Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation & Life Science Editors. Potential Conflicts of Interest: None.

Punchline:The liver and lung microenvironments influence various phenotypes of metastasized triple-negative breast cancer (TNBC) cells in different ways. Liver microenvironment accelerates disease progression and negatively impacts patient outcomes. Interesting paper and seems well done, identifies specific players in the different environment – consistent with the concept that the niche affects the phenotype of metastatic outgrowths.

Why is this an important problem? Metastasis is the primary cause of cancer-related deaths. Understanding how different organ environments influence the behavior of metastatic cancer cells is crucial for developing effective treatments for Stage IV disease. This research specifically focuses on TNBC, an aggressive breast cancer subtype, and its behavior in lung and liver metastatic sites.

What did we already know? * • Breast cancer frequently metastasizes to bone, liver, lungs, and brain. * • TNBC, a particularly aggressive subtype, primarily spreads to visceral organs, mainly the lungs and liver. * • The presence of bone metastases is associated with a less aggressive disease course compared to other sites. * • There are conflicting data on the aggressiveness of disease in the context of lung and liver metastases. * Results: * • Patients with liver metastases, as their first metastatic event, showed significantly shorter overall survival and time to the next metastatic event compared to those with lung metastases. Focused on a subset of patients with "mono-metastasis", meaning that a single metastasis was present in either the lung (12/318 patients with metastases) or liver (10/318 patients with metastases) at the initial diagnosis of metastasis. Kaplan-Meier plots of the progression and survival differences between patients with lung versus liver mono-metastases support the idea that liver metastases are associated with more aggressive disease progression compared to lung metastases in breast cancer patients. * * • Barcode labeling and metastasis clonality assessment in a mouse model of TNBC: mouse TNBC cells (MVT1) were tagged with unique genetic barcodes before being injected into the mammary fat pad of mice. The barcode composition of cells in the circulation (circulating tumor cells) and from each site (liver, lung) was analyzed. A greater number of unique barcodes were found in the lung metastases compared to the liver. Principal component analysis revealed that lung metastases were a distinct population compared to liver metastases and circulating tumor cells. * • After mammary fat pad injection & metastasis, mouse MVT1 or 4T1 cancer cells were isolated from either the lungs or liver, injected into the tail veins of healthy mice. Liver-resident TNBC cells have an enhanced ability to establish secondary metastases at lung and liver when compared to lung-resident cells. * * • MVT1 mouse TNBC cells expressed GFP and a soluble mCherry protein that is taken up by neighboring niche cells. Identified and analyzed both tumor and niche cell populations. * • Single-cell RNA sequencing of cancer cells: MTV1 metastatic TNBC cells have distinct molecular profiles depending on where they reside: energy generation pathways in liver-resident cells (might contribute to their increased metastatic activity) and stress and detoxification pathways in lung-resident cells (suggests a less favorable environment). * • Single-cell RNA sequencing of niche cells: Endothelial cells in the liver metastatic niche, unlike the primary tumor niche and lung niche. The unique abundance of endothelial cells in the liver niche suggests their potential involvement in shaping the metastatic behavior of liver-resident TNBC cells. Specific ligand-receptor pairs suggest a distinct communication network between cancer cells and their niche in the liver and lungs, whereby the liver niche is enriched in endothelial cells secreting Bmp2 and Bmp6 cytokines, while the lung niche is enriched in macrophages secreting Grn and Ssp1. * • Specific cytokine-receptor interactions between cancer cells and their niche were identified, with BMP2/6 secreted by liver endothelial cells and Granulin secreted by lung macrophages. * * • In vivo CRISPR-Cas9 screen used to investigate the roles of the identified cytokine-receptor pairs in metastasis formation. MTV1 TNBC cells were engineered with loss-of-function of the receptors for BMP2/6 (BMPR2, BMPR1A, and ACVR1) implicated in liver metastasis and Granulin (TNFRSF1A/B) implicated in lung metastasis. The engineered cells were injected into the tail vein and allowed to metastasize, isolated from lung and liver, and the abundance of different gene knockouts was analyzed. Additionally, they were reinjected into the tail vein to detect secondary metastasis. * * • Using this approach the organ of primary metastasis influenced the secondary metastasis (lung went to lung, liver to liver) - in contrast to when the experiment was done with WT cells injected into the mammary fat pad and isolated from liver and lung (when liver-derived TNBC showed higher secondary metastasis by tail vein to lung and liver, Fig 1I). This disconnect is a bit confusing. * * • There was no difference between the knockouts. This lack of organ specific knockouts between lung- and liver-resident cells could be due to the pleiotropic role of many of these receptors and the existence of interactions with additional cytokines. Notably, the expression of these receptors in cancer cells at the RNA level was similar in liver and lung metastases. * • Kaplan-Meier curve compares the survival of mice re-injected with either lung- or liver-resident cancer cells. Liver metastases were associated with decreased survival when compared to lung metastasis. Consistent with liver metastases associated with more aggressive disease progression compared to lung metastases. * • To investigate the effect of the niche on TNBC cells, TNBC cells were treated with either BMP2 or Granulin in vitro before being injected into the tail vein. This simulates the effects of the liver and lung microenvironment, respectively. BMP2 pre-treatment of TNBC cells enhanced metastasis formation in the lung, whereas Granulin treatment suppressed it. Supports the model that the liver niche boosts metastasis through BMP2, while the lung niche inhibits it through Granulin. This is a bit confusing with the apparent tropism of liver to liver in figure 5 but more consistent with figure 1.

