Earliest Metabolic Changes Associated with the Initiation of Pancreatic Cancer.

Pancreatic cancer is usually detected at a late stage, when tumors have already metastasized; therefore, it has a poor prognosis with a 5-year survival rate of 11% to 12%. A key to targeting this high mortality is to develop methods for detecting the disease at a stage in which it is still local to the pancreas. However, this needs a better understanding of the events that govern pancreatic cancer oncogenesis. In this issue of Cancer Research, Neuß and colleagues report metabolic changes associated with acinar-to-ductal metaplasia (ADM), an initiating event that leads to the formation of precursor lesions for pancreatic ductal adenocarcinoma (PDAC). Their findings reveal a switch to aerobic glycolysis, increased c-MYC signaling, and increased serine metabolism as driving factors for the ADM process. These findings are important as they demonstrate that metabolic changes that drive the proliferation and metastasis of full-blown PDAC begin in the earliest lesions. The data not only provide insights into how PDAC develops but also a potential explanation for previously described findings, such as circulating lesion cells can be detected even when no carcinoma in situ is present. In summary, this article is highly relevant for furthering our understanding of how metabolic reprogramming drives the earliest events leading to PDAC development and could lay the groundwork for developing methods for early detection or intervention. See related article by Neuß et al., p. 2297.

Biomarkers of epithelial-mesenchymal transition: E-cadherin and beta-catenin in malignant transformation of oral lesions.

Objective: Detecting oral lesions at high risk of becoming cancer may enable early interventions to prevent oral cancer. The diagnosis of dysplasia in an oral lesion is used to predict this risk but is subject to interobserver and intraobserver variability. Studying biomarkers or molecular markers that reflect underlying molecular alterations can serve as an additional and objective method of risk assessment. E-cadherin and beta-catenin, molecular markers of epithelial-mesenchymal transition (EMT), potentially contribute to early malignant progression in oral tissue. This narrative review provides an overview of EMT, its relation to oral cancer, and the interaction among E-cadherin, beta-catenin, and the Wnt pathway in malignant progression of oral tissue. Methods: Full-text literature on EMT, E-cadherin, beta-catenin, oral epithelial dysplasia, and oral cancer was retrieved from PubMed and Google Scholar. Results: Sixty original research articles, reviews, and consensus statements were selected for review. Discussion: EMT, a biological mechanism characterized by epithelial and mesenchymal changes, can contribute to cancer development. Molecular markers of EMT including TWIST, vimentin, and N-cadherin may serve as prognostic markers of oral cancer. Dependent on Wnt pathway activity and the loss of membranous E-cadherin, E-cadherin and beta-catenin can play various roles along the spectrum of malignant progression, including tumour inhibition, early tumour progression, and late-stage tumour progression. Cross-sectional immunohistochemical research has found changes in expression patterns of E-cadherin and beta-catenin from normal oral tissue, oral epithelial dysplasia, to oral squamous cell carcinoma. Conclusion: Future research should explore the longitudinal role of EMT markers in predicting malignant progression in oral tissue.

