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Germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) at diagnosis is associated with superior long-term outcomes compared to non-GCB-DLBCL in patients treated with conventional chemo-immunotherapy. Whether cell of origin (COO) by Hans algorithm retains its prognostic significance in patients with (R/R) relapsed/refractory DLBCL undergoing autologous hematopoietic cell transplant (auto-HCT) is not well established. Three hundred and fifty-seven patients underwent auto-HCT between 2005 and 2018. The COO status was determined in 284 patients and these were included in the analysis. One hundred ninety-four patients had GCB-DLBCL while 90 had non-GCB-DLBCL. Median follow up was 1.7 (0-13) years. The GCB-DLBCL was associated with inferior 5-year overall survival at 44% (95%CI, 36-52) versus 64% (95%CI, 54-77) (P = .004) and a higher relapse incidence at 67% (95%CI, 58-74) versus 49% (95%CI, 35-60) (P = .01) in the non-GCB-DLBCL. The difference between GCB and non-GCB-DLBCL remained statistically significant in multivariate analysis. Additionally, response at the time of transplant was an independent prognostic factor. GCB-DLBCL was enriched in double-hit and triple hit phenotype based on available fluorescence in situ hybridization data. These results suggest an enrichment of high-risk genetic rearrangements in R/R GCB-DLBCL resulting in limited efficacy of auto-HCT.

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described entity of human papillomavirus (HPV)-associated endocervical adenocarcinoma with phenotypic plasticity and aggressive clinical behavior. To identify the cell of origin of ISMC, we investigated the immunohistochemical expression of cervical epithelial cell markers (CK7, PAX8, CK5/6, p63, and CK17), stemness markers (ALDH1 and Nanog), and epithelial-mesenchymal transition (EMT) markers (Snail, Twist, and E-cadherin) in 10 pure and mixed type ISMCs with at least 10% of ISMC component in the entire tumor, seven usual type endocervical adenocarcinomas (UEAs), and seven squamous cell carcinomas (SCCs). In addition, targeted sequencing was performed in 10 ISMCs. ISMC was significantly associated with larger tumor size (p = 0.011), more frequent lymphovascular invasion and lymph node metastasis (p

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is characterized by both clinical and molecular heterogeneity. Despite efforts to tailor therapy for individual patients, treatment remains uniform and a subset of patients have poor outcomes. The past decade has witnessed a dramatic expansion of our understanding of the genomic underpinnings of this disease, especially with the application of next-generation sequencing. In this review, the authors highlight the current genomic landscape of DLBCL and how this information provides a potential molecular framework for precision medicine-based strategies in this disease.

Summary In this issue of Cell Stem Cell, Fumagalli et al. (2020) employ intravital microscopy of colorectal cancer organoid xenografts to investigate the cell of origin of metastases. While tumor-initiating cells are Lgr5+, most disseminated cancer cells are Lgr5− and seed liver metastases in which Lgr5+ cells then appear, showing that bidirectional plasticity of phenotypic states drives metastasis.

Esophageal cancer (EC) has been a leading cause of cancer death worldwide in part due to late detection and lack of precision treatment. EC includes two major malignancies, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Recent studies reveal that ESCC and EAC have distinct cell of origin and contain cancer stem cells (also known as tumor initiating cells) expressing different cell surface markers. These biomarkers have potentially important values for both early detection and finding effective therapy. In this review we summarize the updated findings for cell of origin and provide an overview of cancer cell biomarkers that have been tested for ESCC and EAC. In addition, we also discuss recent progress in the study of molecular mechanisms leading to these malignancies.

It is uncertain whether thymic neuroendocrine tumors (NET) associated with Cushing's syndrome (CS) produce corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) and whether the thymus contains ACTH and/or CRH cells that could originate NET. The clinicopathologic features of 5 typical (TC) and 6 atypical carcinoids (ATC), 10 additional non-neoplastic thymi, 6 adrenal glands with bilateral nodular hyperplasia and 8 adrenal cortical adenomas were reviewed. Representative slides were immunostained for ACTH and CRH. Four (36.4%) of the 11 patients had CS. The incidence of Masaoka stage IV was higher (p 0.0001) in patients with ATC than TC. Only 2 (18.1%) of the 11 patients were alive at follow-up. Ten NET were CRH immunoreactive and 6 were ACTH immunoreactive. Thymic NET with CS exhibited stronger immunoreactivity for ACTH and CRH than those without CS. Non-neoplastic thymi exhibited scattered ACTH and CRH immunoreactive cells. Normal adrenal cortex and glands with bilateral nodular hyperplasia showed diffuse CRH immunoreactivity while adrenal adenomas showed no or only focal CRH immunoreactivity. Literature review showed no association between thymic NET and adrenal adenomas. The thymus contains CRH and ACTH immunoreactive cells that are probably the origin of thymic NET. Neoplasms associated with CS exhibit strong immunoreactivity for both hormones, suggesting that CRH probably plays a role in the pathogenesis of CS. As adrenals with bilateral nodular hyperplasia exhibit diffuse CRH immunoreactivity and adrenal cortical adenomas either lack this finding or show few immunoreactive cells, this marker may be useful to distinguish these lesions.

