Jalees Rehman

Vascular collapse leads to muscle wasting in cancer cachexia - Nature Cancer Muscle atrophy in cachexia drives weight loss and represents a major complication for patients with cancer. The tumor-derived cytokine activin A is now shown to decrease endothelial cell viability in ...

Grateful for thoughtful News and Views by
@cancercachexia.bsky.social pioneers @teresazimmers.bsky.social and Denis Guttridge
nature.com/articles/s43... on our paper nature.com/articles/s43...
@natcancer.nature.com - highlights need for cross-disciplinary approaches to tackle #cancer #cachexia

Skeletal muscle endothelial dysfunction through the activin A–PGC1α axis drives progression of cancer cachexia - Nature Cancer Using multiple in vivo mouse models, Rehman and colleagues report that tumor-induced impairments in the muscle vasculature mediated by circulating activin A contribute to cachexia development during c...

📢Article now online at Nature Cancer!

'Skeletal muscle endothelial dysfunction through the activin A–PGC1α axis drives progression of cancer cachexia'

✏️By Young-Mee Kim, Jalees Rehman and colleagues

🔗 www.nature.com/articles/s43...

It was a tremendous privilege to work on this important research project with Young-Mee Kim. This project took more than 5 years to complete but we hope that in some small way, it will contribute to improving the health of cancer survivors.

Furthermore, Activin-A and other tumor factors could be similarly causing problems in other organs beyond the muscles by impairing the function of additional blood vessels.

This raises a broader question about cardiovascular or - more specifically - vascular health in cancer patients. Ensuring vascular health early on, even during the treatment of the cancer, could be very important for the preservation of muscle function.

Our discovery adds to the body of literature on muscle loss, cachexia, muscle fatigue in cancer survivors. We do not think that blood vessel dysfunction is the only cause of muscle issues in cancer, but it is one contributor that can be treated.

The good news is that we could prevent this by targeting Activin-A with an antibody. We also found that Activin-A suppresses the PGC1-alpha pathway in blood vessel endothelial cells. Gene therapy to upregulate PGC1-alpha in the blood vessels reversed the muscle loss!

One of the primary negative effects of Activin-A is the reduction of the number of functional blood vessels in the skeletal muscle

Through extensive molecular studies, we found that the molecule Activin-A is released into the blood by tumors, and this factor sets in motion a cascade of molecular signals in the blood vessel endothelial cells

This suggested that blood vessel problems in the muscle appear first, even during earlier stages of the tumor, and may actually cause worsening of the muscle loss.

In the mouse studies, we were able to perform a time experiment and we saw the the blood vessels in the muscles of mice bearing tumors showed a reduction of blood vessels in the muscle, and a loss of normal blood vessel function BEFORE muscle loss

The loss of blood vessels in the human muscles did not allow us to address what happened first. Did the cancer patients first lose their muscle mass, and then the muscle blood vessels wither away? Or did the blood vessel loss come first and actually make muscle loss worse?

We therefore specifically looked at the blood vessels in the muscles. Muscles of patients with cancer had reduced blood vessels, even when the tumor was far away from the muscles. The same was true for multiple mouse models of cancer.

Blood vessels supply nutrients and oxygen to all tissues - including muscles. Blood vessels also seem to do more than just serve as a supply pipeline, they appear to send signals or cues to various organs and tissues, and facilitate their regeneration

We wondered whether the tumors cause changes in the muscles which make it difficult for exercise and increased nutrition to work. This would explain why many cancer survivors have such a difficult time regaining their strength and building muscle mass

One of the biggest challenges that many cancer survivors face is the loss of muscle mass (cachexia) which emerges during the cancer, and often persists even after successful cancer treatment. For many survivors, attempts to increase food intake or exercise does not suffice

During the past couple of decades, new cancer treatments have substantially improved survival of #cancer patients. These successes now have to be accompanied by approaches to improve the #healthspan and quality of life of cancer survivors.

Skeletal muscle endothelial dysfunction through the activin A–PGC1α axis drives progression of cancer cachexia - Nature Cancer Using multiple in vivo mouse models, Rehman and colleagues report that tumor-induced impairments in the muscle vasculature mediated by circulating activin A contribute to cachexia development during c...