Objectif: La détection de lésions buccales présentant un risque élevé d'évoluer en cancer peut permettre des interventions précoces pour prévenir le cancer de la bouche. Le diagnostic de dysplasie dans le cas de lésions buccales sert à prédire ce risque, mais il est soumis à une variabilité d'un observateur à l'autre et avec le même observateur. L'étude de marqueurs biologiques ou de marqueurs moléculaires correspondant à des altérations moléculaires sous-jacentes peut constituer une méthode objective supplémentaire d'évaluation des risques. L'E-cadhérine et la bêta-caténine, des marqueurs moléculaires de la transition épithélio-mésenchymateuse (TEM), pourraient contribuer aux premières étapes de l'évolution maligne du tissu buccal. Cette revue narrative donne un aperçu de la TEM, de ses liens avec le cancer de la bouche et de l'interaction entre l'E-cadhérine, la bêta-caténine et la voie de signalisation Wnt dans l'évolution maligne du tissu buccal. Méthodes: On a obtenu le texte intégral d'études portant sur la TEM, l'E-cadhérine, la bêta-caténine, la dysplasie épithéliale buccale et le cancer de la bouche sur PubMed et Google Scholar. Résultats: Soixante articles sur des études originales, des revues et des déclarations de consensus ont été sélectionnés aux fins d'examen. Discussion: La TEM, un mécanisme biologique caractérisé par des changements épithéliaux et mésenchymateux, peut contribuer à l'apparition d'un cancer. Les marqueurs moléculaires de la TEM, notamment TWIST, la vimentine et la N-cadhérine, peuvent servir de marqueurs pronostiques du cancer de la bouche. En fonction de l'activité de la voie de signalisation Wnt et de la perte de l'E-cadhérine membraneuse, l'E-cadhérine et la bêta-caténine peuvent jouer divers rôles dans le spectre de l'évolution maligne, notamment l'inhibition tumorale, la progression tumorale précoce et l'évolution tumorale avancée. Des études transversales d'immunohistochimie ont révélé des changements dans les modèles d'expression de l'E-cadhérine et de la bêta-caténine avec le passage du tissu buccal normal, de la dysplasie épithéliale buccale au carcinome squameux de la bouche. Conclusion: À l'avenir, des études devraient explorer le rôle longitudinal des marqueurs de la TEM dans la prévision de l'évolution maligne dans les tissus buccaux.

Controversies regarding oral lichen planus and lichenoid-dysplastic lesions.

Objective: Oral lichen planus (OLP) is an immune-mediated condition featuring chronic inflammation. The World Health Organization classifies OLP as potentially malignant, but it is believed that the malignant transformation of OLP occurs in lesions with both lichenoid and dysplastic features (LD). This review discusses the issues surrounding OLP and LD, including their malignancy, classification, and categorization, and whether lichenoid inflammation causes dysplastic changes in LD or vice versa. Methods: English full-text literature on OLP, LD and/or dysplasia was retrieved from PubMed, CINAHL, and Google Scholar. Results: Thirty-six publications including original research articles, reviews, meta-analyses, books, reports, letters, and editorials were selected for review. Discussion: Research suggests that OLP has malignant potential, although small, and that LD should not be disregarded, as dysplasia presenting with or without lichenoid features may develop into cancer. There is also disagreement over the classification and categorization of LD. Different terms have been used to classify these lesions, including lichenoid dysplasia, OLP with dysplasia, and dysplasia with lichenoid features. Moreover, in LD, it is not clear if dysplasia or lichenoid infiltration appears first, and if inflammation is a response to dysplasia or if dysplasia is a response to the persistent inflammation. The main limitation in the literature is the inconsistency and subjective nature of histological diagnoses, which can lead to interobserver and intraobserver variation, ultimately resulting in the inaccurate diagnosis of OLP and LD. Conclusion: Although further research is required to understand OLP and LD, both lesions should be considered potentially malignant and should not be disregarded.

