification of tumor burden versus BLI. We utilized the KCKO murine model of PDAC and subjected tumor-bearing (n = 20) and non-tumor control (NTC) (n = 10) animals to weekly BLI and DEXA measurements for up to 10 weeks. While BLI detected tumors at 1-week, it failed to detect tumor growth, displayed a decreasing trend overtime (slope = -9.0x10 8 ; p = 0.0028), and terminal signal did not correlate with ex vivo tumor mass (r = 0.01853; p = 0.6286). In contrast, DEXA did not detect elevated changes in abdominal cavity lean mass until week 2 post inoculation and tumors were not visible until week 3, but successfully quantified a tumor growth trend (slope = 0.7322; p<0.0001), and strongly correlated with final tumor mass (r = 0.9351; p<0.0001). These findings support the use of BLI for initial tumor engraftment and persistence but demonstrate the superiority of DEXA for longitudinal tumor burden studies. As tumor detection by DEXA is not restricted to luciferase expressing models, future studies to assess its value in various cancer models and as an in vivo outcome measure of treatment efficacy are warranted.

DOI: https://doi.org/10.1101/2023.09.17.558153
NPJ Syst Biol Appl. 2023 Oct 06. 9(1): 48

Understanding and leveraging phenotypic plasticity during metastasis formation.

Saumil Shah, Lisa-Marie Philipp, Stefano Giaimo, Susanne Sebens, Arne Traulsen, Michael Raatz.

Cancer metastasis is the process of detrimental systemic spread and the primary cause of cancer-related fatalities. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks simultaneously. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Given the changing selection pressures and competitive interactions that tumor cells face, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model with phenotypic plasticity and resource competition between phenotypes to address this knowledge gap. We find that phenotypically plastic tumor cell populations attain a stable phenotype equilibrium that maintains tumor cell heterogeneity. Considering treatment types inspired by chemo- and immunotherapy, we highlight that plasticity can protect tumors against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use plasticity as a target for adjuvant therapy. We present a parsimonious view of tumor plasticity-driven metastasis that is quantitative and experimentally testable, and thus potentially improving the mechanistic understanding of metastasis at the cell population level, and its treatment consequences.

DOI: https://doi.org/10.1038/s41540-023-00309-1
Trends Cancer. 2023 Sep 29. pii: S2405-8033(23)00189-9. [Epub ahead of print]

Anxiolytics cause anxiety in pancreatic cancer.

Yang Chen, Anirban Maitra.

  Benzodiazepines (BZDs) are commonly prescribed for pancreatic cancer patients. To investigate the correlation between BZDs and survival outcomes a recent study by Cornwell et al. found that lorazepam (LOR) correlates with poor survival. The mechanistic study shows that LOR increases interleukin 6 (IL6) expression in cancer-associated fibroblasts via GPR68.

Keywords:  GPR68; benzodiazepines; fibroblast; interleukin 6; pancreatic cancer; survival

DOI:  https://doi.org/10.1016/j.trecan.2023.09.005
Cell. 2023 Sep 29. pii: S0092-8674(23)00965-0. [Epub ahead of print]

A disordered region controls cBAF activity via condensation and partner recruitment.

Ajinkya Patil, Amy R Strom, Joao A Paulo, Clayton K Collings, Kiersten M Ruff, Min Kyung Shinn, Akshay Sankar, Kasey S Cervantes, Tobias Wauer, Jessica D St Laurent, Grace Xu, Lindsay A Becker, Steven P Gygi, Rohit V Pappu, Clifford P Brangwynne, Cigall Kadoch.