Background: Diffuse large B-cell lymphoma, among non-Hodgkin lymphomas, is one of the most frequent subtypes. Clinical laboratory data and post-treatment outcomes are scarce in the Brazilian population. Objective: The main objective of this retrospective study was to assess the impact of tumor markers, including the Myeloid differentiation primary response 88 (MYD88) mutation. Method: Eighty-three patients were included and treated with R-CHOP or R-CHOP-like regimens. Results: Median age was 64-years old and 58% were female patients. The median follow-up was 42 months. The progression free survival (PFS) at this time was 63% and overall survival (OS), 66%. In the patients with tumors expressing Myc proto-oncogene protein (MYC) and B-cell lymphoma 2 (BCL2), assessed by immunohistochemistry (IHC), known as dual protein expressers, median post-progression survival was 31 (15–45) months. An increased proliferative index were associated with a high rate of progression (hazard ratio 2.31 [95% confidence interval [1.05–5.12]; p = 0.04). The cell of origin (COO), identified by IHC, was not able to predict PFS (p = 0.76). The MYD88 L265P mutation was present in 10.8% (9/83) of patients and did not show a prognostic correlation. Conclusion: In conclusion, the MYD88 mutation, although an important tool for diagnosis and a possible target drug, presented at a low frequency and was not a prognostic marker in this population. Keywords: Diffuse large B-cell lymphomas, MYD88, DLBCL, Tumor markers

Prostate cancer (PCa) has a predominantly luminal phenotype. Basal cells were previously identified as a cell of origin for PCa, but increasing evidence implicates luminal cells as a preferred cell of origin for PCa, as well as key drivers of tumor development and progression. Prostate luminal cells are understudied compared with basal cells. In this review, we describe the contribution of prostate luminal progenitor (LP) cells to luminal cell development and their role in prostate development, androgen-mediated regeneration of castrated prostate, and tumorigenesis. We also discuss the potential value of LP transcriptomics to identify new targets and therapies to treat aggressive PCa. Finally, we propose future research directions focusing on molecular mechanisms underlying LP cell biology and heterogeneity in normal and diseased prostate.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable outcomes. Despite the majority of patients being cured with combination chemoimmunotherapy, up to 30% eventually succumb to the disease. Until recently, baseline prognostic assessment has centred on the International Prognostic Index (IPI), although this index is yet to impact strongly on treatment choice. Molecular features such as cell of origin, MYC and BCL-2 genetic alterations and protein overexpression were identified over a decade ago, yet their prognostic value is still not fully elucidated. Adding complexity are the plethora of new clinical, biological and molecular prognostic markers described in the recent literature, most of which lack independent validation, likely act as surrogate markers for those already in common use and have yet to substantially impact on therapeutic decision making. This review comprehensively assesses the value of individual prognostic markers in the clinical setting and their potential to predict response to novel agents, and ways to optimise their use in future research.

Strong prognostic markers able to stratify lung adenocarcinoma (ADC) patients are lacking. We evaluated whether a six-immunohistochemical markers panel (TTF1, SP-A, Napsin A, MUC5AC, CDX2 and CK5), defining the putative neoplastic “cell of origin,” allows to identify prognostic subgroups among lung ADC. We screened a large cohort of ADC specimens (2003–2013) from Torino Institutional Repository identifying: (i) marker positivity by immunohistochemistry, (ii) main morphological appearance by light microscopy, (iii) presence of “hotspot” mutations of candidate genes by Sequenom technology. To evaluate possible predictors of survival and time to recurrence, uni- and multivariable-adjusted comparisons were performed. We identified 4 different subgroups: “alveolar,” “bronchiolar,” “mixed” and “null type." Alveolar-differentiated ADC were more common in young (P =.065), female (P =.083) patients, frequently harboring EGFR-mutated (P =.003) tumors with acinar pattern (P