Objectif: Le lichen plan buccal (LPB) est une pathologie auto-immune qui se présente sous la forme d'une inflammation chronique. Selon la classification de l'Organisation mondiale de la santé, le LPB est une pathologie potentiellement maligne. Toutefois, on soupçonne que la transformation maligne du LPB se produit dans des lésions présentant à la fois des caractéristiques lichénoïdes et dysplasiques (LD). Cet examen porte sur les questions relatives au LPB et aux LD, notamment leur malignité, leur classification et leur catégorisation, et pour savoir si l'inflammation du lichénoïde entraîne des changements dysplasiques des LD ou vice versa. Méthodes: On a utilisé le texte intégral de documents rédigés en anglais sur le LPB, les LD et la dysplasie issus de PubMed, de CINAHL et de Google Scholar. Résultats: Trente-six publications, notamment des articles sur des études originales, des revues, des méta-analyses, des livres, des rapports, des lettres et des éditoriaux, ont été sélectionnées aux fins d'examen. Discussion: Des études suggèrent que le LPB est potentiellement malin, bien que ce potentiel soit faible, et que les LD ne doivent pas être ignorés : en effet, une dysplasie peut évoluer en cancer, qu'elle présente des caractéristiques lichénoïdes ou non. On constate également un désaccord quant à la classification et à la catégorisation des LD. Différents termes ont été utilisés pour la classification de ces lésions, notamment « dysplasie lichénoïde ¼, « LPB dysplasique ¼ et « dysplasie à caractéristiques lichénoïdes ¼. De plus, dans le cas des LD, on ne sait pas avec certitude si la dysplasie ou l'infiltration lichénoïde apparaît en premier, ni si l'inflammation découle de la dysplasie ou si la dysplasie est une conséquence de l'inflammation persistante. La principale limite de la littérature est due aux incohérences et à la nature subjective des diagnostics histologiques, qui peut entraîner des variations d'un observateur à l'autre ou même avec un même observateur, ce qui entraîne à terme des diagnostics erronés de LPB et de LD. Conclusion: Bien que d'autres études soient nécessaires pour comprendre le LPB et les LD, les lésions de ces 2 catégories doivent être considérées comme potentiellement malignes et ne doivent pas être ignorées.

Transformation of t(14;18)-negative follicular lymphoma to plasmablastic lymphoma: a case report with analysis of genetic evolution.

BACKGROUND: Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement-negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL). CASE PRESENTATION: A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion. CONCLUSIONS: We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.

CASE OF THE TRANSFORMATION OF PSORIASIS INTO CUTANEOUS T-CELL LYMPHOMA.

Psoriasis is a long-known skin pathology, the incidence of which is constantly rising, though it is not possible to clearly establish the trend due to the differences in the research design. In recent years, the number of cases among children and adolescents has increased. Psoriasis becomes more aggressive, severe forms are more common. It can be combined with other diseases but is rarely complicated. Isolated cases of the transformation of psoriatic plaques into skin cancer have already been described in the literature. Probable causes were the long-term use of photosensitizers and phototherapy, naphthalene, and tar. However, in general, the risk of the malignant recurrence in patients with psoriasis does not increase significantly. We present a clinical observation of the transformation of psoriasis into cutaneous T-cell lymphoma in a patient with more than 37 years of psoriasis experience, where on the background of typical psoriatic rashes, fungal growths of doughy consistency appeared, which were initially misinterpreted as a warty form of psoriasis. Based on the data of additional methods of examination and the results of histological examination, the diagnosis was clarified. Specific treatment was prescribed, which proved its effectiveness. The probable causes of degeneration, in our opinion, are prolonged irritating external therapy and excessive insolation.

Residual biliary intraepithelial neoplasia without malignant transformation at resection margin for perihilar cholangiocarcinoma does not require expanded resection: a dual center retrospective study.

BACKGROUND: Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN). METHOD: Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics. RESULTS: 306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup. CONCLUSION: For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin.

Identification of Ppy-lineage cells as a novel origin of pancreatic ductal adenocarcinoma.