  Intrinsically disordered regions (IDRs) represent a large percentage of overall nuclear protein content. The prevailing dogma is that IDRs engage in non-specific interactions because they are poorly constrained by evolutionary selection. Here, we demonstrate that condensate formation and heterotypic interactions are distinct and separable features of an IDR within the ARID1A/B subunits of the mSWI/SNF chromatin remodeler, cBAF, and establish distinct "sequence grammars" underlying each contribution. Condensation is driven by uniformly distributed tyrosine residues, and partner interactions are mediated by non-random blocks rich in alanine, glycine, and glutamine residues. These features concentrate a specific cBAF protein-protein interaction network and are essential for chromatin localization and activity. Importantly, human disease-associated perturbations in ARID1B IDR sequence grammars disrupt cBAF function in cells. Together, these data identify IDR contributions to chromatin remodeling and explain how phase separation provides a mechanism through which both genomic localization and functional partner recruitment are achieved.

Keywords:  ARID1A; ARID1B; ATP-dependent chromatin remodeling; IDRs; cBAF complexes; condensates; intrinsically disordered regions; mammalian SWI/SNF complexes; phase separation; transcription factors

DOI:  https://doi.org/10.1016/j.cell.2023.08.032
Oncogene. 2023 Oct 04.

S100PBP is regulated by mutated KRAS and plays a tumour suppressor role in pancreatic cancer.

K Srivastava, K E Lines, D Jach, T Crnogorac-Jurcevic.

We have previously shown that expression of S100PBP, an S100P binding partner, gradually decreases during progression of pancreatic ductal adenocarcinomas (PDAC). Here, we show that loss of S100PBP leads to oncogenic transformation of pancreatic cells; after deregulation of S100PBP expression, both in silico and in vitro analyses highlighted alterations of genes known to modulate cytoskeleton, cell motility and survival. Overexpression of S100P reduced S100PBP expression, while co-immunoprecipitation indicated the interaction of S100P with S100PBP-p53-ubiquitin protein complex, likely causing S100PBP degradation. The doxycycline-induced KrasG12D activation resulted in decreased S100PBP levels, while low-dose treatment with HDAC inhibitor MS-275 rescued its expression in both human and mouse PDAC cell lines. This indicates KrasG12D as an upstream epigenetic regulator of S100PBP. Finally, analysis of TCGA PanCancer Atlas PDAC datasets demonstrated poor prognosis in patients with high S100P and low S100PBP expression, suggesting that S100PBP is a novel tumour suppressor gene with potential clinical utility.

DOI: https://doi.org/10.1038/s41388-023-02851-y
Mol Cancer Ther. 2023 Oct 05.

Neutrophil elastase remodels mammary tumors to facilitate lung metastasis.

Amriti R Lulla, Said Akli, Cansu Karakas, Joseph A Caruso, Lucas D Warma, Natalie W Fowlkes, Xiayu Rao, Jing Wang, Kelly K Hunt, Stephanie S Watowich, Khandan Keyomarsi.

Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways by NE. These NE-regulated pathways are critical for cell-to-cell contact and motility and consistent with the delay in metastasis in NE-/- mice. To evaluate whether pharmacological inhibition of NE inhibited pulmonary metastasis and phenotypically mimicked PyMT NE-/- mice, we utilized AZD9668, a clinically available and specific NE inhibitor. We found AZD9668 treated PyMT-NE+/+ mice showed significantly reduced lung metastases, improved recurrence-free, metastasis-free and overall survival, and their tumors showed similar molecular alterations as those observed in PyMT-NE-/- tumors. Lastly, we identified a NE-specific signature that predicts recurrence and metastasis in breast cancer patients. Collectively, our studies suggest that genetic ablation and pharmacological inhibition of NE reduces metastasis and extends survival of mouse models of breast cancer, providing rationale to examine NE inhibitors as a treatment strategy for the clinical management of metastatic breast cancer patients.

DOI: https://doi.org/10.1158/1535-7163.MCT-23-0414
Aging (Albany NY). 2023 Sep 27. 15

WNT enhancing signals in pancreatic cancer are transmitted by LGR6.

Jing Wang, Dominik T Koch, Felix O Hofmann, Daniel Härtwig, Iris Beirith, Klaus Peter Janssen, Alexandr V Bazhin, Hanno Niess, Jens Werner, Bernhard W Renz, Matthias Ilmer.

  The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells' WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional in vitro assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.