Sézary Syndrome (SS) is a rare aggressive epidermotropic cutaneous T-cell lymphoma (CTCL) defined by erythroderma, pruritis, and a circulating atypical CD4 + T-cell clonal population. The diversity of Sézary cell (SC) phenotype and genotype may reflect either plasticity or heterogeneity, which was difficult to evaluate dynamically until the achievement of long-term SC expansion. Therefore, we developed six defined culture conditions allowing for the expansion of SC defined by their phenotype and monoclonality in four of seven SS cases. Engraftment of SC through the intrafemoral route into immunodeficient NOD.Cg-Prkdc(scid)Il2rg(tm1Wjll)/SzJ (NSG) mice was achieved in 2 of 14 SS cases. Secondary xenograft by percutaneous injection mimicked most of the features of SS with dermal infiltration, epidermotropism, and blood spreading. These models also allowed assessing the intra-individual heterogeneity of patient SC. Subclones sharing the same TCR gene rearrangement evolved independently according to culture conditions and/or after xenografting. This clonal selection was associated with some immunophenotypic plasticity and limited genomic evolution both in vitro and in vivo. The long-term amplification of SC allowed us to develop eight new SC lines derived from four different patients. These lines represent the cell of origin diversity of SC and provide new tools to evaluate their functional hallmarks and response to therapy.

Summary Cell lineage analysis aims to uncover the developmental history of an organism back to its cell of origin. Recently, novel in vivo methods utilizing genome editing enabled important insights into the cell lineages of animals. In contrast, human cell lineage remains restricted to retrospective approaches, which still lack resolution and cost-efficient solutions. Here, we demonstrate a scalable platform based on short tandem repeats targeted by duplex molecular inversion probes. With this human cell lineage tracing method, we accurately reproduced a known lineage of DU145 cells and reconstructed lineages of healthy and metastatic single cells from a melanoma patient who matched the anatomical reference while adding further refinements. This platform allowed us to faithfully recapitulate lineages of developmental tissue formation in healthy cells. In summary, our lineage discovery platform can profile informative somatic mutations efficiently and provides solid lineage reconstructions even in challenging low-mutation-rate healthy single cells., Graphical abstract, Highlights • A human cell lineage discovery platform based on somatic STR mutations • The platform has been validated with a high resolution of ex vivo cell lineage tree • A melanoma lineage tree inferred from STR agrees with sampling location • Lineage trees of healthy cells support separation of embryonic germ layers, Motivation Human cell lineage trees can provide answers to the most profound open questions in human biology and medicine. Obtaining this knowledge is a long journey worth taking. We pioneered the concept, the mathematical foundations, and the implementation of the human cell lineage discovery method utilizing naturally acquired microsatellite mutations by individual cells, to reconstruct trees among human cells. We kept improving its power. From 128 microsatellites per cell to 2,000, we have now reached a panel of over 50,000 loci, barcoded and sequenced cost effectively. Retrieving this unprecedented amount of microsatellite data would enable precise cell lineage tree reconstruction., Tao et al. present a biological-computational cell lineage discovery platform that enables efficient acquisition of tens of thousands of short tandem repeat targets in human single cells and tailored cell lineage reconstruction with its integrated bioinformatic pipeline and database management system.

Background There are well known cases of hybrid tumors of chromophobe renal cell carcinoma (RCC) and oncocytoma in kidney, where both tumors have the same cell of origin – intercalated cell of the collecting duct. However, collision tumors composed of neoplasms originating from different cell lineages such as oncocytoma and papillary RCC are extremely rare. Herein, we made a collective literature review of reported cases of collision tumors composed of oncocytoma and papillary RCC, adding a case that we recently experienced. Material and methods A PubMed database was search for collision tumors of the kidney composed of oncocytoma and papillary RCC and a collective literature review was made. To this cohort, we also added a recently encountered case with similar, confirmed by immunohistochemistry, morphological features. Results To date 8 cases of a collision tumor composed of papillary RCC and oncocytoma have been described in the literature. All of them had a smaller papillary RCC component present within a larger oncocytoma. Conclusion Because of a few cases of such a collision tumors reported, it is difficult to make classification and right clinical management of these patients. None of the reported cases had tumor recurrence or progression on a follow-up. The presence of only small portion of papillary RCC in a large oncocytoma raises a possibility of under-sampling of malignant component in large oncocytomas in core biopsy or surgically resected specimens. We recommend better sampling, particularly at the periphery of otherwise classic oncocytomas to unveil this possible association.

