Thread by @Samuel_Bakhoum

(1/n) A brief #tweetorial highlighting the key aspects of our recent paper in #Cancer Discovery ⁦@CD_AACR⁩ on how cancers with #Chromosomal_Instability evade immune surveillance prompting #metastasis #ScienceTwitter cancerdiscovery.aacrjournals.org/content/early/…

We’ve previously shown that CIN can drive #metastasis through the generation of chronic #inflammation arising from persistent activation of #cGAS #STING signaling. However it wasn’t clear how cells eschewed the immune stimulating effect of this pathway. nature.com/articles/natur…

To address this, we compared isogenic cells with high vs. low levels of CIN and found that cells with high levels of CIN upregulated #ENPP1 an extracellular enzyme shown by @lingyinli1 and Tim Mitchison to hydrolyze #cGAMP

When we stained for #ENPP1 we found it selectively upregulated on both the protein and mRNA level in different models. Even within a tumor, cells that have invaded the lymph nodes exhibit higher membrane staining of ENPP1

A transmembrane protein with an extracellular catalytic domain, #ENPP1 selectively degrades #cGAMP in the extracellular space: its loss increased extracellular cGAMP whereas over-expression of WT - but not the catalytically inactive mutant - reduced extracellular cGAMP

We asked whether extracellular cGAMP hydrolysis enables cancer cells with chronic CIN and #cGAS activation to evade the immune stimulators effects of cGAMP. Indeed #ENPP1 loss led to reduced metas is whereas it’s overexpression in two separate models promoted metastasis

This was only the case when we overexpressed WT but not catalytically dead mutant of #ENPP1 and this was dependent on the presence of #STING in host cells, supporting the notion that ENPP1 disrupts tumor-to-host cGAMP transfer

We next asked whether cGAMP hydrolysis can be a source of adenosine. To our great surprised loss of #cGAS or #ENPP1 led to 40% reductions in extracellular adenosine suggesting that in addition to #ATP, #cGAMP can be a meaningful source of extracellular adenosine

Not surprisingly KO of #ENPP1 led to a significant increase in tumor immune infiltration which we think is due to the simultaneous activation of host #STING and reductions in extracellular #Adenosine

Importantly, loss of #ENPP1 in #immunotherapy resistant tumors restored their responsiveness to immune checkpoint blockade whereas its addition to sensitive tumors rendered them resistant

We next stained for #ENPP1 protein expression in nearly 500 human cancers and found conspicuous expression in metastasis particularly in lymph node metastases

#breastcancer one is the immunotherapy resistant tumor tumor types had widespread #ENPP1 expression with 65% of triple negative and ~90% of ER+ tumors showing moderate or strong staining and it was prognostic and dependent on tumor #cGAS expression

#ENPP1 expression was inversely correlated with tumor infiltrating lymphocytes and associated with metastasis in triple negative breast cancer

we think #ENPP1 is an important therapeutic target in cancers with chromosomal instability as well as a potential biomarker for immunotherapy response esp in breast cancer. Using a simple trick #cancer can transform immune stimulatory cGAMP into immune suppressor adenosine

Thanks to the AMAZING team in the lab led by the talented Jun Li and Mercedes Duran, great collaborators @BizarMd @eileen_parkes and finding sources @NIH_CommonFund @theNCI @BWFUND @PICIatMSK

Finally thank you to the @sloan_kettering news team for highlighting our work mskcc.org/news/taking-st…