Keywords:  LGR6; WNT signaling; cancer stem cells; epithelial-mesenchymal transition; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.18632/aging.205101
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04714-4. [Epub ahead of print]117(2S): S24

Comprehensive Genomic Analysis Stratified by KRAS Status in Patients with Pancreatic Adenocarcinoma and Its Prognostic Significance.

J Kim, R Kumar, L Hathout, S K Jabbour, M P Deek.

PURPOSE/OBJECTIVE(S): KRAS mutations (MUT) are one of the major drivers in pancreatic ductal adenocarcinoma (PDA) with over 90% of patients having alterations. However, the genetic landscape of PDA based on KRAS status is not well studied. The aim of this study is to investigate genomic alterations based on KRAS status and to identify driver mutations in patients with KRAS wild type (WT).MATERIALS/METHODS: Next-generation sequencing with 324 pre-specified genes was performed on patients with histologically confirmed PDA. The landscape of somatic mutations was stratified by KRAS status. Outcomes of interest included overall survival (OS), local failure (LF) following radiotherapy, time to metastasis, and CA 19-9 level. All outcomes were stratified by KRAS status. Genetic alterations exclusive to patients with KRAS WT were analyzed. OS was calculated using the Kaplan-Meier estimates and log-rank test, and LF was measured using cumulative incidence. A multivariate cox-regression analysis (MVA) was performed to identify prognostic factors for survival. Gene ontology analysis of KRAS WT exclusive genes was performed via DAVID (Database for Annotation, Visualization, and Integrated Discovery).
RESULTS: A total of 272 patients with metastatic PDA were included. The median age at diagnosis was 65.4 (range, 26.77-83.21) years. The median follow-up was 15.7 (0.06-136.7) months. 91% percent (n = 248) of patients were found to be KRAS MUT. The chi-square test showed that the primary tumor site (p = 0.027) and perineural invasion (p = 0.006) were associated with KRAS status. The median CA 19-9 was 143.6 (15.5-27996) U/ml and 341.15 (0-100000) U/ml for KRAS WT and KRAS MUT, respectively (p = 0.23). The median OS for KRAS WT and MUT was 31.4 (95% CI 25.1-NA) and 13.3 (95% CI 11.3-14.5) months, respectively (p = 0.0008). In patients with metachronous recurrence, the median time to metastasis was 22.4 (1.37-52.97) months and 12.8 (1.8-84.97) months for KRAS WT and KRAS MUT, respectively (p = 0.057). KRAS MUT types including G12 and Q21 were not associated with OS (p = 0.58). On MVA, including KRAS status, age, sex, and metastatic types (de novo vs. metachronous), only KRAS mutation was associated with worse OS [HR 2.64; 95% CI 1.53 to 4.56; p = 0.0004]. In patients treated with radiation, the LF rate at 12 months was 12.5% in patients with KRAS WT and 33.8% in KRAS MUT (p = 0.13). Heatmap analysis identified that RAD50, ALK, BCORL1, BRAF, CDC73, FAM123B, NF2, ERBB4, and ERCC4 were exclusively mutated in patients with KRAS WT. These genes were enriched in pathways associated with tyrosine kinase catalytic domain activity, ubiquitination, and nuclear localization signal.
CONCLUSION: This study identified driver mutations in patients with KRAS WT. KRAS status was associated with pathologic features and disease prognosis after treatment. Further study leveraging more powered cohorts is warranted.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.280
Cell Death Discov. 2023 Sep 30. 9(1): 363

Activation of AMPK ameliorates acute severe pancreatitis by suppressing pancreatic acinar cell necroptosis in obese mice models.

Kunlei Wang, Anbang Zhao, Dilinigeer Tayier, Kai Tan, Wenjing Song, Qian Cheng, Xinyin Li, Zhinan Chen, Qifeng Wei, Yufeng Yuan, Zhiyong Yang.