The Ppy gene encodes pancreatic polypeptide (PP) secreted by PP- or γ-cells, which are a subtype of endocrine cells localised mainly in the islet periphery. For a detailed characterisation of PP cells, we aimed to establish PP cell lines. To this end, we generated a mouse model harbouring the SV40 large T antigen (TAg) in the Rosa26 locus, which is expressed upon Ppy-promoter-mediated Cre-loxP recombination. Whereas Insulin1-CreERT-mediated TAg expression in beta cells resulted in insulinoma, surprisingly, Ppy-Cre-mediated TAg expression resulted in the malignant transformation of Ppy-lineage cells. These mice showed distorted islet structural integrity at 5 days of age compared with normal islets. CK19+ duct-like lesions contiguous with the islets were observed at 2 weeks of age, and mice developed aggressive pancreatic ductal adenocarcinoma (PDAC) at 4 weeks of age, suggesting that PDAC can originate from the islet/endocrine pancreas. This was unexpected as PDAC is believed to originate from the exocrine pancreas. RNA-sequencing analysis of Ppy-lineage islet cells from 7-day-old TAg+ mice showed a downregulation and an upregulation of endocrine and exocrine genes, respectively, in addition to the upregulation of genes and pathways associated with PDAC. These results suggest that the expression of an oncogene in Ppy-lineage cells induces a switch from endocrine cell fate to PDAC. Our findings demonstrate that Ppy-lineage cells may be an origin of PDAC and may provide novel insights into the pathogenesis of pancreatic cancer, as well as possible therapeutic strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The E3 ubiquitin ligase TRIP12 is required for pancreatic acinar cell plasticity and pancreatic carcinogenesis.

The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC-derived cell lines. We further demonstrated that TRIP12 was required for PDAC-derived cell growth and for the expression of E2F-targeted genes. Acinar-to-ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of KrasG12D-induced preneoplastic lesions and impaired metastasis formation in the presence of mutated KrasG12D and Trp53R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Hypoxia Increases the Efficiencies of Cellular Reprogramming and Oncogenic Transformation in Human Blood Cell Subpopulations In Vitro and In Vivo.

Patients with chronic hypoxia show a higher tumor incidence; however, no primary common cause has been recognized. Given the similarities between cellular reprogramming and oncogenic transformation, we directly compared these processes in human cells subjected to hypoxia. Mouse embryonic fibroblasts were employed as controls to compare transfection and reprogramming efficiency; human adipose-derived mesenchymal stem cells were employed as controls in human cells. Easily obtainable human peripheral blood mononuclear cells (PBMCs) were chosen to establish a standard protocol to compare cell reprogramming (into induced pluripotent stem cells (iPSCs)) and oncogenic focus formation efficiency. Cell reprogramming was achieved for all three cell types, generating actual pluripotent cells capable for differentiating into the three germ layers. The efficiencies of the cell reprogramming and oncogenic transformation were similar. Hypoxia slightly increased the reprogramming efficiency in all the cell types but with no statistical significance for PBMCs. Various PBMC types can respond to hypoxia differently; lymphocytes and monocytes were, therefore, reprogrammed separately, finding a significant difference between normoxia and hypoxia in monocytes in vitro. These differences were then searched for in vivo. The iPSCs and oncogenic foci were generated from healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). Although higher iPSC generation efficiency in the patients with COPD was found for lymphocytes, this increase was not statistically significant for oncogenic foci. Remarkably, a higher statistically significant efficiency in COPD monocytes was demonstrated for both processes, suggesting that physiological hypoxia exerts an effect on cell reprogramming and oncogenic transformation in vivo in at least some cell types.

Malignant Transformation of Dysplastic Vocal Fold Lesions: A Systematic Review and Meta-Analysis.