What's new? Sheds light on how the liver and lung microenvironments (endothelial vs macrophage, respectively) distinctly influence the behavior of TNBC cells and why liver metastasis is associated with poor survival. Offers potential therapeutic targets for liver vs lung metastases. The discovery of the contrasting roles of BMP2 and Granulin, and their cellular sources within the respective metastatic niches, is interesting.

Potential impact * • Treatment strategies for TNBC patients with liver or lung metastases could potentially be tailored based on the identified niche-specific vulnerabilities. * • Targeting BMP2 signaling in liver metastases could potentially reduce secondary spread. * • Stimulating Granulin activity could offer a new approach to inhibiting TNBC metastasis.

Limitations: * • The study primarily focused on TNBC, and further research is needed to determine if these findings apply to other cancer types metastasizing to the liver and lungs. * • I would have liked to see preclinical models with xenografts. Therapeutic potential not shown. * • The CRISPR-Cas9 screen did not identify organ-specific knockouts, likely due to the pleiotropic roles of the targeted receptors and the complex interplay of various cytokines within the niche.

Future work: * • Investigate the applicability of these findings to other cancer types with similar metastatic patterns. * • Further explore the complex interplay of cytokines and signaling pathways within the liver and lung metastatic niches. * • Develop therapeutic strategies to target BMP2 signaling in liver metastases and stimulate Granulin activity in lung metastases. * • Validate these findings in a larger cohort of patients to determine their clinical relevance.

George Monbiot zur Entscheidung Sunaks, die Öl- und Gasproduktion in der Nordsee zu maximieren. Er spricht vom pollution paradox: Die Firmen, die dem Planeten am meisten schaden, haben die triftigsten Gründe, in Politik und Desinformation zu investieren. Indiz für Desinformation sei der Rückgriff auf CCS. Die Konservativen erhalten große Spenden von der Fossilindustrie. Sunak hat verschuldet, dass der CO₂-Preis in Uk nur noch halb so hoch ist wie in der EU. https://www.theguardian.com/commentisfree/2023/aug/01/rishi-sunak-north-sea-planet-climate-crisis-plutocrats

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for - definition - human climate niche

Die englische Regierung hat in der letzten Oktoberwoche 27 Lizenzen zur Öl- und Gasförderung in der Nordsee vergeben. George Monbiot konfrontiert diese Entscheidung mit aktuellen Erkenntnissen zum sechsten Massenaussterben und dem drohenden Zusammenbruch lebensunterstützender Systeme des Planeten https://www.theguardian.com/commentisfree/2023/oct/31/flickering-earth-systems-warning-act-now-rishi-sunak-north-sea

• for: gene culture coevolution, carrying capacity, unsustainability, overshoot, cultural evolution, progress trap

• Title: The genetic and cultural evolution of unsustainability

• Author: Brian F. Snyder

• Abstract

• Summary
• Paraphrase
  • Anthropogenic changes are accelerating and threaten the future of life on earth.
  • While the proximate mechanisms of these anthropogenic changes are well studied
    • climate change,
    • biodiversity loss,
    • population growth
  • the evolutionary causality of these anthropogenic changes have been largely ignored.
  • Anthroecological theory (AET) proposes that the ultimate cause of anthropogenic environmental change is
    • multi-level selection for niche construction and ecosystem engineering.
  • Here, we integrate this theory with
    • Lotka’s Maximum Power Principle
  • and propose a model linking
    • energy extraction from the environment with
    • genetic, technological and cultural evolution
  • to increase human ecosystem carrying capacity.
  • Carrying capacity is partially determined by energetic factors such as
    • the net energy a population can acquire from its environment and
    • the efficiency of conversion from energy input to offspring output.
  • These factors are under Darwinian genetic selection
  • in all species,
  • but in humans, they are also determined by
    • technology and
    • culture.
  • If there is genetic or non-genetic heritable variation in
    • the ability of an individual or social group
  • to increase its carrying capacity,
  • then we hypothesize that - selection or cultural evolution will act - to increase carrying capacity.
  • Furthermore, if this evolution of carrying capacity occurs - faster than the biotic components of the ecological system can respond via their own evolution,
    • then we hypothesize that unsustainable ecological changes will result.

13:00 talks on finding a (1) zone of fascination, (2) go into a congregation (a community, a discours), and (3) master the thing (and fulfil the hero's journey), and (4) add these to the congregation - Scott relates this to the hero's journey

It has been suggested that - the human species may be undergoing an evolutionary transition in individuality (ETI).

there is disagreement about - how to apply the ETI framework to our species - and whether culture is implicated - as either cause or consequence.