Critical reviews in oncology, hematology 116, 99 - 105(2017). doi:10.1016/j.critrevonc.2017.05.009, Published by Elsevier Science, Amsterdam [u.a.]

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies. Improvements in our understanding of PDAC carcinogenesis will hopefully improve its detection, management, and outcomes, as has been achieved with other malignancies. Here we review the literature on the natural history of PDAC, including its cell of origin, the initiating somatic mutational events, pathways deranged in the mature tumor, its biological heterogeneity, and the relationship of the primary tumor with metastases. We also suggest areas for further research and highlight translatable findings that are beginning to make clinical inroads.

Objective Perivascular epithelioid cell tumors (PEComa) are an uncommon family of soft tissue tumors. Previously, we described that the presence of pericyte antigens among PEComa family tumors differs extensively by histologic appearance. Methods Here, we extend our findings using the pericyte antigens Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2), using immunohistochemical detection in human tumor samples. Results While Ang-1 showed no expression across any PEComa family tumor, Ang-2 showed expression that like other pericyte markers was largely determined by cytologic appearance. Conclusion/implications Pericytic marker expression in PEComa may represent a true pericytic cell of origin, or alternatively aberrant pericyte marker adoption.

The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,′3′-cyclic nucleotide 3′-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

Composite lymphoma (CL) is an infrequently diagnosed entity in which two or more distinct types of lymphomas occur synchronously in the same organ or anatomical site. Most commonly, CLs are composed of two non-Hodgkin B-cell lymphomas. We present a case of a composite lymphoma with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) and classical Hodgkin lymphoma (CHL) components involving the terminal ileum, colon and pericolic lymph nodes. Immunohistochemical evaluation for determination of cell of origin of the DLBCL-NOS component indicated a germinal center B-cell subtype. Immunoglobulin heavy chain fragment length analysis revealed identical dominant monoclonal peaks on the DH1-6-JH reaction, and also a dominant monoclonal peak observed only in the framework II reaction done on the CHL component, indicating a partial clonal relationship between the two components. Additionally, a review of the available literature reveals a total of 20 previously reported cases of CL with DLBCL-NOS and CHL components, and most of the tested cases showed clonal relationship between the two components. The overall findings indicate that in most cases, the two components of CL with DLBCL-NOS and CHL components are clonally related, and suggest a shared origin from a common B-cell precursor.

Major progress in the understanding of diffuse large B-cell lymphoma (DLBCL) biology has been made in the last decade. Many specific compounds have now entered early phase clinical trials. However, further efforts are needed to find an accurate, fast, reproducible, and affordable technique to translate DLBCL subtype determination by gene expression profiles into clinical application. This article discusses the advantages and drawbacks of the currently available techniques of DLBCL subtype determination as well as important prognostic implications related to the cell of origin. Furthermore, the article provides a schematic description of how molecularly defined DLBCL subtypes could guide tailored therapy.

Differentiation features in cancer cells are typically attributed to the cell of origin. In this issue of Cancer Cell, Drummond et al. demonstrate a transdifferentiation program apparent in rhabdomyosarcomas (cancers with skeletal muscle differentiation features) arising through cell fate reprogramming from a single oncogene activation in endothelial cell precursors.

Summary Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.

Summary Single-cell RNA sequencing (scRNA-seq) is an evolving technology used to elucidate the cellular architecture of adult organs. Previous scRNA-seq on breast tissue utilized reduction mammoplasty samples, which are often histologically abnormal. We report a rapid tissue collection/processing protocol to perform scRNA-seq of breast biopsies of healthy women and identify 23 breast epithelial cell clusters. Putative cell-of-origin signatures derived from these clusters are applied to analyze transcriptomes of ~3,000 breast cancers. Gene signatures derived from mature luminal cell clusters are enriched in ~68% of breast cancers, whereas a signature from a luminal progenitor cluster is enriched in ~20% of breast cancers. Overexpression of luminal progenitor cluster-derived signatures in HER2+, but not in other subtypes, is associated with unfavorable outcome. We identify TBX3 and PDK4 as genes co-expressed with estrogen receptor (ER) in the normal breasts, and their expression analyses in >550 breast cancers enable prognostically relevant subclassification of ER+ breast cancers., Graphical abstract, Highlights Healthy breast contains 23 subclusters of epithelial cells Breast cancers may originate from 3 luminal mature and 1 progenitor subclusters TBX3 and PDK4, co-expressed with estrogen receptor (ER), subclassify ER+ breast cancers, Bhat-Nakshatri et al. describe the single-cell atlas and document 23 epithelial cell subclusters in the healthy breast. Although experimentally validating cell of origin of a tumor is technically challenging, overlap analysis of subcluster-enriched gene signatures with breast tumor transcriptomes revealed dominant representation of differentiated luminal subclusters-derived signatures in breast cancers.