Obese people with acute pancreatitis (AP) have an increased risk of developing severe acute pancreatitis (SAP), which prolongs the length of hospital stay and increases mortality. Thus, elucidation of the mechanisms through which SAP occurs in obese individuals will provide clues for possible treatment targets. Differences in early events in obese or lean patients with AP have not been conclusively reported. We selected C57BL/6 mice as lean mice models, ob/ob mice or diet induced obese (DIO) mice as obese mice models and then induced experimental AP in mice via injections of caerulein. There were suppressed p-AMPK expressions in the pancreas of obese mice, compared with same-age lean C57BL/6 mice, which were further reduced in AP mice models. Obese AP mice were treated using AICAR, a direct AMPK agonist, which prevented pancreatic damage and cell death, suppressed pancreatic enzyme levels in serum, reduced the areas of fat saponification in the peritoneal cavity, prevented injury in other organs and decreased mice mortality rate. Further assays showed that AICAR activates p-AMPK to stabilize pro-caspase-8. Pro-caspase-8 enhances RIPK3 degradation, inhibits pancreatic acinar cell necroptosis, and downregulates the release of pancreatic enzymes. Thus, activation of AMPK by AICAR alleviates pancreatic acinar cell necroptosis and converts SAP to mild acute pancreatitis in obese mice.

DOI: https://doi.org/10.1038/s41420-023-01655-z
Nat Methods. 2023 Oct;20(10): 1530-1536

Spatial single-cell mass spectrometry defines zonation of the hepatocyte proteome.

Florian A Rosenberger, Marvin Thielert, Maximilian T Strauss, Lisa Schweizer, Constantin Ammar, Sophia C Mädler, Andreas Metousis, Patricia Skowronek, Maria Wahle, Katherine Madden, Janine Gote-Schniering, Anna Semenova, Herbert B Schiller, Edwin Rodriguez, Thierry M Nordmann, Andreas Mund, Matthias Mann.

Single-cell proteomics by mass spectrometry is emerging as a powerful and unbiased method for the characterization of biological heterogeneity. So far, it has been limited to cultured cells, whereas an expansion of the method to complex tissues would greatly enhance biological insights. Here we describe single-cell Deep Visual Proteomics (scDVP), a technology that integrates high-content imaging, laser microdissection and multiplexed mass spectrometry. scDVP resolves the context-dependent, spatial proteome of murine hepatocytes at a current depth of 1,700 proteins from a cell slice. Half of the proteome was differentially regulated in a spatial manner, with protein levels changing dramatically in proximity to the central vein. We applied machine learning to proteome classes and images, which subsequently inferred the spatial proteome from imaging data alone. scDVP is applicable to healthy and diseased tissues and complements other spatial proteomics and spatial omics technologies.

DOI: https://doi.org/10.1038/s41592-023-02007-6
Elife. 2023 10 02. pii: RP88049. [Epub ahead of print]12

Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity.

Chandramohan Chitraju, Alexander W Fischer, Yohannes A Ambaw, Kun Wang, Bo Yuan, Sheng Hui, Tobias C Walther, Robert V Farese.

  Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT (brown adipose tissue) activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.

Keywords:  adipose tissue; fat; glucose metabolism; lipodystrophy; medicine; metabolism; mouse; triglyceride

DOI:  https://doi.org/10.7554/eLife.88049
Cell Metab. 2023 Oct 03. pii: S1550-4131(23)00334-0. [Epub ahead of print]35(10): 1673-1674

Restricting mealtime ameliorates neurodegeneration.

Xiao Tian, David A Sinclair.

Alzheimer's disease is often accompanied by disruptions in circadian rhythms, which may exacerbate the disease's progression. In this issue, Whittaker and colleagues demonstrate that the modulation of circadian rhythms by time-restricted feeding can alter the disease trajectory in Alzheimer's mouse models.

DOI: https://doi.org/10.1016/j.cmet.2023.09.006
Toxicol Res. 2023 Oct;39(4): 637-647

Atg5 knockout induces alternative autophagy via the downregulation of Akt expression.

Hye-Gyo Kim, Myeong-Han Ro, Michael Lee.