Importance: The reported rates of malignant transformation of dysplastic laryngeal lesions are highly variable, as is time to malignant degeneration. Objective: To evaluate the rate of and time to malignant transformation of dysplastic laryngeal lesions based on the World Health Organization (WHO) dysplasia classification system. Data Sources: PubMed, MEDLINE, Embase, CINAHL, CENTRAL, and Cochrane Reviews were searched from the date of database inception to June 8, 2023. Study Selection: English-language articles assessing the rate of malignant transformation using the 2005 WHO dysplasia classification system were included in this systematic review and meta-analysis. Data Extraction and Synthesis: The study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data extraction was performed by 2 independent investigators. Study quality was assessed using a validated quality tool. When possible, data were pooled using random-effects meta-analysis. Main Outcome Measures: The primary outcome measure was the malignant transformation rate in each laryngeal dysplasia category. Secondary outcome measure was the time interval over which malignant transformation had occurred. Results: A total of 5585 records were screened, 61 full texts were assessed, and 18 retrospective cohort studies with 3243 participants were included in the final review. The weighted pooled mean malignant transformation rates of mildly, moderately, and severely dysplastic lesions were 10.9%, 23.3%, and 30.5%, respectively. Malignant transformation rate of nondysplastic laryngeal lesions was 4.5%. Moderately and severely dysplastic lesions had significantly higher odds of malignant transformation compared with mildly dysplastic lesions (moderate: odds ratio [OR], 2.90 [95% CI, 2.06-4.09]; I2 = 0%; severe: OR, 3.42 [95% CI, 2.11-5.52]; I2 = 40%). Lesions without dysplasia had a significantly lower odds of malignant transformation compared with lesions with mild dysplasia (OR, 0.48; 95% CI, 0.28-0.81; I2 = 0%). The overall mean time to malignant transformation was 28.8 months (range, 22.0-35.6 months) for all dysplasia grades. Conclusion and Relevance: This systematic review and meta-analysis found that the rate of malignant transformation increased with the grade of laryngeal dysplasia. Moderately dysplastic lesions were more likely to undergo malignant degeneration compared with mildly dysplastic lesions.

Ganglioglioma with anaplastic/high-grade transformation: Histopathologic, molecular, and epigenetic characterization of 3 cases.

Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.

Primary thymic adenoid cystic carcinoma with high-grade transformation: A clinicopathological and immunohistochemical analysis of 4 cases.

Four cases of a distinct carcinoma of the thymic gland are presented. The patients were 4 adult males with an age range from 40 to 47 years (mean, 43.5 years). Clinically, all patients presented with non-specific respiratory symptoms. None of the patients had any prior history of head and neck neoplasm or surgery in that anatomic area. Large anterior mediastinal masses were found on diagnostic imaging with concurrent metastatic disease to pleura, lungs, regional lymph nodes and bones. Microscopically, all tumors were composed of a solid proliferation of hyperchromatic, monomorphic small cells with focal cytoplasmic clearing embedded in a fibromyxoid stroma. In one case, occasional duct-like structures were identified. Immunohistochemically, the tumors were positive for pancytokeratin, CD117 and MYB and negative for myoepithelial markers. Systemic chemotherapy was initiated in all patients. Despite therapy, clinical follow-up revealed that all 4 patients died of their disease 11-23 months after their initial diagnosis. The cases in this series highlight a tumor that is different from conventional thymic carcinoma and that has the morphological and immunohistochemical features commonly seen in adenoid cystic carcinomas with high-grade transformation. Correct diagnosis is essential for patient management.

Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

Origins of cancer: ain't it just mature cells misbehaving?

A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.

Mouse models of CLL: In vivo modeling of disease initiation, progression, and transformation.

Chronic lymphocytic leukemia (CLL) is a highly complex disease characterized by the proliferation of CD5+ B cells in lymphoid tissues. Current modern treatments have brought significant clinical benefits to CLL patients. However, there are still unmet needs. Patients relapse on Bruton's tyrosine kinase inhibitors and BCL2 inhibitors and often develop more aggressive diseases including Richter transformation (RT), an incurable complication of up to ∼10% patients. This evidence underscores the need for improved immunotherapies, combination treatment strategies, and predictive biomarkers. A mouse model that can recapitulate human CLL disease and certain components of the tumor immune microenvironment represents a promising preclinical tool for such purposes. In this review, we provide an overview of CRISPR-engineered and xenograft mouse models utilizing either cell lines, or primary CLL cells suitable for studies of key events driving the disease onset, progression and transformation of CLL. We also review how CRISPR/Cas9 established mouse models carrying loss-of-function lesions allow one to study key mutations driving disease progression. Finally, we discuss how next generation humanized mice might improve to generation of faithful xenograft mouse models of human CLL.