Thrilled to share this publication from our lab on muscle wasting in #Cancer and #vascularbiology, spearheaded by Young-Mee Kim in @natcancer.nature.com
nature.com/articles/s43.... Bluetorial on #cachexia, #cancer, #cardiovascular health
@uicancercenter.bsky.social @uofilsystem.bsky.social

Thank you for sharing it!

Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy - Nature Communications Senescent cells accumulate in tissues with aging and disease but are difficult to detect due to distinct cell-type-specific senescence phenotypes. Here, the authors present the SenePy algorithm to ide...

Senescent cells contribute to disease and are found in many tissues but are hard to analyze because markers have been derived in culture and do not account for cell-type differences. Here, we define new signatures based on millions of single cells (1/5) www.nature.com/articles/s41...

Analysis of multi-condition single-cell data with latent embedding multivariate regression - Nature Genetics Latent embedding multivariate regression models multi-condition single-cell RNA-seq using a continuous latent space, enabling data integration, per-cell gene expression prediction and clustering-free ...

Analysis of multi-condition single-cell data with latent embedding multivariate regression

www.nature.com/articles/s41... by@const-ae.bsky.social @wkhuber.bsky.social in @naturegenet.bsky.social

LEMUR Github: github.com/const-ae/lemur

pyLEMUR: github.com/const-ae/pyL...

Multiome Perturb-seq unlocks scalable discovery of integrated perturbation effects on the transcriptome and epigenome Single-cell CRISPR screens link genetic perturbations to transcriptional states, but high-throughput methods connecting these induced changes to their…

Multiome Perturb-seq unlocks scalable discovery of integrated perturbation effects on the transcriptome and epigenome

www.sciencedirect.com/science/arti...

Best practices for differential accessibility analysis in single-cell epigenomics - Nature Communications The authors conduct a comprehensive assessment of statistical methods for identifying differentially accessible (DA) regions in scATAC-seq data, using a compendium of scATAC-seq experiments paired wit...

Best practices for differential accessibility analysis in single-cell epigenomics

www.nature.com/articles/s41... @naturecomms.bsky.social

TurboCas: A method for locus-specific labeling of genomic regions and isolating their associated protein interactome

www.cell.com/molecular-ce...

A long noncoding eRNA forms R-loops to shape emotional experience–induced behavioral adaptation

www.science.org/doi/10.1126/...

Perspective: A neuronal gene that loops the loop

www.science.org/doi/10.1126/...

in @science.org

Identification of antigen-presenting cell–T cell interactions driving immune responses to food The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal ant...

Identification of antigen-presenting cell–T cell interactions driving immune responses to food

www.science.org/doi/10.1126/... in @science.org

Synthetic organizer cells guide development via spatial and biochemical instructions Synthetic organizer cells, engineered to spatially self-assemble around stem cells, can be used to create specific morphogen gradients and systematically guide in vitro development.

Synthetic organizer cells guide development via spatial and biochemical instructions

www.cell.com/cell/fulltex... in @cp-cell.bsky.social

"synthetic organizer cells" integrate spatial, temporal, and biochemical information, direct fate trajectories within the morphogenetic landscape

Conventional chemotherapy: millions of cures, unresolved therapeutic index - Nature Reviews Cancer Conventional chemotherapy has successfully cured millions of patients with cancer, yet the mechanisms of action for this remain unclear. In this Perspective, Letai and de The assess the existing mecha...

Conventional chemotherapy: millions of cures, unresolved therapeutic index

www.nature.com/articles/s41... in @natrevcancer.bsky.social

Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitoc...

Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice

www.science.org/doi/10.1126/... in @science.org

Coupling antigens from multiple subtypes of influenza can broaden antibody and T cell responses The seasonal influenza vaccine contains strains of viruses from distinct subtypes that are grown independently and then combined. However, most individuals exhibit a more robust response to one of the...

Coupling antigens from multiple subtypes of influenza can broaden antibody and T cell responses

www.science.org/doi/10.1126/...
@science.org

"coupling of heterologous antigens improves antibody responses across influenza strains by broadening T cell help"