  Autophagy play contradictory roles in cellular transformation. We previously found that the knockout (KO) of autophagy-related 5 (Atg5), which is essential for autophagy, leads to the malignant transformation of NIH 3T3 cells. In this study, we explored the mechanism by which autophagy contributes to this malignant transformation using two transformed cell lines, Atg5 KO and Ras-NIH 3T3. Monomeric red fluorescent protein-green fluorescent protein-light chain 3 reporter and Cyto-ID staining revealed that Ras-NIH 3T3 cells exhibited higher basal autophagy activity than NIH 3T3 cells. Additionally, transformed cells, regardless of their Atg5 KO status, were more sensitive to autophagy inhibitors (SBI-0206965, chloroquine, and obatoclax) than the untransformed NIH 3T3 cells, suggesting that the transformed cells are more autophagy-dependent than the normal cells. Loss of Atg5 improved the cell viability and mobility, especially in Ras-NIH 3T3 cells. Furthermore, we discovered that autophagy was alternatively induced in a Rab9-dependent manner in Ras-NIH 3T3 and NIH 3T3/Atg5 KO cells. In particular, Atg5 KO cells showed reduced mTOR-mediated phosphorylation of Akt (pAkt S473), indicating the mTOR-independent occurrence of alternative autophagy in Atg5 KO cells. Therefore, our study provides evidence that alternative autophagy may contribute to tumorigenesis in cells with an impaired Atg5-dependent autophagy pathway.Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00191-3.

Keywords:  Atg5; Autophagy; Cell transformation; Knockout; Tumorigenesis

DOI:  https://doi.org/10.1007/s43188-023-00191-3
bioRxiv. 2023 Sep 19. pii: 2023.09.18.558231. [Epub ahead of print]

Evolutionary fingerprints of EMT in pancreatic cancers.

Luigi Perelli, Li Zhang, Sarah Mangiameli, Andrew J C Russell, Francesca Giannese, Fuduan Peng, Federica Carbone, Courtney Le, Hania Khan, Francesca Citron, Melinda Soeung, Truong Nguyen Anh Lam, Sebastian Lundgren, Cihui Zhu, Desiree Catania, Ningping Feng, Enrico Gurreri, Alessandro Sgambato, Giampaolo Tortora, Giulio F Draetta, Giovanni Tonon, Andrew Futreal, Virginia Giuliani, Alessandro Carugo, Andrea Viale, Timothy P Heffernan, Linghua Wang, Davide Cittaro, Fei Chen, Giannicola Genovese.

Mesenchymal plasticity has been extensively described in advanced and metastatic epithelial cancers; however, its functional role in malignant progression, metastatic dissemination and therapy response is controversial. More importantly, the role of epithelial mesenchymal transition (EMT) and cell plasticity in tumor heterogeneity, clonal selection and clonal evolution is poorly understood. Functionally, our work clarifies the contribution of EMT to malignant progression and metastasis in pancreatic cancer. We leveraged ad hoc somatic mosaic genome engineering, lineage tracing and ablation technologies and dynamic genetic reporters to trace and ablate tumor-specific lineages along the phenotypic spectrum of epithelial to mesenchymal plasticity. The experimental evidences clarify the essential contribution of mesenchymal lineages to pancreatic cancer evolution and metastatic dissemination. Spatial genomic analysis combined with single cell transcriptomic and epigenomic profiling of epithelial and mesenchymal lineages reveals that EMT promotes with the emergence of chromosomal instability (CIN). Specifically tumor lineages with mesenchymal features display highly conserved patterns of genomic evolution including complex structural genomic rearrangements and chromotriptic events. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross species analysis of pancreatic and other human epithelial cancers. Mechanistically, we discovered that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, which in turn results in delayed mitosis and catastrophic cell division. Therefore, EMT favors the emergence of high-fitness tumor cells, strongly supporting the concept of a cell-state, lineage-restricted patterns of evolution, where cancer cell sub-clonal speciation is propagated to progenies only through restricted functional compartments. Restraining those evolutionary routes through genetic ablation of clones capable of mesenchymal plasticity and extinction of the derived lineages completely abrogates the malignant potential of one of the most aggressive form of human cancer.