Highlights • We identified two sub-groups of infant MLL-AF4-driven ALL, iALL-HOXA9, and iALL-IRX1. • The subgroups exhibit mutually exclusive expression of HOXA9/HOXA10 and IRX1. • The transcriptional profile of iALL-IRX1 patients revealed a more aggressive disease. • The two subgroups exhibit different expression of potential therapeutic targets., Infant t(4;11) acute lymphoblastic leukemia is the most common leukemia in infant patients and has a highly aggressive nature. The patients have a dismal prognosis, which has not improved in more than a decade, suggesting that a better understanding of this disease is required. In the study described here, we analyzed two previously published RNA-sequencing data sets and gained further insights into the global transcriptomes of two known subgroups of this disease, which are characterized by the presence or absence of a homeobox gene expression signature. Specifically, we identified a remarkable mutually exclusive expression of the HOXA9/HOXA10 and IRX1 genes and termed the two subgroups iALL-HOXA9 and iALL-IRX1. This expression pattern is critical as it suggests that there is a fundamental difference between the two subgroups. Investigation of the transcriptomes of the two subgroups reveals a more aggressive nature for the iALL-IRX1 group, which is further supported by the fact that patients within this group have a worse prognosis and are also diagnosed at a younger age. This could be reflective of a developmentally earlier cell of origin for iALL-IRX1. Our analysis further uncovered critical differences between the two groups that may have an impact on treatment strategies. In summary, after a detailed investigation into the transcriptional profiles of iALL-HOXA9 and iALL-IRX1 patients, we highlight the importance of acknowledging that these two subgroups are different and that this is of clinical importance.

Nodal-based peripheral T-cell lymphomas are heterogeneous malignancies with overlapping morphology and clinical features. However, the current World Health Organization classification scheme separates these tumors into prognostically relevant categories. Since its publication, efforts to uncover the gene expression profiles and molecular alterations have subdivided these categories further, and distinct subgroups are emerging with specific profiles that reflect the cell of origin for these tumors and their microenvironment. Identification of the perturbed biologic pathways may prove useful in selecting patients for specific therapies and associating biomarkers with survival and relapse.

Summary Modeling of neurological diseases using induced pluripotent stem cells (iPSCs) derived from the somatic cells of patients has provided a means of elucidating pathogenic mechanisms and performing drug screening. T cells are an ideal source of patient-specific iPSCs because they can be easily obtained from samples. Recent studies indicated that iPSCs retain an epigenetic memory relating to their cell of origin that restricts their differentiation potential. The classical method of differentiation via embryoid body formation was not suitable for T cell-derived iPSCs (TiPSCs). We developed a neurosphere-based robust differentiation protocol, which enabled TiPSCs to differentiate into functional neurons, despite differences in global gene expression between TiPSCs and adult human dermal fibroblast-derived iPSCs. Furthermore, neurons derived from TiPSCs generated from a juvenile patient with Parkinson's disease exhibited several Parkinson's disease phenotypes. Therefore, we conclude that TiPSCs are a useful tool for modeling neurological diseases., Highlights • TiPSCs are a suitable source for neural disease modeling • Developing a robust neurosphere-based induction protocol • An optimized differentiation protocol can overcome clonal variations • Modeling Parkinson's disease using TiPSC-derived neurons, In this article, Okano, Akamatsu, and colleagues show that an established neural induction protocol was able to induce neural cells from TiPSCs as well as fibroblast-derived iPSCs. We also observed that neurons derived from PARK2-TiPSCs can exhibit several Parkinson's disease-specific phenotypes observed in fibroblast-derived PARK2-iPSCs. Thus, T cells, which are easily accessible in patients, are suitable source for neural disease modeling.

