Developing Cures: Targeting Ontogenesis in Cancer

Lin, Victor T.; Pruitt, Hawley C.; Samant, Rajeev S.; Shevde, Lalita A.

doi:10.1016/j.trecan.2016.12.007

Cited by 11 publications

(9 citation statements)

References 90 publications

(93 reference statements)

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“…This association is commonly attributed to increased stochastic chances of expressing neo-epitopes that stimulate adaptive nonself-recognition [42, 43]. In immune active cancers, enriched mutations affect the function of cancer driver genes, leading to the hypothesis that cancer evolution in the immune-competent host faces a stochastic binary choice: some cancers accrue an orderly succession of genetic alterations that engender essential growth advantages in strict avoidance of additional unnecessary functions; this process may be compared to the assembly of normal tissues orchestrated by differentiating stem cells during development [44]. The mutational profile characteristic of immunogenic tumors is in contrast with the higher frequency of copy number alterations observed in immune silent tumors.…”

Section: Introductionmentioning

confidence: 99%

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Bedognetti¹,

Ceccarelli²,

Galluzzi³

et al. 2019

j. immunotherapy cancer

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Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host’s response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14–15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual’s recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4–5, 2019.

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Section: Introductionmentioning

confidence: 99%

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Bedognetti¹,

Ceccarelli²,

Galluzzi³

et al. 2019

j. immunotherapy cancer

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“…The luminal progenitor cells are thought to give rise to all molecular subtypes of breast cancer except claudin low tumors 3 . Disrupted pathways and processes observed during breast cancer progression in many ways mimic those witnessed during normal mammary gland development and tissue remodeling 5 , 31 . The reasons behind the erroneous manifestation of these developmental events that promote breast cancer progression remain to be uncovered.…”

Section: Discussionmentioning

confidence: 99%

Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors

et al. 2021

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Molecular dynamics of developmental processes are repurposed by cancer cells to support cancer initiation and progression. Disruption of the delicate balance between cellular differentiation and plasticity during mammary development leads to breast cancer initiation and metastatic progression. STAT5A is essential for differentiation of secretory mammary alveolar epithelium. Active STAT5A characterizes breast cancer patients for favorable prognosis. N-Myc and STAT Interactor protein (NMI) was initially discovered as a protein that interacts with various STATs; however, the relevance of these interactions to normal mammary development and cancer was not known. We observe that NMI protein is expressed in the mammary ductal epithelium at the onset of puberty and is induced in pregnancy. NMI protein is decreased in 70% of patient specimens with metastatic breast cancer compared to primary tumors. Here we present our finding that NMI and STAT5A cooperatively mediate normal mammary development. Loss of NMI in vivo caused a decrease in STAT5A activity in normal mammary epithelial as well as breast cancer cells. Analysis of STAT5A mammary specific controlled genetic program in the context of NMI knockout revealed ISG20 (interferon stimulated exonuclease gene 20, a protein involved in rRNA biogenesis) as an unfailing negatively regulated target. Role of ISG20 has never been described in metastatic process of mammary tumors. We observed that overexpression of ISG20 is increased in metastases compared to matched primary breast tumor tissues. Our observations reveal that NMI-STAT5A mediated signaling keeps a check on ISG20 expression via miR-17–92 cluster. We show that uncontrolled ISG20 expression drives tumor progression and metastasis.

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“…For example, many pivotal signaling pathways, such as the Notch, Hedgehog, Wnt/β-catenin pathways, as well as genes, such as HMGA2, Bcl-2, Bmi-1, Ras, C-myc, and HIF1-α, that regulate normal stem cell self-renewal, differentiation, and survival are connected with tumor stem cell. [89][90][91][92][93][94] In different systems, the expression of some tumor associated molecules, such as histone deacetylase, DNA methyltransferases, vascular endothelial growth factor receptors and PD1/PD-L1, [95][96][97][98][99][100][101] are related to the cellular origin of tumors. Scattered literature implies that the invasiveness of tumor stem cells may be related to the innate state of key signaling pathways or genes from normal counterpart origin cells through epigenetic memory during the transformation.…”

Section: Discussion and Perspectivementioning

confidence: 99%

Re-Recognizing the Cellular Origin of the Primary Epithelial Tumors of the Liver

Ji-liang¹,

Zhu²,

Yin³

et al. 2021

JHC

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The primary epithelial tumors of the liver (PETL) are composed of a series of heterogeneous tumors. Although the classification of PETLs has been updated several times by the World Health Organization, the cellular origins of some tumors in this family remain to be precisely depicted. In addition, certain tumors in different categories have similar histology, molecular phenotypes and biological characteristics, suggesting that they may have the same cellular origin. In this work, a narrative review method was adopted to review the relevant papers. By comparing the expression profiles of biomarkers of liver epithelium at different lineages and stages of differentiation, the cells-of-origin of some major members of the PETL family were reassessed. We propose that 1) hepatic adenomas, hepatocellular carcinomas (HCCs) and pure fetal hepatoblastomas (HBs) share the same spectrum in their cellular origin including the hepatocytic-committed progenitors (HCP) and their differentiated descendants. 2) Bile duct adenomas, peribiliary cysts and intrahepatic cholangiocellular carcinomas (ICCs) can share the same spectrum in their cellular origin including the cholangiocytic-committed progenitors (CCP) and their differentiated descendants. 3) The cells-of-origin of embryonal HBs include liver stem cells (LSCs), hepatoblasts, and transitional cells between them. Embryonal HB with small cell element, small cell undifferentiated HB and small cell neuroendocrine carcinoma of the liver can have the same or similar cellsof-origin from LSC. Embryonal HB lacking the small cell component of the LSC phenotype and presenting both hepatocytic and bile duct/ductule components may originate from actual hepatoblasts/hepatic progenitor cells (HPCs) as the combined HCC-ICC does. 4) Teratoid hepatoblastoma and mixed epithelial/mesenchymal HBs can be derived from the LSCs or even less committed extrahepatic pluripotent stem cell. 5) Many members of the PETLs family, including those derived from LSCs, hepatoblasts/HPCs, early HCPs and CCPs, have neuroendocrine potentiality. Except for those primary hepatic neuroendocrine tumor (PHNET) exhibit hepatocytic and/or cholangiocytic phenotypes, other PHNETs subtype may be derived from the descendants of LSC that differentiate towards the upper digestive tract, pancreas or other lineages.

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Developing Cures: Targeting Ontogenesis in Cancer

Cited by 11 publications

References 90 publications

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors

Re-Recognizing the Cellular Origin of the Primary Epithelial Tumors of the Liver

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