Long-term gene–culture coevolution (GCC) i- s - also poorly understood.

argued that - culture steers human evolution,

Others proposed - genes hold culture on a leash.

After review of the literature and evidence on long-term GCC in humans - emerge a set of common themes. - First, culture appears to hold greater adaptive potential than genetic inheritance - and is probably driving human evolution. - The evolutionary impact of culture occurs - mainly through culturally organized groups, - which have come to dominate human affairs in recent millennia. - Second, the role of culture appears to be growing, - increasingly bypassing genetic evolution and weakening genetic adaptive potential. -Taken together, these findings suggest that human long-term GCC is characterized by - an evolutionary transition in inheritance - from genes to culture - which entails a transition in individuality (from genetic individual to cultural group). Research on GCC should focus on the possibility of - an ongoing transition in the human inheritance system.

// In Other Words

• we must undo the myopic cultural evolution that has already taken place with a more collectively conscious form of cultural evolution //

• Title: Gene–culture coevolution and the nature of human sociality
• Author: Herbert Gintis

//Abstract - Summary - Human characteristics are the product of gene–culture coevolution, - which is an evolutionary dynamic involving the interaction of genes and culture - over long time periods. - Gene–culture coevolution is a special case of niche construction. - Gene–culture coevolution is responsible for: - human other-regarding preferences, - a taste for fairness, - the capacity to empathize and - salience of morality and character virtues.

• Title: Human niche construction in interdisciplinary focus
• Author:
  • Jeremy Kendal
  • Jamshid J. Tehrani
  • John Oding-Smee
• Abstract
  • summary
  • Niche construction is an endogenous causal process in evolution,
• reciprocal to the causal process of natural selection.
  • It works by adding ecological inheritance,
  • comprising the inheritance of natural selection pressures previously modified by niche construction,
  • to genetic inheritance in evolution.
  • Human niche construction modifies selection pressures in environments in ways that affect both human evolution, and the evolution of other species.
  • Human ecological inheritance is exceptionally potent
  • because it includes the social transmission and inheritance
  • of cultural knowledge, and material culture.
  • Human genetic inheritance
  • in combination with human cultural inheritance
  • thus provides a basis for gene–culture coevolution,
  • and multivariate dynamics in cultural evolution.
  • Niche construction theory potentially integrates the biological and social aspects of the human sciences.
  • We elaborate on these processes,
  • and provide brief introductions to each of the papers published in this theme issue.

//Summary* - The central question of the Anthropocene: - why did behaviorally modern humans gain the unprecedented capacity to change an entire planet? - cannot be answered by genetic changes in human behavior. - To explain why human societies scaled up to become a global force capable of changing the Earth and why there are so many different forms of human societies and ecologies shaped by them, - explanations must be sought beyond the theories of - biology, - chemistry or - physics. - Here I introduce a new evolutionary theory, sociocultural niche construction, - aimed at explaining the origins of human capacity to transform the Earth . - As will be seen, this theory also explains why - behaviorally modern human societies came to - transform ecology in so many different ways over the past 50,000 years as they expanded across the Earth. //

• Abstract
• summary
  • The exhibition of increasingly intensive and complex niche construction behaviors through time
  • is a key feature of human evolution,
  • culminating in the advanced capacity for ecosystem engineering exhibited by Homo sapiens.
  • A crucial outcome of such behaviors has been the dramatic reshaping of the global biosphere,
    • a transformation whose early origins are increasingly apparent
    • from cumulative archaeological and paleoecological datasets.
  • Such data suggest that, by the Late Pleistocene,
  • humans had begun to engage in activities
  • that have led to alterations in the distributions of a vast array of species
  • across most, if not all, taxonomic groups.
  • Changes to biodiversity have included
    • extinctions,
    • extirpations, and
    • shifts in species
      • composition,
      • diversity, and
      • community structure.
  • We outline key examples of these changes,
  • highlighting findings from the study of new datasets, like
    • ancient DNA (aDNA),
    • stable isotopes, and
    • microfossils, as well as
    • the application of new statistical and computational methods to datasets that have accumulated significantly in recent decades.
  • We focus on four major phases that witnessed broad anthropogenic alterations to biodiversity:
    • the Late Pleistocene global human expansion,
    • the Neolithic spread of agriculture,
    • the era of island colonization, and
    • the emergence of early urbanized societies and commercial networks.
  • Archaeological evidence documents millennia of anthropogenic transformations
  • that have created novel ecosystems around the world.
  • This record has implications for:
    • ecological and evolutionary research,
    • conservation strategies, and
    • the maintenance of ecosystem services,
  • pointing to a significant need for broader cross-disciplinary engagement between:
    • archaeology
    • the biological sciences and
    • the environmental sciences.

• Title: Ecological consequences of human niche construction: Examining long-term anthropogenic shaping of global species distributions
• Author:
  • Nicole L. Bolvin
  • Melinda A. Zeder
  • Dorian O. Fuller
  • Michael D. Petraglia

key no sólo procesos de aprendizaje si no también desarrollo de redes sociales de contención

El nivel micro, donde ocurre la innovación, protegida de la selección del mercado cuando todavía se encuentra en etapas de baja performance.