MLL rearrangements are the predominant cause of acute infant leukaemias, which initiate in utero within foetal HSPCs and distinctly lack additional cooperating mutations. Strikingly, MLL-AF9 causes an AML or B-ALL, but in adults almost exclusively an AML. Thus, by understanding the contribution from the foetal cell of origin, we can explain differences between patients with respect to disease initiation, progression and outcomes. We utilised inducible MLL-AF9 expression to explore AML and B-ALL initiation from foetal and adult murine HSPCs. MLL-AF9 imparts distinct lineage, proliferation and self-renewal outputs within and between foetal and adult HSPC populations. In contrast to adult HSPCs, MLL-AF9 generated significant increases in lymphoid output under lymphoid conditions across foetal HSPC in vitro, even overriding CMP myeloid bias for B-lymphoid output, highlighting the specific nature of infant biology. HSC/MPP and LMPP consistently gave rise to a pro-B phenotype, suggesting these as cells of origin for the clinically dismal infant pro-B ALL. In AML, transplantation of HSC/MPP causes the most aggressive disease marked by shortest latency and invasive nature. Interestingly, in myeloid assays, foetal HSC/MPP and LMPP display an initial delay in proliferation, unlike CMP and GMP, which proliferate through a foetal-specific phenotype of CD11b+ blasts at first plating. Adult CMP do not replicate the proliferative phenotype of foetal CMP, highlighting the differences in disease initiation between developmental stages. An MLL rearrangement represents the worst prognostic factor for B-ALL, and in AML a description of which foetal cells can initiate disease is lacking. Given the prevalence of unfavourable prognostic factors, defining how foetal blood cell biology shapes the aetiology of infant leukaemia will inform rationale for drug discovery and therapy applications.

Summary: To better understand the influence of ultraviolet (UV) irradiation on the initial steps of skin carcinogenesis, we examine patches of labeled keratinocytes as a proxy for clones in the interfollicular epidermis (IFE) and measure their size variation upon UVB irradiation. Multicolor lineage tracing reveals that in chronically irradiated skin, patches near hair follicles (HFs) increase in size, whereas those far from follicles do not change. This is explained by proliferation of basal epidermal cells within 60 μm of HF openings. Upon interruption of UVB, patch size near HFs regresses significantly. These anatomical differences in proliferative behavior have significant consequences for the cell of origin of basal cell carcinomas (BCCs). Indeed, a UV-inducible murine BCC model shows that BCC patches are more frequent, larger, and more invasive near HFs. These findings have major implications for the prevention of field cancerization in the epidermis.

Summary: Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate with MYCN amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates MYCN oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In in vitro cell transformation assays, we show that Chd5 loss confers most of the MYCN-independent tumor suppressor effects of 1p36 LOH. In contrast, MYCN-driven tumorigenesis selects for NCCs with Arid1a deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing Arid1a as the MYCN-associated tumor suppressor. Our findings reveal that Arid1a loss collaborates with oncogenic MYCN and better define the tumor suppressor functions of 1p36 LOH in NBL. : Garcia-Lopez et al. present a mouse model of high-risk neuroblastoma that includes 1p36 loss and Mycn overexpression. This study substantiates previous predictions from NBL genetic studies, which proposed that two tumor suppressor regions exist in 1p36. It further demonstrates that Mycn overexpression selects for loss of Arid1a during tumorigenesis. Keywords: chromatin remodelers, 1p36 LOH, ARID1A, CHD5, high-risk neuroblastoma

Human hepatocarcinogenesis is a complex process with many unresolved issues, including the cell of origin (differentiated and/or progenitor/stem cells) and the initial steps leading to tumor development. With the aim of providing new tools for studying hepatocellular carcinoma initiation and progression, we developed an innovative model based on primary human hepatocytes (PHHs) lentivirus-transduced with SV40LT+ST, HRASV12 with or without hTERT. The differentiation status of these transduced-PHHs was characterized by RNA sequencing (including lncRNAs), and the expression of some differentiation markers confirmed by RT-qPCR and immunofluorescence. In addition, their transformation capacity was assessed by colony formation in soft agar and tumorigenicity evaluated in immune-deficient mice. The co-expression of SV40LT+ST and HRASV12 in PHHs, in association or not with hTERT, led to the emergence of transformed clones. These clones exhibited a poorly differentiated cell phenotype with expression of stemness and mesenchymal-epithelial transition markers and gave rise to cancer stem cell subpopulations. In vivo, they resulted in poorly differentiated hepatocellular carcinomas with a reactivation of endogenous hTERT. These experiments demonstrate for the first time that non-cycling human mature hepatocytes can be permissive to in vitro transformation. This cellular tool provides the first comprehensive in vitro model for identifying genetic/epigenetic changes driving human hepatocarcinogenesis.