DOI: https://doi.org/10.1101/2023.09.18.558231
Nat Med. 2023 Oct 05.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Deirdre K Tobias, Jordi Merino, Abrar Ahmad, Catherine Aiken, Jamie L Benham, Dhanasekaran Bodhini, Amy L Clark, Kevin Colclough, Rosa Corcoy, Sara J Cromer, Daisy Duan, Jamie L Felton, Ellen C Francis, Pieter Gillard, Véronique Gingras, Romy Gaillard, Eram Haider, Alice Hughes, Jennifer M Ikle, Laura M Jacobsen, Anna R Kahkoska, Jarno L T Kettunen, Raymond J Kreienkamp, Lee-Ling Lim, Jonna M E Männistö, Robert Massey, Niamh-Maire Mclennan, Rachel G Miller, Mario Luca Morieri, Jasper Most, Rochelle N Naylor, Bige Ozkan, Kashyap Amratlal Patel, Scott J Pilla, Katsiaryna Prystupa, Sridharan Raghavan, Mary R Rooney, Martin Schön, Zhila Semnani-Azad, Magdalena Sevilla-Gonzalez, Pernille Svalastoga, Wubet Worku Takele, Claudia Ha-Ting Tam, Anne Cathrine B Thuesen, Mustafa Tosur, Amelia S Wallace, Caroline C Wang, Jessie J Wong, Jennifer M Yamamoto, Katherine Young, Chloé Amouyal, Mette K Andersen, Maxine P Bonham, Mingling Chen, Feifei Cheng, Tinashe Chikowore, Sian C Chivers, Christoffer Clemmensen, Dana Dabelea, Adem Y Dawed, Aaron J Deutsch, Laura T Dickens, Linda A DiMeglio, Monika Dudenhöffer-Pfeifer, Carmella Evans-Molina, María Mercè Fernández-Balsells, Hugo Fitipaldi, Stephanie L Fitzpatrick, Stephen E Gitelman, Mark O Goodarzi, Jessica A Grieger, Marta Guasch-Ferré, Nahal Habibi, Torben Hansen, Chuiguo Huang, Arianna Harris-Kawano, Heba M Ismail, Benjamin Hoag, Randi K Johnson, Angus G Jones, Robert W Koivula, Aaron Leong, Gloria K W Leung, Ingrid M Libman, Kai Liu, S Alice Long, William L Lowe, Robert W Morton, Ayesha A Motala, Suna Onengut-Gumuscu, James S Pankow, Maleesa Pathirana, Sofia Pazmino, Dianna Perez, John R Petrie, Camille E Powe, Alejandra Quinteros, Rashmi Jain, Debashree Ray, Mathias Ried-Larsen, Zeb Saeed, Vanessa Santhakumar, Sarah Kanbour, Sudipa Sarkar, Gabriela S F Monaco, Denise M Scholtens, Elizabeth Selvin, Wayne Huey-Herng Sheu, Cate Speake, Maggie A Stanislawski, Nele Steenackers, Andrea K Steck, Norbert Stefan, Julie Støy, Rachael Taylor, Sok Cin Tye, Gebresilasea Gendisha Ukke, Marzhan Urazbayeva, Bart Van der Schueren, Camille Vatier, John M Wentworth, Wesley Hannah, Sara L White, Gechang Yu, Yingchai Zhang, Shao J Zhou, Jacques Beltrand, Michel Polak, Ingvild Aukrust, Elisa de Franco, Sarah E Flanagan, Kristin A Maloney, Andrew McGovern, Janne Molnes, Mariam Nakabuye, Pål Rasmus Njølstad, Hugo Pomares-Millan, Michele Provenzano, Cécile Saint-Martin, Cuilin Zhang, Yeyi Zhu, Sungyoung Auh, Russell de Souza, Andrea J Fawcett, Chandra Gruber, Eskedar Getie Mekonnen, Emily Mixter, Diana Sherifali, Robert H Eckel, John J Nolan, Louis H Philipson, Rebecca J Brown, Liana K Billings, Kristen Boyle, Tina Costacou, John M Dennis, Jose C Florez, Anna L Gloyn, Maria F Gomez, Peter A Gottlieb, Siri Atma W Greeley, Kurt Griffin, Andrew T Hattersley, Irl B Hirsch, Marie-France Hivert, Korey K Hood, Jami L Josefson, Soo Heon Kwak, Lori M Laffel, Siew S Lim, Ruth J F Loos, Ronald C W Ma, Chantal Mathieu, Nestoras Mathioudakis, James B Meigs, Shivani Misra, Viswanathan Mohan, Rinki Murphy, Richard Oram, Katharine R Owen, Susan E Ozanne, Ewan R Pearson, Wei Perng, Toni I Pollin, Rodica Pop-Busui, Richard E Pratley, Leanne M Redman, Maria J Redondo, Rebecca M Reynolds, Robert K Semple, Jennifer L Sherr, Emily K Sims, Arianne Sweeting, Tiinamaija Tuomi, Miriam S Udler, Kimberly K Vesco, Tina Vilsbøll, Robert Wagner, Stephen S Rich, Paul W Franks.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

