Ageing promotes metastasis via activation of the integrated stress response - Nature Ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrate...

new out in Nature www.nature.com/articles/s41...

UCL – University College London UCL is consistently ranked as one of the top ten universities in the world (QS World University Rankings 2010-2022) and is No.2 in the UK for research power (Research Excellence Framework 2021).

Our lab is hiring!

This is for a postdoctoral position @ucl.ac.uk in Respiratory Medicine.

Please check out the link for more details:
www.ucl.ac.uk/work-at-ucl/...

Congratulations Josh and Fred!!

Congratulations Josh, Collette, and all coauthors!🎉

Congrats to Kate and Hari for a very nice story and wonderful collaboration!

TMPRSS11B is a target of KLF4 and part of a chemo-refractory hillock-like state we see in squamous lung cancer. This gene contributes to acidified TME.

More coming on the hillock state after addressing FIVE reviewers!
👇🏼

KLF4 promotes a KRT13+ hillock-like state in squamous lung cancer Lung squamous cell carcinoma (LUSC) is basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumor-propagating cell states in squamous tumors, the broad...

And check out exciting new work from the Oliver lab
@tgoliver.bsky.social showing that KLF4 promotes a KRT13+hillock-like state in squamous lung cancer👇:
www.biorxiv.org/content/10.1...

Finally, we are grateful for our funding sources:
DoD, ALA, CPRIT, NCI, Welch Foundation, and V Foundation.

This work was led by my student Hari Shankar Sunil (who defended his thesis last week and is now officially Dr. Sunil). Special THANKS to all our AMAZING collaborators: Trudy Oliver @tgoliver.bsky.social, Jinming Gao, Tae Hyun Hwang, Ralph DeBerardinis @rjdlab.bsky.social, John Minna, et al.

Collectively, our results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive microenvironment. This work also nominates this enzyme as a promising therapeutic target in squamous lung cancer.

Utilizing ultra-pH-sensitive nanoparticle imaging and in vivo metabolite analysis, we identify regions of acidification, elevated lactate, and enrichment of immunosuppressive macrophages in LUSC tumors.

RNA FISH and spatial transcriptomics in the Rosa26-Sox2-Ires-GfpLSL/LSL; Nkx2-1fl/fl; Lkb1fl/fl (SNL) model reveal an enrichment of Tmprss11b expression in lung squamous tumors (LUSCs), specifically in Krt13+ hillock-like cells.

In our new study, we show that TMPRSS11B depletion reduces tumor burden and triggers an infiltration of immune cells in immunocompetent mice.

We initially identified TMPRSS11B in a Sleeping Beauty transposon mutagenesis screen (PMID:30463017). Our prior work showed that TMPRSS11B promotes the transformation of human bronchial epithelial cells and enhances lactate export from human lung squamous cell carcinoma cells.

I am pleased to present a new paper from my lab led by Hari Shankar Sunil showing that the transmembrane serine protease TMPRSS11B promotes an acidified tumor microenvironment and immune suppression in squamous lung cancer, OUT NOW in EMBO Reports👇:
embopress.org/doi/full/10....

Congratulations to all the awardees - but especially my husband Joshua Mendell on this well-deserved recognition. VERY proud!!! 🎉

Congratulations Trudy and Abbie, et al! Beautiful work!

Basal cell of origin resolves neuroendocrine–tuft lineage plasticity in cancer Nature - Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining...

Super pleased to announce our latest suggesting the cell of origin for #SCLC is most likely the basal cell @nature.com, not the accepted neuroendocrine cell. Implications for the earliest events in cancer, & providing new models of tuft-like cancer.
rdcu.be/eGUtj

Congratulations Niladri!!

Congratulations!!!

Congratulations Debbie! Exciting news!

It was a pleasure to speak to our SURF students - thank you for the invite Dr. Diaz!

Thank you @aacrjournals.bsky.social for selecting our story for the cover of Cancer Research!

A special thanks to ALL our collaborators for their important contributions to this work and to NIH/NCI, CPRIT, V Foundation, Welch Foundation, and DoD for their support, and I’m excited that our submission was selected for the cover (credit: Jose Cabrera)!

Collectively, our studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients.

Finally, we showed that ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 and TIGIT blockade with the ISR inhibitor ISRIB.

Our analysis of primary human lung tumors identified a significant correlation between PD-L1 and CD155 expression. This is particularly interesting because other groups have shown that CD155 expression is associated with resistance to anti-PD-1 therapy in lung cancer.

Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoints through bypass of inhibitory uORFs in their 5' UTRs.

The ISR is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. We previously showed that ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity (Suresh et al, Nature Cancer, 2020).

The Integrated Stress Response (ISR) Pathway Coordinates Translational Control of Multiple Immune Checkpoints in Lung Cancer url: aacrjournals.org/cancerres/ar...

This is my first post here. The past few months have been challenging for science, but I enjoy learning about others' work here and wanted to share our latest study. Congrats to postdoc Shayna Thomas-Jardin on her outstanding work published in Cancer Research @theaacr.bsky.social