Background The cell of origin (COO) classification has been shown to predict survival outcomes in de-novo diffuse large B-cell lymphoma (DLBCL), however, it is unclear if this holds true following high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) in relapsed DLBCL patients. The current analysis aims to compare survival outcomes based on COO classification in relapsed DLBCL patients who received auto-HCT. Methods This retrospective study includes relapsed/refractory DLBCL patients, aged 18 and above, who received auto-HCT with standard of care conditioning from January 2007 to December 2016 at our institution. Hans algorithm using CD10, BCL6 and MUM1 markers was performed to classify patients as per COO into the GCB and non-GCB types. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS). Results A total of 122 DLBCL (71 GCB, 51 non-GCB) patients were analyzed. Detailed patient characteristics are provided in Table 1. Except for GCB cohort being older (64 vs. 58 years, p 70 (HR=2.9, p=0.03) and IPI score 0 (HR=0.3, p=0.005) were significant variables in predicting PFS. After adjusting for these variables, no significant differences were seen in PFS between two groups. The median OS has not yet been reached in both groups therefore a difference in OS cannot be analyzed. Conclusion Our results suggest that cell of origin is not prognostic for patients with relapsed/refractory DLBCL treated with high dose chemotherapy followed by auto-SCT.

Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known.We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells.Although KrasOne mechanism by which tissues may be susceptible or resistant to KRAS

Hepatocellular carcinoma (HCC) accounts for approximately 6% of all new cancer cases diagnosed, and due to its aggressiveness, it is the second most common cause of cancer mortality worldwide. Based on different etiological factors, genetic backgrounds, and longtime development of the disease, HCC is characterized by a high phenotypic and functional heterogeneity. Tumor variability occurs both among patients (intertumoral heterogeneity) and within a single tumor (intratumoral heterogeneity). The intratumoral heterogeneity, in particular the variability of the markers of cancer stem cells (CSC) population may determine specific behavior and prognosis of the tumor. Understanding the cellular mechanisms originating CSC will provide an important hint in the management of HCC. The characterization of the cells of origin of cancer can have significant implication in early diagnosis, in the development of appropriate therapies and in the prevention of relapse. Here, we review recent evidences on the possible cellular origin of CSC that play a role in the heterogeneity of the HCC.

Intertumoral heterogeneity is driven by a combination of intrinsic and extrinsic mechanisms. Intrinsic mechanisms include the genetic/epigenetic mutational profile of cells and the nature of the 'cell of origin'. There is accumulating evidence that distinct 'cells of origin' within an organ can give rise to different subtypes of cancer. Tissue-specific stem and progenitor cells are the predominant targets exploited for tumor initiation. Extrinsic factors imposed by the microenvironment may also directly influence the cell of origin by eliciting dedifferentiation. Identification of these target cell populations is important for earlier diagnosis, the detection of premalignant clones during relapse, and the design of prevention therapies for high-risk cancer families. Here we review recent developments in deciphering the cellular origins of solid cancers.

Early primitive stem cells have long been viewed as the cancer cells of origin (tumor initiating target cells) due to their intrinsic features of self-renewal and longevity. However, emerging evidence suggests a surprising capacity for normal committed cells to function as reserve stem cells upon reprogramming as a consequence of tissue damage resulting in inflammation and wound healing. This results in an alternative concept positing that tumors may originate from differentiated cells that can re-acquire stem cell properties due to genetic or epigenetic reprogramming. It is likely that both models are correct, and that a continuum of potential cells of origin exists, ranging from early primitive stem cells to committed progenitor or even terminally differentiated cells. A combination of the nature of the target cell and the specific types of gene mutations introduced determine tumor cell lineage, as well as potential for malignant conversion. Evidence from mouse skin models of carcinogenesis suggests that initiated cells at different stages within a stem cell hierarchy have varying degrees of requirement for reprogramming (e.g. inflammation stimuli), depending on their degree of differentiation. This article will present evidence in favor of these concepts that has been developed from studies of several mouse models of skin carcinogenesis.

Different approaches predict the outcome for patients with hepatocellular carcinoma (HCC). The expression of biliary-hepatic progenitor cell markers generally correlates with poor prognosis. This article focuses on the pathogenesis of HCC, how differentiation or dedifferentiation leads to a phenotype switch, and heterogeneity in the same tumor. A tumor cell decides its fate based on a complex interplay of signaling pathways. Interaction with the microenvironment decides whether it will invade, proliferate, or enter survival mode. Several signaling pathways contribute to stemness features, reflecting a small chemoresistant subpopulation of the tumor that expresses biliary-hepatic progenitor cell markers.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). BPDCN cells show high frequencies of mutations in TET2 and p53; however, the molecular mechanisms underlying the pathogenesis of BPDCN have not yet been elucidated. Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN, which is reversed by the deletion of super-enhancer of RUNX2 or the inhibition of BRD4 function. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53. Since BPDCN cells show lower expression levels of pDCs-signature genes than mature pDCs in patients and mice, we find that macrophage-dendritic cell progenitors, but not mature pDCs, are at least one of the cells of origin of BPDCN by examining the in vivo tumor initiating capacity of those cells. This study provides a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.