DOI: https://doi.org/10.1038/s41591-023-02502-5
Sci Rep. 2023 10 02. 13(1): 16517

A deep learning model to triage and predict adenocarcinoma on pancreas cytology whole slide imaging.

Andrew Sohn, Daniel Miller, Efrain Ribeiro, Nakul Shankar, Syed Ali, Ralph Hruban, Alexander Baras.

Pancreatic fine-needle aspirations are the gold-standard diagnostic procedure for the evaluation of pancreatic ductal adenocarcinoma. A suspicion for malignancy can escalate towards chemotherapy followed by a major surgery and therefore is a high-stakes task for the pathologist. In this paper, we propose a deep learning framework, MIPCL, that can serve as a helpful screening tool, predicting the presence or absence of cancer. We also reproduce two deep learning models that have found success in surgical pathology for our cytopathology study. Our MIPCL significantly improves over both models across all evaluated metrics (F1-Score: 87.97% vs 88.70% vs 91.07%; AUROC: 0.9159 vs. 0.9051 vs 0.9435). Additionally, our model is able to recover the most contributing regions on the slide for the final prediction. We also present a dataset curation strategy that increases the number of training examples from an existing dataset, thereby reducing the resource burden tied to collecting and scanning additional cases.

DOI: https://doi.org/10.1038/s41598-023-42045-w
Sci Data. 2023 Oct 04. 10(1): 677

ALFI: Cell cycle phenotype annotations of label-free time-lapse imaging data from cultured human cells.

Laura Antonelli, Federica Polverino, Alexandra Albu, Aroj Hada, Italia A Asteriti, Francesca Degrassi, Giulia Guarguaglini, Lucia Maddalena, Mario R Guarracino.

Detecting and tracking multiple moving objects in a video is a challenging task. For living cells, the task becomes even more arduous as cells change their morphology over time, can partially overlap, and mitosis leads to new cells. Differently from fluorescence microscopy, label-free techniques can be easily applied to almost all cell lines, reducing sample preparation complexity and phototoxicity. In this study, we present ALFI, a dataset of images and annotations for label-free microscopy, made publicly available to the scientific community, that notably extends the current panorama of expertly labeled data for detection and tracking of cultured living nontransformed and cancer human cells. It consists of 29 time-lapse image sequences from HeLa, U2OS, and hTERT RPE-1 cells under different experimental conditions, acquired by differential interference contrast microscopy, for a total of 237.9 hours. It contains various annotations (pixel-wise segmentation masks, object-wise bounding boxes, tracking information). The dataset is useful for testing and comparing methods for identifying interphase and mitotic events and reconstructing their lineage, and for discriminating different cellular phenotypes.

DOI: https://doi.org/10.1038/s41597-023-02540-1