Cancer associated fibroblasts (CAFs) are a subpopulation of cells that reside within the tumor microenvironment and promotes the transformation process by encouraging tumor growth, angiogenesis, inflammation, and metastasis. CAF-specific proteins serve as both prognostic markers and targets for anticancer drugs. With the growing interest in CAFs, several controversial issues have been raised, including the genomic landscape of these cells, the identity of specific markers, and their cell of origin. Here, we tackle these debated issues and put forward a new definition for 'CAF' as a cell 'state' rather than a cell type. We hope this conceptualization can resolve the ongoing discrepancies revolving around CAF research and aid in designing better anti-cancer treatment strategies.

Introduction Patients who present with metastatic cancer often pose diagnostic challenges as to the origin of their cancer despite exhaustive efforts to locate an anatomic primary site. In patients with CUP clinicians rely on their familiarity with the initial relapse patterns of known primary cancers as a guide to locating the primary site. In the following case the pathologic evaluation failed to confirm the clinical impression which suggested lung as a primary site. GEP provided additional insight as to the cell of origin. The GEP results were unexpected and completely changed the treatment strategy and outcome.

Metaplastic breast carcinomas are histologically heterogeneous and rare tumours constituting In situ evidence implicating the myoepithelial cell as cell of origin is presented and discussed in view of recent in vitro studies using immortalized human mammary stem/progenitor cell lines.

Primary tumors of the liver can be classified pathologically based on their cell of origin into epithelial tumors, arising from hepatocytes or biliary epithelium, and nonepithelial tumors, including mesenchymal tumors and lymphoma. Characteristic findings on MR imaging can be seen in many cases. This article reviews the MR imaging appearance of these tumors with pathologic correlation.

Neuroendocrine bladder cancer is a relatively rare but often lethal malignancy, with cell of origin, oncogenomic architecture and standard treatment poorly defined. Here we performed comprehensive whole-genome and transcriptome sequencing on a unique cohort of genitourinary neuroendocrine neoplasms, mainly small cell carcinomas of the urinary bladder. The mutational landscape and signatures of neuroendocrine bladder cancer strikingly resembled those in conventional urothelial carcinoma, along with typically mixed histologies, supporting a common cellular origin. We identified pervasive age-related and APOBEC-mediated mutagenesis patterns, and one patient displayed a somatic fingerprint attributable to aristolochic acid exposure, an established etiology of urothelial cell carcinoma. Deep RNA sequencing revealed dysregulated tumorigenic pathways and novel fusion transcripts, including a targetable in-frame PVT1-ERBB2 variant associated with aberrant expression of ERBB2 gene (encoding HER2 receptor). Furthermore, we provided preliminary evidence that combined TP53 and RB1 depletion favored lineage switching from oncogene-addicted urothelial cancer cells to neuroendocrine-like tumor cells, and resulted in decreased response to targeted agents. Together, these data present the first high-resolution genomic portrait of neuroendocrine bladder cancer, which holds important implications for the biological understanding and rational treatment of this deadly disease.

Although ovarian epithelial tumors are widely believed to arise in the coelomic epithelium that covers the ovarian surface, it was also suggested that they could instead arise from tissues that are embryologically derived from the mullerian ducts. This article revisits this debate based on recent epidemiological and molecular biological observations as well as evidence based on histopathological observations of surgical specimens from individuals with familial ovarian cancer predisposition. Morphological, embryological, and molecular biological characteristics of ovarian epithelial tumors that must be accounted for in formulating a theory about their cell of origin are reviewed, followed by comments about the ability of these two hypotheses to account for each of these characteristics. An argument is made that primary ovarian epithelial tumors fallopian tube carcinomas, and primary peritoneal carcinomas are all mullerian in nature and could therefore be regarded as a single disease entity. Although a significant proportion of cancers presently regarded as of primary ovarian origin arise in the fimbriated end of the fallopian tube, this site cannot account for an equally significant proportion of these tumors, which are most likely derived from components of the secondary mullerian system.